Primary Prevention of Cardiovascular Disease With HRT

Kate Maclaran; John C Stevenson


Women's Health. 2012;8(1):63-74. 

In This Article

Clinical Data

Early Observational Studies

Three decades of observational studies appeared to consistently demonstrate the cardioprotective nature of postmenopausal HRT, with a reduction in cardiovascular deaths of approximately 40% reported.[25,26]

The largest of these epidemiological studies was the Nurses' Health Study (NHS),[27] which examined the effects of HRT in 70,533 postmenopausal women with no known CVD. Women were classified as never users, past users or current users of HRT. After 20 years follow-up, current use of HRT, after adjustment for a variety of cardiovascular risk factors, was associated with a significantly decreased risk of a major coronary event (relative risk [RR]: 0.61; 95% CI: 0.52–0.71). However, higher estrogen doses and estrogen/progestogen therapy (rather than estrogen alone) were associated with a higher risk of stroke.

Randomized Controlled Trial Data

Despite a wealth of observational evidence there have been few RCTs to support these findings. However, early RCTs using surrogate makers of atherosclerosis appeared to support the observational studies. Hodis and colleagues carried out a randomized, placebo-controlled trial involving 222 postmenopausal women with no known CVD.[28] They found that treatment with 1 mg of 17β-estradiol daily for 2 years was associated with reduced progression of subclinical atherosclerosis, as assessed using carotid artery intima-media thickness (IMT).

By contrast, results from the initial WHI publication appear to contradict previous data.[7] The WHI studies were a series of clinical trials and an observational study designed to assess the primary prevention of CVD, with hard clinical outcomes of CVD as end points. The trial had several different arms, including an estrogen plus progestin arm and an estrogen-only arm for hysterectomized women. The inclusion age for the studies was 50–79 years; however, they mainly involved older postmenopausal women, as the average age at enrolment was 63 years.

The estrogen/progestin arm examined the effects of oral CEE 0.625 mg and medroxyprogesterone acetate (MPA) 2.5 mg versus placebo in 16,608 postmenopausal women. This study halted early after 5.2 years due to an apparent increased risk of breast cancer in the treatment arm.[7] The initial analysis reported that estrogen/progestin therapy was associated with an increased risk of CHD events of almost 30% (hazard ratio [HR]: 1.29, nominal 95% CI: 1.02–1.63), with a particular increase in events in the first year following treatment. The estrogen only arm, involving 10,739 hysterectomized women receiving 0.625 mg CEE or placebo, was also terminated early, although not by the Data and Safety Monitoring Board, with an average follow-up of 6.8 years. The initial analysis from the estrogen-only arm also failed to show any cardiovascular benefit with estrogen use (HR: 0.91, adjusted 95% CI: 0.72–1.15).[29] Results from the WHI observational study, which were similar to previously published observational data, have been reported along with the clinical trial data, and began to highlight reasons for the discrepancies between the results.[30,31]

Despite initial conclusions from WHI that HRT does not offer protection against CVD, further data analysis and ongoing follow-up has brought these conclusions into question. Secondary analysis of both the CEE and CEE/MPA arms suggested that CHD was nonsignificantly reduced in younger women within 10 years of menopause using HRT and that increased risk was confined to those initiating therapy later after menopause.[9] Postintervention follow-up of patients from the estrogen-only arm for a mean of 10.7 years (with a mean duration of estrogen use of 5.9 years) echoed the initial findings, with no significant decrease in CHD across all ages (HR: 0.97, 95% CI: 0.75–1.25).[10] However, analysis by age group showed a significant reduction of CHD in younger postmenopausal women (HR: 0.59, 95% CI: 0.38–0.90), with no significant increase or decrease in the 60–69 and 70–79 year old age groups. Furthermore, the lower incidence of breast cancer in the initial study became statistically significant with prolonged follow-up (HR: 0.77, 95% CI: 0.62–0.95).

In a subgroup of WHI participants, coronary artery calcification, a surrogate marker for atheromatous plaque burden, was measured by computerized tomography 1.3 years after study termination.[32] In this group of 1064 young hysterectomized women (age 50–59 years at study entry), the use of CEE compared with placebo was associated with a 20–40% reduction in calcified plaque, increasing to 50–60% in the treatment group with highest compliance.


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