Effects of oral conjugated equine estrogens with or without medroxyprogesterone acetate on incident hypertension in the Women's Health Initiative hormone therapy trials

Abstract

Objective: The aim of the study was to determine the effect of menopausal hormone therapy on incident hypertension in the two Women's Health Initiative hormone therapy trials and in extended postintervention follow-up.

Methods: A total of 27,347 postmenopausal women aged 50 to 79 years were enrolled at 40 US centers. This analysis includes the subsample of 18,015 women who did not report hypertension at baseline and were not taking antihypertensive medication. Women with an intact uterus received conjugated equine estrogens (CEE; 0.625 mg/d) plus medroxyprogesterone acetate (MPA; 2.5 mg/d) (n = 5,994) or placebo (n = 5,679). Women with prior hysterectomy received CEE alone (0.625 mg/d) (n = 3,108) or placebo (n = 3,234). The intervention lasted a median of 5.6 years in the CEE plus MPA trial and 7.2 years in the CEE-alone trial with 13 years of cumulative follow-up until September 30, 2010. The primary outcome for these analyses was self-report of a new diagnosis of hypertension and/or high blood pressure requiring treatment with medication.

Results: During the CEE and CEE plus MPA intervention phase, the rate of incident hypertension was 18% higher for intervention than for placebo (CEE: hazard ratio [HR], 1.18; 95% CI, 1.09-1.29; CEE plus MPA: HR, 1.18; 95% CI, 1.09-1.27). This effect dissipated postintervention in both trials (CEE: HR, 1.06; 95% CI, 0.94-1.20; CEE plus MPA: HR, 1.02; 95% CI, 0.94-1.10).

Conclusions: CEE (0.625 mg/d) administered orally, with or without MPA, is associated with an increased risk of hypertension in older postmenopausal women. Whether lower doses, different estrogen formulations, or transdermal route of administration offer lower risks warrant further study.

Figure 1

A & B. Subgroup analysis by a forest plot of HRs, CEE versus placebo, of incident hypertension during the intervention phase (randomization through February 29, 2004; left panel) and post-intervention phase (March 1, 2004 through September 30, 2010; right) for the CEE trial. CEE indicates conjugated equine estrogens; HR, hazard ratio; CI, confidence interval; P, p-value for the significance test of the main effect or test of interaction/trend. ^a Percentages are annualized. ^b Incident hypertension defined as self-report of hypertension.

Figure 2

A & B. Subgroup analysis by a forest plot of HRs, CEE+MPA versus placebo, of incident hypertension during the intervention phase (randomization through July 7, 2002; left panel) and post-intervention phase (July 8, 2002 through September 30, 2010; right) for the CEE+MPA trial. CEE indicates conjugated equine estrogens; MPA, medroxyprogesterone acetate; HR, hazard ratio; CI, confidence interval; P, p-value for the significance test of the main effect, or test of interaction/trend. ^a Percentages are annualized. ^b Incident hypertension defined as self-report of hypertension.