Highlights from the latest WHI publications and the latest North American Menopause Society position statement on use of menopausal hormone therapy

UPDATES FROM THE WOMEN’S HEALTH INITIATIVE

Since the publication of the 2007 NAMS position statement, three additional important analyses have emerged from the WHI randomized trial. The first report, by Rossouw et al, examined the effects of HT on the risk of cardiovascular disease (CVD) and other outcomes according to age and time since menopause.² The second analysis, by Manson et al, was a post hoc study of the extent of coronary artery calcification in the 50- to 59-year-old group in the ET arm of the WHI.³ The third analysis, by Heiss et al, reported health outcomes at 2.4 years after treatment was stopped in the EPT arm of the WHI.⁴

Cardiovascular results

The analysis by Rossouw et al of the CVD effects of HT by age and years since menopause has been reported in detail in the preceding paper by Hodis. In brief, the authors concluded that the data confirm a very low risk for women in their 50s who use HT for menopausal symptoms. The authors cautioned that the low risk from ages 50 to 59 does not guarantee lack of harm with prolonged use into older ages. Stroke and thrombosis risk were not dependent on years since menopause.

The WHI Coronary Artery Calcium Study was conducted in the ET arm approximately 1.3 years after the intervention (ET or placebo) was discontinued.3 Participants had completed a mean 7.4 years of intervention. The 1,064 eligible and available participants were aged 50 to 59 at WHI baseline. They underwent computed tomography of the heart. More than half of the women had a coronary artery calcium (CAC) score of 0. Overall, the mean CAC score was 83.1 among those randomized to ET and 123.1 among those randomized to placebo (P = .02). Classic CVD risk factors such as smoking, diabetes, hypertension, and high cholesterol were also associated with increased CAC scores, but they did not significantly modify the effect of ET on CAC. The authors cautioned that because of the multiple and complex effects of estrogen in the cardiovascular system, further study should be completed before ET is used for prevention of CAC.

Postintervention assessment

The third key HT-related WHI paper⁴ published since the 2007 NAMS position statement is the first to report the health events that occurred in the EPT arm since discontinuation of the study drugs.

Design and end points. The intervention phase of the WHI trial of EPT included 16,608 postmenopausal women (with intact uterus) aged 50 to 79 years at baseline who were randomized to treatment with EPT or placebo for a mean of 5.6 years before the treatment intervention was discontinued in July 2002 because the overall health risks of EPT were found to exceed the health benefits. Of these original participants, 15,730 women (95%) completed a planned postintervention follow-up consisting of semi-annual monitoring for adjudicated outcomes from July 2002 through March 2005. The mean duration of postintervention follow-up was 2.4 years.⁴

The primary outcomes of this postintervention analysis were CVD events and invasive breast cancer. These end points, together with endometrial cancer, colorectal cancer, stroke, pulmonary embolism, hip fracture, and death, were also factored into a global index of risks versus benefits with EPT.

Results. CVD. There was neither an elevated risk nor a decreased risk of CHD after discontinuation of EPT (hazard ratio [HR] = 0.95; 95% CI, 0.73 to 1.26). Risks that were elevated in the intervention phase, such as deep vein thrombosis (DVT) and stroke, disappeared after EPT was stopped. Women originally randomized to EPT had a similar rate of all CVD events compared with those who had been randomized to placebo (HR = 1.04; 95% CI, 0.89 to 1.21).

Breast and other cancers. The annualized incidence of invasive breast cancer in the postintervention period was 0.42% in the group that had been randomized to EPT versus 0.33% in the group randomized to placebo. This translated to a nonsignificant HR of 1.27 (95% CI, 0.91 to 1.78) for the postintervention period. In contrast, the annualized rate of all cancers (endometrial, colorectal, and breast combined) in the postintervention period was significantly higher in the EPT group (1.56%) than in the placebo group (1.26%) (HR = 1.24; 95% CI, 1.04 to 1.48). More extensive analysis of this finding is under way.

The cancer findings from this 2.4-year postintervention phase of the WHI parallel those from the 2.7-year postintervention phase of the Heart and Estrogen/progestin Replacement Study (HERS), in which between-group differences in the rates of breast and colon cancers approached null as the incidences of lung and other cancers increased in the group that had been randomized to EPT.⁷

Fractures. During the intervention phase, EPT was associated with a significant reduction in fractures; however, the EPT fracture benefit disappeared within the 2.4-year follow-up period.

Mortality. There was little difference in all-cause mortality between the treatment groups in the intervention phase. Although the difference was not statistically significant, there was a 15% higher mortality rate in the EPT group during the postintervention phase (HR = 1.15; 95% CI, 0.95 to 1.39). Contributing in part to this difference was an increased risk of mortality from lung cancer that requires further exploration.

Global index. The global index of risks versus benefits from enrollment to the present analysis remained significantly elevated (HR = 1.12; 95% CI, 1.03 to 1.21), suggesting more risk than benefit from use of EPT. The increase in the global index loses significance when the postintervention phase is considered alone (HR = 1.11; 95% CI, 0.99 to 1.27).

Conclusions. The researchers concluded that a number of outcome patterns observed with EPT in the intervention period of the WHI randomized trial did not persist during the 3-year postintervention follow-up:

• CHD, DVT, and stroke risks disappeared
• Hip fracture and total fracture benefits disappeared
• The composite risk of all cancers increased and was statistically significant in the postintervention phase, although the elevated risk of breast cancer was no longer statistically significant in the postintervention phase.

Summary of the new WHI reports

These three recent papers from the WHI suggest lower risks with short-term use of EPT in women ages 50 to 59 compared with older women. A delay in atherosclerosis and a decrease in all-cause mortality were also noted in this age group. The postintervention follow-up findings of a rapid disappearance of most risks and benefits of EPT will be of interest to patients who want to know what to expect when they discontinue HT. The late development (in years 5 to 8) of an increase in the composite risk of all cancers merits further investigation.