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Coronary Heart Disease in Postmenopausal Recipients of Estrogen Plus Progestin Therapy: Does the Increased Risk Ever Disappear?: A Randomized Trial

Sengwee Toh, ScD; Sonia Hernández-Díaz, MD, DrPH; Roger Logan, PhD; Jacques E. Rossouw, MD; and Miguel A. Hernán, MD, DrPH
[+] Article and Author Information

From Harvard School of Public Health, Boston, and Harvard-MIT Division of Health Sciences and Technology, Cambridge, Massachusetts, and the National Heart, Lung, and Blood Institute, Bethesda, Maryland.


Acknowledgment: The authors thank the investigators and staff at the Women's Health Initiative Clinical Centers; the Women's Health Initiative Clinical Coordinating Center; and the National Heart, Lung, and Blood Institute Program Office. A complete list of Women's Health Initiative centers and investigators is available at www.whiscience.org/publications/WHI_investigators_longlist.pdf. They also thank Alvaro Alonso, MD, PhD (University of Minnesota), for analytic support and Garnet Anderson, PhD (Fred Hutchinson Cancer Research Center), for expert advice.

Grant Support: By the National Institutes of Health (grant R01 HL080644-01).

Potential Conflicts of Interest:Consultancies: S. Hernández-Díaz (AstraZeneca, Novartis, Pfizer). Grants received: S. Hernández-Díaz (Pfizer, Lilly, Novartis, Wyeth). Other disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M09-0301.

Reproducible Research Statement:Study protocol: Available at www.whiscience.org/about/design.php. Statistical code: Available from Dr. Toh (e-mail, darrentoh@post.harvard.edu). Data set: The limited-access data set is available through application at the National Heart, Lung, and Blood Institute (https://biolincc.nhlbi.nih.gov/home/).

Corresponding Author: Sengwee Darren Toh, ScD, Department of Population Medicine, Harvard Medical School/Harvard Pilgrim Health Care Institute, 133 Brookline Avenue, 6th Floor, Boston, MA 02215; e-mail, darrentoh@post.harvard.edu.

Current Author Addresses: Dr. Toh: Department of Population Medicine, Harvard Medical School/Harvard Pilgrim Health Care Institute, 133 Brookline Avenue, 6th Floor, Boston, MA 02215.

Drs. Hernández-Díaz, Logan, and Hernán: Department of Epidemiology, Harvard School of Public Health, 677 Huntington Avenue, Boston, MA 02115.

Dr. Rossouw: Women's Health Initiative Branch, Division of Prevention and Population Sciences, National Heart, Lung, and Blood Institute, 6701 Rockledge Drive, Rockledge 2 Building, Suite 10018, Bethesda, MD 20892.

Author Contributions: Conception and design: S. Toh, M.A. Hernán.

Analysis and interpretation of the data: S. Toh, S. Hernández-Díaz, R. Logan, J.E. Rossouw, M.A. Hernán.

Drafting of the article: S. Toh, M.A. Hernán.

Critical revision of the article for important intellectual content: S. Toh, S. Hernández-Díaz, J.E. Rossouw, M.A. Hernán.

Final approval of the article: S. Toh, S. Hernández-Díaz, J.E. Rossouw, M.A. Hernán.

Provision of study materials or patients: S. Toh.

Statistical expertise: S. Toh, R. Logan, M.A. Hernán.

Obtaining of funding: S. Hernández-Díaz, J.E. Rossouw, M.A. Hernán.

Administrative, technical, or logistic support: R. Logan, M.A. Hernán.

Collection and assembly of data: S. Toh, R. Logan.


Ann Intern Med. 2010;152(4):211-217. doi:10.7326/0003-4819-152-4-201002160-00005
Text Size: A A A

Background: Estrogen plus progestin therapy increases the risk for coronary heart disease (CHD) in postmenopausal women. However, this increased risk might be limited to the first years of use and to women who start therapy late in menopause.

Objective: To estimate the effect of continuous estrogen plus progestin therapy on CHD risk over time and stratified by years since menopause.

Design: Women's Health Initiative randomized, double-blinded, placebo-controlled trial. (ClinicalTrials.gov registration number: NCT00000611)

Setting: 40 U.S. clinical centers.

Patients: 16 608 postmenopausal women with an intact uterus at baseline from 1993 to 1998.

Intervention: Conjugated equine estrogens, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, or placebo.

Measurements: Adherence-adjusted hazard ratios and CHD-free survival curves estimated through inverse probability weighting.

