Observational studies analyzed like randomized experiments: an application to postmenopausal hormone therapy and coronary heart disease.
BACKGROUND
The Women's Health Initiative randomized trial found greater coronary heart disease (CHD) risk in women assigned to estrogen/progestin therapy than in those assigned to placebo. Observational studies had previously suggested reduced CHD risk in hormone users.


METHODS
Using data from the observational Nurses' Health Study, we emulated the design and intention-to-treat (ITT) analysis of the randomized trial. The observational study was conceptualized as a sequence of "trials," in which eligible women were classified as initiators or noninitiators of estrogen/progestin therapy.


RESULTS
The ITT hazard ratios (HRs) (95% confidence intervals) of CHD for initiators versus noninitiators were 1.42 (0.92-2.20) for the first 2 years, and 0.96 (0.78-1.18) for the entire follow-up. The ITT HRs were 0.84 (0.61-1.14) in women within 10 years of menopause, and 1.12 (0.84-1.48) in the others (P value for interaction = 0.08). These ITT estimates are similar to those from the Women's Health Initiative. Because the ITT approach causes severe treatment misclassification, we also estimated adherence-adjusted effects by inverse probability weighting. The HRs were 1.61 (0.97-2.66) for the first 2 years, and 0.98 (0.66-1.49) for the entire follow-up. The HRs were 0.54 (0.19-1.51) in women within 10 years after menopause, and 1.20 (0.78-1.84) in others (P value for interaction = 0.01). We also present comparisons between these estimates and previously reported Nurses' Health Study estimates.


CONCLUSIONS
Our findings suggest that the discrepancies between the Women's Health Initiative and Nurses' Health Study ITT estimates could be largely explained by differences in the distribution of time since menopause and length of follow-up.
Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA. miguel_hernan@post.harvard.edu
Miguel A
MA
Hernán
Alvaro
A
Alonso
Roger
R
Logan
Francine
F
Grodstein
Karin B
KB
Michels
Walter C
WC
Willett
Joann E
JE
Manson
James M
JM
Robins
D002318:Cardiovascular Diseases / Q000517:prevention & control*; D003627:Data Interpretation, Statistical; D015914:Estrogen Replacement Therapy / Q000009:adverse effects*; D004967:Estrogens / Q000009:adverse effects; D004966:Estrogens, Conjugated (USP) / Q000009:adverse effects; D005260:Female; D006306:Health Surveys; D006801:Humans; D008137:Longitudinal Studies; D008875:Middle Aged; D019370:Observation / Q000379:methods*; D016017:Odds Ratio; D011372:Progestins / Q000009:adverse effects; D016032:Randomized Controlled Trials as Topic / Q000379:methods*; D013997:Time Factors
D004967:Estrogens; D004966:Estrogens, Conjugated (USP); D011372:Progestins