Postmenopausal Hormone Use and Secondary Prevention of Coronary Events in the Nurses’ Health Study

Abstract & Commentary

Synopsis: The risk of recurrent major coronary events was mildly increased by short-term (< 1 year) hormone use by postmenopausal women but decreased with increasing duration of use. The results of the present study are similar to those of the HERS trial, showing a bimodal response to HRT in women with established cardiovascular disease.

Source: Grodstein F, et al. Ann Intern Med. 2001;135:1-8.

The Heart and Estrogen/progestin Replacement Study (HERS) hypothesized that postmenopausal hormone use in women with established cardiovascular disease would reduce recurrence of cardiovascular events. In this study, 2763 women with active heart disease were randomized to either placebo or Prempro® and followed for 5 years. In the first year, the rate of recurrence was 52% higher in the hormone replacement therapy (HRT) arm. In the second year, there was no difference between arms. However, in the fourth and fifth years, the women assigned to hormone use had a 33% lower risk for coronary events. Grodstein and associates used the data from the Nurses’ Health Study to examine the same hypothesis. Although the Nurses’ Health Study is observational, the population size is large and the participants have been followed for up to 20 years. Thus, the relationship between postmenopausal hormone use and secondary prevention of cardiovascular disease was examined in 2489 women. Ascertainment of hormone use and cardiovascular events was rigorous and complete, with total follow-up exceeding 92%. Of the hormone users, 53% used oral conjugated estrogen alone, 19% used oral conjugated estrogen plus oral progestin, and 28% used other types, mostly transdermal or oral estradiol. The overall age-adjusted relative risk (RR) for recurrent major coronary events was 0.56 (confidence interval [CI], 0.39-0.80) among current users as compared with never-users. When the duration of hormone use was examined, a 25% increase in the risk of recurrent cardiovascular events was found among women with less than 1 year of use, but this increase was statistically nonsignificant, RR = 1.25 (CI, 0.78-2.00), because only 24 of the 141 cases fell into this group. However, longer-term users experienced a statistically significant decreased risk of 0.38 (CI, 0.22-0.66).

Comment by Sarah L. Berga, MD

The popular press is now reporting that postmenopausal hormone use does not reduce the risk of cardiovascular disease. Although that statement is a gross oversimplification of the results of the HERS, it continues to sway opinion and practice. The sophistry is kept alive by the difficulty inherent in explaining to patients the difference between primary and secondary prevention. Further, while primary care clinicians and gynecologists generally see patients seeking primary prevention, cardiologists typically see them after the initial cardiovascular event. Thus, we tend to counsel very different subsets of women. Available data suggest that HRT is better for primary rather than secondary prevention and this has left most cardiologists feeling understandably disenchanted with the promise of HRT. Given these considerations, it becomes increasingly important for clinicians to be able to clearly articulate why it is too soon to discount HRT use by women with established or latent cardiovascular disease. Is HRT as potent a therapy as statins for women with CVD or at high risk for CVD? Probably not. But statins do not provide the panoply of benefits that accrue to long-term HRT use. It falls to us to explain to women that HRT use is but one of the strategies for promoting health as one ages, but an important one nonetheless. Is one form of HRT better than another in helping to retard the ill effects of aging or for use in women with active heart disease? There are few data on this point. Is HRT the only strategy one should recommend? Of course not. So much of remaining healthy comes from having a healthy lifestyle, and we should not fool ourselves or our patients that HRT can reverse or counter the damage that comes from obesity, smoking, inactivity, and the like. HRT is best seen as an adjunct to a healthy lifestyle and not as a magic bullet that erases established cardiovascular disease, but this does not mean that HRT is useless or without benefit. This is what our patients need to know.

The bimodal response to therapy, with increased risk of recurrent cardiovascular disease confined to the first year of use, is puzzling. Many explanations have been proffered. It would be nice to know the reason, because if we did, we might be able to do something in the first year of HRT use to reduce that risk. It has been widely hypothesized that the increased risk is due to enhanced coagulation and that this may be due to the hepatic first-pass effect of oral estrogen use. We do know that standard oral therapy increases the risk of thromboembolic events. Would this risk be obviated by transdermal estradiol use when the circulating estradiol level is titrated to the subphysiological range? The present study simply did not have sufficient power to address this hypothesis.

Dr. Berga is Professor and Director, Division of Reproductive Endocrinology and Infertility, University of Pittsburgh, Pittsburgh, Pa.