Editorials

Does Estrogen Therapy Have a Role in Cardiovascular Prevention?

Am Fam Physician. 1999 Mar 1;59(5):1125-1131.

Providing appropriate information about the cardiovascular risks and benefits of hormone replacement therapy (HRT) is a challenging task in a marketplace flush with fixes for cardiovascular disease. These treatments span the breadth of pharmaceutical, medical and “natural” therapies. We suggest that the possible benefits of HRT have been greatly overstated; for the time being, the prevention of coronary artery disease should not be considered an indication for treatment with HRT.

Mechanism of Benefit

Randomized controlled trials using risk factor end points including lipid levels, blood pressure measurements and coagulation status have confirmed mostly beneficial changes with estrogen therapy, with or without added progestogen.1 These studies are supported by results of both animal and human laboratory studies that suggest estrogen has other potentially beneficial effects on vascular responsiveness, coagulation parameters and atherosclerosis.2 In most cases, these effects have been only partially reversed by the addition of a progestogen.

Risks

Any discussion of cardiovascular risk must distinguish between relative and absolute risk. An intervention that may produce a 50 percent reduction in the risk of heart disease sounds impressive, but it is probably of little importance to a healthy 50-year-old woman.3 Because her risk of death from coronary disease by the age of 65 years is only 1.4 percent (one in 70), even a 50 percent relative reduction yields a reduction in absolute risk of only 0.7 percent (one in 140). Thus, 140 women would need to be treated for 15 years to prevent a single death from coronary artery disease. In this scenario, even a small risk of complications from the intervention would probably be unacceptable.

Primary Prevention of Coronary Artery Disease

Does HRT reduce the risk of heart disease in healthy women? An abundance of observational studies suggest a protective effect of HRT: more than 30 case-control and cohort studies reported over the past 20 years have shown that the risk of coronary disease is 20 to 50 percent lower in users of estrogen therapy.4 To date, however, no randomized placebo-controlled studies with clinical cardiovascular end points have been completed.

Because observational studies are not randomized, they cannot eliminate the potential bias that women who choose to take estrogens may be inherently healthier than those who do not.5 Subjects with good compliance in the placebo arm of several cardiovascular intervention trials have shown a substantially lower (less than 30 percent) risk of subsequent vascular events, compared with those in the placebo arm who were not compliant. Women who are observed to comply with HRT are probably no different.6

Given the information above, should HRT be used for the primary prevention of heart disease? Even with the assumption that the observational data would be confirmed in controlled trials, the case is not strong enough to support the use of HRT in healthy women. In the context of a low absolute risk of coronary disease for most perimenopausal women, even a 50 percent risk reduction is unlikely to result in substantial absolute benefit. Women who are at higher risk of coronary artery disease because of older age or multiple other risk factors may attain sufficient absolute benefit to justify long-term intervention.

Secondary Prevention

Women who have established coronary disease are at high risk for recurrent coronary events. Here, the potential for absolute benefit may be substantial, and observational studies have suggested greater benefit in this population than in women without heart disease. The first large, placebo-controlled trial examining clinical cardiovascular end points in women with preexisting coronary disease, the Heart and Estrogen/Progestin Replacement Study (HERS),7 was published in August 1998. This important study failed to demonstrate a net beneficial effect of combined HRT on overall coronary disease end points after an average follow-up of 4.1 years. A significant increase in the rate of thromboembolic events that occurred in the early years of the study suggests that the lack of reduction of coronary artery disease events may be partly due to early thrombogenic effects of HRT.

Although the results of HERS7 showed a trend toward declining coronary disease events with active treatment later during follow-up, the decrease was not as great as would be predicted from the lipoprotein changes that were achieved (11 percent decrease in low-density cholesterol levels and 10 percent increase in high-density cholesterol levels in the group receiving HRT). This finding suggests that the many nonlipoprotein effects of HRT that have been so well described in the laboratory may not be of clinical significance, and it also implies that unknown negative pathways of the action of HRT still remain to be discovered. Whatever the explanation, the conclusion remains that women with established vascular disease should not be started on HRT unless further randomized controlled trials provide overwhelming evidence in support of this practice.

Most agents that have been shown to be effective in the primary prevention of coronary disease have an even greater effect in the secondary intervention setting. Thus, the absence of a beneficial effect demonstrated in HERS7 strongly implies that we should be cautious in the use of HRT in primary prevention, pending results of adequate controlled trials.

Further Lessons from HERS

Interventions shown to prevent recurrent events in women with coronary artery disease include aspirin, lipid-lowering drugs and beta blockers. However, the use of these agents at the time of study entry in the HERS population was 78 percent, 46 percent and 33 percent, respectively. In contrast, calcium channel blockers were being used in 55 percent of these patients and multivitamins in 30 percent; neither of these therapies has been shown to be effective. Our efforts to improve the outcome in women with coronary artery disease should focus on established treatments rather than on those presented without firm evidence, regardless of how enthusiastically they are promoted.

For the time being, prevention of cardiovascular disease should not be considered an indication for starting HRT. As medical practitioners, we should also take a long hard look at the way we promote other apparent beneficial effects of HRT that have not yet been confirmed in controlled trials examining clinical outcomes. As citizens, we should address the more difficult problems of social factors and aggressive marketing that foster unhealthy lifestyles, particularly for younger women.

Dr. Newnham is senior lecturer and an endocrinologist in the Department of Medicine at Monash University, Victoria, Australia. Dr. Silberberg is a cardiologist in the Cardiovascular Unit at John Hunter Hospital, Newcastle, Australia.

Address correspondence to Harvey H. Newnham, M.B.B.S., PH.D., Monash University Department of Medicine, Box Hill Hospital, Nelson Road, Box Hill 3128, Victoria, Australia.

REFERENCES

1. Writing Group for the PEPI Trial. Effects of estrogen/progestin regimens on heart disease risk factors in postmenopausal women: the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA. 1995;273:199–208.

2. Guetta V, Cannon III, Richard O. Cardiovascular effects of estrogen and lipid-lowering therapies in postmenopausal women. Circulation. 1996;93:1928–37.

3. Newnham HH, Silberberg JS. Women's hearts are hard to break. Lancet. 1997;349:S13–6.

4. Stampfer MJ, Colditz GA. Estrogen replacement therapy and coronary heart disease: a quantitative assessment of the epidemiologic evidence. Prev Med. 1991;20:47–63.

5. Barrett-Connor E. Postmenopausal estrogen and prevention bias. Ann Intern Med. 1991;116:455–6.

6. Pettiti DB. Coronary heart disease and estrogen replacement therapy: can compliance bias explain the results of observational studies? Ann Epidemiol. 1994;4:115–8.

7. 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;280:605–13.


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