Dr. Ron’s Research Review – February 21, 2018

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This week’s research review focuses on HRT and breast cancer: the WHO follow-up.

A follow-up of the two Women's Health Initiative Estrogen Plus Progestin and Estrogen-Alone Trials examined mortality through 2014. Intervention were Conjugated equine estrogens (CEE, 0.625 mg/d) plus medroxyprogesterone acetate (MPA, 2.5 mg/d) (n = 8506) vs placebo (n = 8102) for 5.6 years or CEE alone (n = 5310) vs placebo (n = 5429) for 7.2 years. (Manson et al., 2017)

All-cause and Cardiovascular Mortality

All-cause mortality was 27.1% in the hormone therapy group vs 27.6% in the placebo group (hazard ratio [HR], 0.99 [95% CI, 0.94-1.03]) in the overall pooled cohort; with CEE plus MPA, the HR was 1.02 (95% CI, 0.96-1.08); and with CEE alone, the HR was 0.94 (95% CI, 0.88-1.01).
For cardiovascular mortality, the HR was 1.00 (95% CI, 0.92-1.08 [8.9 % with hormone therapy vs 9.0% with placebo]); for total cancer mortality, the HR was 1.03 (95% CI, 0.95-1.12 [8.2 % with hormone therapy vs 8.0% with placebo]); and for other causes, the HR was 0.95 (95% CI, 0.88-1.02 [10.0% with hormone therapy vs 10.7% with placebo]), and results did not differ significantly between trials.

Old and Young Women

When examined by 10-year age groups comparing younger women (aged 50-59 years) to older women (aged 70-79 years) in the pooled cohort, the ratio of nominal HRs for all-cause mortality was 0.61 (95% CI, 0.43-0.87) during the intervention phase and the ratio was 0.87 (95% CI, 0.76-1.00) during cumulative 18-year follow-up.
Among postmenopausal women, hormone therapy with CEE plus MPA for a median of 5.6 years or with CEE alone for a median of 7.2 years was not associated with risk of all-cause, cardiovascular, or cancer mortality during a cumulative follow-up of 18 years.
Women treated at age 50-59 had a greater reduction in all cause mortality than women treated at 70-79 years both during treatment (hazard ratio 0.61; 0.43 to 0.87) and after 18 years’ follow-up (0.87; 0.76 to 1.00).

Breast Cancer

Most notable in the new analyses are differences in mortality from breast cancer between formulations. During the original trials, breast cancer risk was increased in the estrogen plus progestin arm (1.25; 1.07 to 1.46) but not in the estrogen only arm (0.77; 0.57 to 1.01). Ten years after the trials ended, women who took only estrogen had a significantly lower risk of breast cancer than the placebo group (0.77; 0.62 to 0.95). This difference can now be extended to breast cancer mortality.
After 18 years of follow-up, women originally randomized to estrogen alone had significantly lower breast cancer mortality than women randomized to placebo (0.55; 0.33 to 0.92). Women randomized to estrogen plus progestin, however, had a moderate but non-significant increase in risk (1.44; 0.97 to 2.15).

The Risk

A very important learning point is that taking HRT does not affect the risk of dying from breast cancer. Women need to be made aware that this increased risk is less than being overweight or having a glass or two of wine each night. Telling them this often really helps to put it into perspective. (Newson, 2016)

Dr. Ron

 


Articles

 

Menopause Management--Getting Clinical Care Back on Track.
            (Manson and Kaunitz, 2016) Download
The North American Menopause Society provides a free mobile app called MenoPro to facilitate the individualized risk assessment required for counseling menopausal women regarding hormone therapy.

