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. 2008 Nov;19(6):766-79.
doi: 10.1097/EDE.0b013e3181875e61.

Observational studies analyzed like randomized experiments: an application to postmenopausal hormone therapy and coronary heart disease

Miguel A Hernán  1 , Alvaro Alonso, Roger Logan, Francine Grodstein, Karin B Michels, Walter C Willett, Joann E Manson, James M Robins
Affiliations

Observational studies analyzed like randomized experiments: an application to postmenopausal hormone therapy and coronary heart disease

Miguel A Hernán et al. Epidemiology. 2008 Nov.

Abstract

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.

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Figures

Figure 1
Figure 1
Distribution of eligible women by number of Nurses’ Health Study “trials” of hormone therapy initiation in which they participated
Figure 2
Figure 2
Proportion of women free of CHD by baseline treatment group in the Nurses’ Health Study “trials”
Figure 3
Figure 3
Proportion of women who adhered to their baseline treatment in the Nurses’ Health Study “trials”
Figure 4
Figure 4
Proportion of women free of CHD under full adherence with the baseline treatment in the Nurses’ Health Study “trials”
Appendix Figure 1
Appendix Figure 1
Sensitivity analysis for lack of adjustment for treatment arm in the inverse probability weighted analysis that adjusts for selection bias due to death between the start of follow-up and the return of questionnaire in the Nurses’ Health Study “trials.” The parameter alpha is the log odds ratio for the hypothesized association between treatment arm and death before returning the questionnaire. Log HR is the log hazard ratio of CHD for initiators versus noninitiators during the first 2 years of follow-up.
Appendix Figure 2
Appendix Figure 2
Distribution of eligible women by number of NHS “trials” of hormone therapy discontinuation in which they participated.
See this image and copyright information in PMC

Comment in

References

    1. Ioannidis JP, Haidich AB, Pappa M, et al. Comparison of evidence of treatment effects in randomized and nonrandomized studies. Jama. 2001;286(7):821–30. - PubMed
    1. Benson K, Hartz AJ. A comparison of observational studies and randomized, controlled trials. N Engl J Med. 2000;342(25):1878–86. - PubMed
    1. Concato J, Shah N, Horwitz RI. Randomized, controlled trials, observational studies, and the hierarchy of research designs. N Engl J Med. 2000;342(25):1887–92. - PMC - PubMed
    1. Grodstein F, Stampfer M, Manson J, et al. Postmenopausal estrogen and progestin use and the risk of cardiovascular disease (Erratum in: N Engl J Med 1996;335:1406) New England Journal of Medicine. 1996;335(7):453–61. - PubMed
    1. Grodstein F, Manson JE, Colditz GA, Willett WC, Speizer FE, Stampfer MJ. A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease. Annals of Internal Medicine. 2000;133(12):933–41. - PubMed

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