Results: Compared with no use of hormone therapy, the hazard ratio for continuous use of estrogen plus progestin therapy was 2.36 (95% CI, 1.55 to 3.62) for the first 2 years and 1.69 (CI, 0.98 to 2.89) for the first 8 years. For women within 10 years after menopause, the hazard ratios were 1.29 (CI, 0.52 to 3.18) for the first 2 years and 0.64 (CI, 0.21 to 1.99) for the first 8 years, and the CHD-free survival curves for continuous use and no use of estrogen plus progestin crossed at about 6 years (CI, 2 years to 10 years).

Limitation: The analysis may not have fully adjusted for joint determinants of adherence and CHD risk. Sample sizes for some subgroup analyses were small.

Conclusion: No suggestion of a decreased risk for CHD was found within the first 2 years of estrogen plus progestin use, including in women who initiated therapy within 10 years after menopause. A possible cardioprotective effect in these women who initiated therapy closer to menopause became apparent only after 6 years of use.

Primary Funding Source: National Heart, Lung, and Blood Institute.

Figures

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Figure 1.
Proportion of women who took at least 80% of the study pills, by treatment group, in the Women's Health Initiative estrogen plus progestin randomized trial.
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Figure 2.
Estimated proportion of women free of CHD under continuous adherence to the assigned treatment in the Women's Health Initiative estrogen plus progestin randomized trial.

CHD = coronary heart disease.

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Appendix Figure.
Proportion of women free of CHD in intention-to-treat analysis in the Women's Health Initiative estrogen plus progestin randomized trial.

CHD = coronary heart disease.

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Implications of the Women's Health Initiative beyond indications for hormone replacement therapy.
Posted on February 19, 2010
Jerome L. Sullivan, MD, PhD
University of Central Florida College of Medicine
Conflict of Interest: None Declared

It is useful to recall that the Women's Health Initiative (WHI) was based on an expectation of not less than 30% reduction in cardiovascular disease mortality in women taking hormone replacement therapy (HRT) [1]. With the "timing hypothesis" effectively eliminated [2], the meaning of the results of the trial should be revisited. Failure to demonstrate a 30% mortality decrease, or any mortality decrease, has far reaching implications, beyond the recommendation that HRT not be used for prevention of cardiovascular disease. The large expected decrease in disease was related to the sharply lower cardiovascular disease rates of menstruating women. In view of the strong WHI findings of no mortality decrease with HRT, not even in the newly postmenopausal, the belief that menstruating women are protected from cardiovascular disease by direct effects of female hormones should be questioned. The working conclusion seems to be that young women are protected by their hormones, but that, at whatever age menopause occurs, this protection is lost. An alternative, simpler view consistent with WHI, is that female hormones confer a small cardiovascular risk at any age. In other words, lower risk in young, menstruating women occurs in spite of the disease promoting effects of female hormones. Premenopausal women may be protected by some other factor, which, when lost after menopause, makes this increased risk apparent in those taking HRT. An alternative protective factor in menstruating women has been proposed [3-6].

Reference List

1. Eaker E, Hahn RA. Women's health initiative. N Engl J Med 1994; 330(1):70-71.

2. Toh S, Hernandez-Diaz S, Logan R, Rossouw JE, Hernan MA. Coronary Heart Disease in Postmenopausal Recipients of Estrogen Plus Progestin Therapy: Does the Increased Risk Ever Disappear? Ann Intern Med 2010; 152(4):211-217.

3. Sullivan JL. Iron and the sex difference in heart disease risk. Lancet 1981; 1(8233):1293-1294.

4. Sullivan JL. Are menstruating women protected from heart disease because of, or in spite of, estrogen? Relevance to the iron hypothesis. Am Heart J 2003; 145(2):190-194.

5. Sullivan JL. Is homocysteine an iron-dependent cardiovascular risk factor? Kidney Int 2006; 69(4):642-644.

6. Sullivan JL. Do Hemochromatosis Mutations Protect Against Iron- Mediated Atherogenesis? Circ Cardiovasc Genet 2009; 2(6):652-657.