Menopausal Hormone Therapy and Long-term All-Cause and Cause-Specific Mortality: The Women's Health Initiative Randomized Trials.
            (Manson et al., 2017) Download
Importance:  Health outcomes from the Women's Health Initiative Estrogen Plus Progestin and Estrogen-Alone Trials have been reported, but previous publications have generally not focused on all-cause and cause-specific mortality. Objective:  To examine total and cause-specific cumulative mortality, including during the intervention and extended postintervention follow-up, of the 2 Women's Health Initiative hormone therapy trials. Design, Setting, and Participants:  Observational follow-up of US multiethnic postmenopausal women aged 50 to 79 years enrolled in 2 randomized clinical trials between 1993 and 1998 and followed up through December 31, 2014. Interventions:  Conjugated equine estrogens (CEE, 0.625 mg/d) plus medroxyprogesterone acetate (MPA, 2.5 mg/d) (n = 8506) vs placebo (n = 8102) for 5.6 years (median) or CEE alone (n = 5310) vs placebo (n = 5429) for 7.2 years (median). Main Outcomes and Measures:  All-cause mortality (primary outcome) and cause-specific mortality (cardiovascular disease mortality, cancer mortality, and other major causes of mortality) in the 2 trials pooled and in each trial individually, with prespecified analyses by 10-year age group based on age at time of randomization. Results:  Among 27 347 women who were randomized (baseline mean [SD] age, 63.4 [7.2] years; 80.6% white), mortality follow-up was available for more than 98%. During the cumulative 18-year follow-up, 7489 deaths occurred (1088 deaths during the intervention phase and 6401 deaths during postintervention follow-up). All-cause mortality was 27.1% in the hormone therapy group vs 27.6% in the placebo group (hazard ratio [HR], 0.99 [95% CI, 0.94-1.03]) in the overall pooled cohort; with CEE plus MPA, the HR was 1.02 (95% CI, 0.96-1.08); and with CEE alone, the HR was 0.94 (95% CI, 0.88-1.01). In the pooled cohort for cardiovascular mortality, the HR was 1.00 (95% CI, 0.92-1.08 [8.9 % with hormone therapy vs 9.0% with placebo]); for total cancer mortality, the HR was 1.03 (95% CI, 0.95-1.12 [8.2 % with hormone therapy vs 8.0% with placebo]); and for other causes, the HR was 0.95 (95% CI, 0.88-1.02 [10.0% with hormone therapy vs 10.7% with placebo]), and results did not differ significantly between trials. When examined by 10-year age groups comparing younger women (aged 50-59 years) to older women (aged 70-79 years) in the pooled cohort, the ratio of nominal HRs for all-cause mortality was 0.61 (95% CI, 0.43-0.87) during the intervention phase and the ratio was 0.87 (95% CI, 0.76-1.00) during cumulative 18-year follow-up, without significant heterogeneity between trials. Conclusions and Relevance:  Among postmenopausal women, hormone therapy with CEE plus MPA for a median of 5.6 years or with CEE alone for a median of 7.2 years was not associated with risk of all-cause, cardiovascular, or cancer mortality during a cumulative follow-up of 18 years. Trial Registration:  clinicaltrials.gov Identifier: NCT00000611.

Best practice for HRT: unpicking the evidence.
            (Newson, 2016) Download
A very important learning point is that taking HRT does not affect the risk of dying from breast cancer. Women need to be made aware that this increased risk is less than being overweight or having a glass or two of wine each night. Telling them this often really helps to put it into perspective.

Reassurance for many healthy women considering HRT.
            (Shufelt and Bairey Merz, 2017) Download
In Manson and colleagues’ new, age group analyses, women treated at age 50-59 had a greater reduction in all cause mortality than women treated at 70-79 years both during treatment (hazard ratio 0.61; 0.43 to 0.87) and after 18 years’ follow-up (0.87; 0.76 to 1.00). These findings are important because they align with current guidelines that support the use of hormone therapy by healthy and recently menopausal women for symptom control.Most notable in the new analyses are differences in mortality from breast cancer between formulations. During the original trials, breast cancer risk was increased in the oestrogen plus progestin arm (1.25; 1.07 to 1.46)8 but not in the oestrogen only arm (0.77; 0.57 to 1.01).9 Ten years after the trials ended, women who took only oestrogen had a significantly lower risk of breast cancer than the placebo group (0.77; 0.62 to 0.95).10 This difference can now be extended to breast cancer mortality. After 18 years of follow-up, women originally randomised to oestrogen alone had significantly lower breast cancer mortality than women randomised to placebo (0.55; 0.33 to 0.92).4 Women randomised to oestrogen plus progestin, however, had a moderate but non-significant increase in risk (1.44; 0.97 to 2.15). Use of hormone therapy for five years with oestrogen plus medroxyprogesterone increases women’s risk of breast cancer, while oestrogen alone does not have the same risk and may now be associated with reduced mortality from breast cancer in the longer term.


 

References

Manson, JE and AM Kaunitz (2016), ‘Menopause Management--Getting Clinical Care Back on Track.’, N Engl J Med, 374 (9), 803-6. PubMed: 26962899
Manson, JE, et al. (2017), ‘Menopausal Hormone Therapy and Long-term All-Cause and Cause-Specific Mortality: The Women’s Health Initiative Randomized Trials.’, JAMA, 318 (10), 927-38. PubMed: 28898378
Newson, LR (2016), ‘Best practice for HRT: unpicking the evidence.’, Br J Gen Pract, 66 (653), 597-98. PubMed: 27621293
Shufelt, C and CN Bairey Merz (2017), ‘Reassurance for many healthy women considering HRT.’, BMJ, 359 j4652. PubMed: 29030494