Randomized clinical trials of menopausal hormone therapy have shown increased risks of coronary heart disease in the first few years after randomization, and neutral or increased risk over the full trial period. These results diverge substantially from the protective associations of menopausal hormone use with coronary heart disease found in observational studies. In common with many other studies, conventional analyses in the Women’s Health Initiative Observational Study cohort of estrogen plus progestin users showed an association with reduced risk of coronary heart disease even after adjustment for potential confounders. However, upon allowing risk to vary by time since initiation, the hazard ratios did not differ significantly from those observed in the clinical trial. In analyses combining clinical trial and observational data the hazard ratios were 1.58 (1.12, 2.24) within the first 2 years after initiation, 1.19 (0.87, 1.63) between 2 and 5 years, and 0.63 (0.59, 1.26) after 5 years. Similar analyses for estrogen alone also reconciled trial and observational data. These findings were confirmed in novel re-analyses of the Nurses’ Health Study when investigators for the first time included outcomes occurring in the interval between the biennial study cycles. The key towards understanding the underestimation of coronary heart disease in observational studies of menopausal hormone therapy appears to lie in the time-dependent nature of coronary heart disease risk rather than differences in study populations. Observational studies typically do not capture early events in current users and the data mostly reflect the experience of long-term users who have survived the early risk, while clinical trials by design capture early events very efficiently and mainly reflect short-term use.
This is a preview of subscription content, log in to check access.
Barrett-Connor E, Grady D (1998) Hormone replacement therapy, heart disease, and other considerations. Annu Rev Public Health 19:55–72
Hulley S, Grady D, Bush T, et al. (1998) Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 280:605–613
Rossouw JE, Anderson GL, Prentice RL, et al. (Writing Group for the Women’s Health Initiative Investigators) (2002) Risks and benefits of estrogen plus progestin for healthy postmenopausal women. JAMA 288:321–333
Anderson GL, Limacher M, Assaf AR, et al. (Women’s Health Initiative Steering Committee) (2004) Effects of conjugated equine estrogen in postmenopausal women with hysterectomy. JAMA 291:1701–1712
Grodstein F, Manson JE, Stampfer MJ (2006) Hormone therapy and coronary heart disease: the role of time since menopause and age at hormone initiation. J Women’s Health 15:35–44
Michels KB, Manson JE (2003) Postmenopausal hormone therapy: a reversal of fortune. Circulation 107:1830–1833
Prentice RL, Langer RD, Stefanick ML, et al. (2005) 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 162:404–414
Prentice RL, Langer RD, Stefanick ML, et al. (2006) Combined analysis of Women’s Health Initiative observational and clinical trial data on postmenopausal hormone treatment and cardiovascular disease. Am J Epidemiol 163:589–599
Prentice RL, Manson JE, Langer RD, et al. (2009) Benefits and risks of postmenopausal hormone therapy when it is initiated soon after menopause. Am J Epidemiol 170:12–23
Hernán MA, Alonso A, Logan R, Grodstein F, Michels KB, Willett WC, Manson JE, Robins JM (2008) Observational studies analyzed like randomized experiments: an application to postmenopausal hormone therapy and coronary heart disease. Epidemiology 19:766–779
Toh S, Hernández-Díaz S, Logan R, Rossouw JE, Hernán MA (2010) Coronary heart disease in postmenopausal recipients of estrogen plus progestin therapy: does the increased risk ever disappear? A randomized trial. Ann Intern Med 152:211–217
Rossouw JE, Prentice RL, Manson JE, et al. (2007) Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA 297:1465–1477
Prentice RL (2008) Commentary: data analysis methods and the reliability of analytic epidemiologic research. Epidemiology 19:785–788