Conflict of Interest:

None declared

Duration and Timing Effects on Risks and Benefits of Menopausal Hormones
Posted on March 9, 2010
S Mitchell Harman
Kronos Longevity Research Institute
Conflict of Interest: None Declared

We applaud the efforts of Toh et al. (1) to delve deeper into the still controversial issue of inconsistencies in the cardiovascular disease (CVD) outcomes between the Women's Health Initiative (WHI) E P hormone trial and previous large observational studies. Current evidence supports the concept that both timing of menopausal hormone therapy (MHT) initiation and duration of treatment (2, 3) are important determinants of the risk:benefit ratio. The data presented by Toh et al., suggesting that the slightly higher CVD event risk in the first two years of treatment transitions to a lower risk after six or more years of use only in study drug-compliant WHI women initiating treatment less than ten years postmenopausally, are relevant to both of these questions. We regret that the authors focused on the statistically nonsignificant early increase in risk and discounted possible long-term benefits by stating that, "Because the typical duration of use of hormone therapy is short, most women contemplating estrogen plus progestin therapy for the relief of menopausal symptoms should not expect protection against CHD." On the contrary, before publication of the original WHI report in 2002 (4), MHT was frequently prescribed long-term to reduce both risks of osteoporotic fractures and CVD. Ironically, the WHI conclusion that MHT produced net harm was the primary basis for the change in the FDA official guidance and subsequent clinical practice discouraging long-term MHT use. This change owed precisely to the lack of distinction between risks and benefits for recently vs. remotely menopausal women in the initial report, an issue that WHI investigators and others performing follow-up analyses have attempted to address (5). Thus, it seems to us that an alternative interpretation of the new analysis by Toh et al. would be that recently menopausal women have little to fear in the early period of hormone treatment when incident CVD rates are low, and they may stand to benefit from long-term continuation of MHT into the later postmenopausal years when CVD risk is much higher. This may be seen as simply a matter of perspective (glass half-empty vs. glass half-full), but the health and lives of millions of women will depend on how the results of this and future research are interpreted by the medical community and the public.

References

1. Toh S, Hernandez-Diaz S, Logan R, Rossouw JE, Hernan MA. Coronary heart disease in postmenopausal recipients of estrogen plus progestin therapy: does the increased risk ever disappear? A randomized trial. Ann Intern Med. 2010;152(4):211-7.

2. Grodstein F, Manson JE, Stampfer MJ. Postmenopausal hormone use and secondary prevention of coronary events in the nurses' health study. a prospective, observational study. Ann Intern Med. 2001;135(1):1-8.

3. Chilvers CE, Knibb RC, Armstrong SJ, Woods KL, Logan RF. Post menopausal hormone replacement therapy and risk of acute myocardial infarction--a case control study of women in the East Midlands, UK. Eur Heart J. 2003;24(24):2197-205.

4. WHI Trials Group. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA. 2002;288(3):321-33.

5. Manson JE, Hsia J, Johnson KC, et al. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med. 2003;349:523-534.

Conflict of Interest:

Authors are co-PI's of the Kronos Early Estrogen Prevention Study (KEEPS) investigating cardiovascular effects of oral vs. transdermal hormone treatment in recently menopausal women

Discrepancy between authors' abstract and summary for women
Posted on March 29, 2010
Amos Pines
The International Menopause Society
Conflict of Interest: None Declared

Sirs, Ever since the first paper from WHI in 2002 there has been debate over the validity of the methods of data analysis. At first it was related to the use of adjusted or unadjusted hazard ratios, then there was the issue of combining the data from the CEE-MPA arm with CEE-alone arm, or from the WHI clinical study with the observational study. Recently, when the age factor became a major player in the risk-benefit balance of hormone therapy, another debate involved the "timing hypothesis". While these arguments should be placed in the domain of epidemiologists and statisticians, the lay physicians who practice menopause medicine and prescribe hormones should get clear messages from the WHI investigators, and the consumers of hormones should be informed and educated to a similar extent. It is therefore of utmost importance not to send conflicting messages, but this is unfortunately exactly the case with the new release by Toh et al in the Annals of Internal Medicine (1). The key conclusions brought in the article's abstract are different from the summary that is offered for women in the same issue of the Annals (2). Here are the exact citations from the two above mentioned sources: the Abstract says - "Conclusion: No suggestion of a decreased risk for CHD was found within the first 2 years of estrogen plus progestin use, including in women who initiated therapy within 10 years after menopause. A possible cardioprotective effect in these women who initiated therapy closer to menopause became apparent only after 6 years of use". Thus this message concerning risk of CAD seems neutral and perhaps even a bit positive. In contrast, the message to women is phrased in a more alarming way. It starts with "facts" - " The problem: Women who receive hormone therapy after menopause have an increased risk for heart attacks and other problems related to the arteries in their heart. Results: A possible increased risk was present in the first 2 years in women who started hormone therapy within 10 years after menopause, and increased risk persisted until about 6 years after use. Implications of the study: Most women use combined hormone therapy to treat the symptoms of menopause, which means they start hormone therapy soon after menopause and generally use it for less than 6 years... These women may need to worry about a possible slightly increased risk for heart attacks". In our view, such discrepancies between the investigators' own conclusions and the summary for women is un-ethical and likely to increase confusion and anxiety in those who need this therapy. We urge the Journal to address this double- faced conclusions and to request an explanation from the authors.

1) Toh S et al. Ann Intern Med 2010;152:211

2) Summaries for women. Ann Intern Med 2010;152:I-40

Conflict of Interest:

None declared

Authors' response
Posted on April 6, 2010
Sengwee Toh
Department of Population Medicine, Harvard Medical School / Harvard Pilgrim Health Care Institute
Conflict of Interest: None Declared

To the editors:

We echo Dr. Harman and colleagues' comment about the importance of both timing of postmenopausal hormone therapy initiation and duration of treatment in relation to coronary heart disease (CHD), a point we made in our paper (1). Unlike several analyses of observational studies, the Women's Health Initiative (WHI) estrogen plus progestin (E+P) trial did not find a benefit of postmenopausal hormone therapy on either CHD risk or mortality. In contrast, the WHI findings were consistent with observational analyses for stroke, venous thromboembolism, breast cancer (increased risk), hip fractures, and colorectal cancer (decreased risk) (2). Subsequent re-analyses of the observational data (3,4) have suggested that an early harmful effect of E+P therapy on CHD may explain the randomized-observational discrepancy: the WHI trial fully captured the early events, while several previous analyses of observational data did not. Our analyses of WHI and Nurses' Health Study data indicate that women who initiate E+P long after the menopause have a greater CHD risk during at least the first 8 years of use, and that women who initiate E+P within 10 years after menopause do not have a lower CHD risk during the first 3-6 years of use (1,4). In fact, as Drs. Pines and Sturdee point out, our findings are also consistent with a small increase in the short-term CHD risk among these younger women. Regardless of whether one chooses to emphasize the lack of early benefit (as we did in our article) or the possibility of early harm, the insufficient evidence for long-term CHD benefit, together with the adverse effects on stroke, venous thromboembolism and breast cancer, argue against a return of E+P (at least of the regimen studied in the WHI) as a viable option for the prevention of chronic diseases.

In response to Dr. Sullivan, it is unclear whether natural menopause is associated with a sharp increase in CHD incidence beyond the log-linear relationship with age (5). Additionally, findings from the WHI trial regimens (orally administered conjugated equine estrogen with or without medroxyprogesterone acetate) may not be directly relevant to a possible role of endogenous sex hormones in explaining the gender difference in CHD rates.

References:

1. Toh S, Hernandez-Diaz S, Logan R, Rossouw JE, Hernan MA. Coronary heart disease in postmenopausal recipients of estrogen plus progestin therapy: does the increased risk ever disappear? Ann Intern Med. 2010;152:211-17.

2. Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, et al; Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA. 2002;288:321-33.

3. Prentice RL, Langer R, Stefanick ML, Howard BV, Pettinger M, Anderson G, et al; Women's Health Initiative Investigators. Combined postmenopausal hormone therapy and cardiovascular disease: toward resolving the discrepancy between observational studies and the Women's Health Initiative clinical trial. Am J Epidemiol. 2005;162:404-14.

4. Hernan MA, Alonso A, Logan R, Grodstein F, Michels KB, Willett WC, et al. Observational studies analyzed like randomized experiments: an application to postmenopausal hormone therapy and coronary heart disease. Epidemiology. 2008;19:766-79.

5. Tunstall-Pedoe H. Myth and paradox of coronary risk and the menopause. Lancet. 1998;351:1425-7.

Conflict of Interest:

None declared

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Summary for Patients

The Effect of Estrogen Plus Progestin on Coronary Heart Disease

The summary below is from the full report titled “Coronary Heart Disease in Postmenopausal Recipients of Estrogen Plus Progestin Therapy: Does the Increased Risk Ever Disappear? A Randomized Trial.” It is in the 16 February 2010 issue of Annals of Internal Medicine (volume 152, pages 211-217). The authors are S. Toh, S. Hernández-Díaz, R. Logan, J.E. Rossouw, and M.A. Hernán.

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