Among postmenopausal women in the Women’s Health Initiative trials, use of hormone therapy (HRT) for five to seven years was not associated with risk of all-cause, cardiovascular or cancer death over 18 years of follow-up, according to a Harvard study. The WHI study puts the increased incidence of breast cancer with HRT at one more case in 1,000, equivalent to the effect of drinking a glass of wine a night.
The Women’s Health Initiative (WHI) hormone therapy trials were designed to assess the benefits and risks of menopausal hormone therapy taken for chronic disease prevention by predominantly healthy postmenopausal women. Health outcomes have been reported, but previous publications have generally not focused on all-cause and cause-specific mortality. All-cause mortality is a critically important summary measure representing the net effect of hormone therapy on serious and life-threatening health conditions.
Dr JoAnn E Manson, of Brigham and Women’s Hospital, Harvard Medical School, and colleagues examined total and cause-specific mortality during cumulative 18-year follow-up (intervention plus extended post-intervention phases) of the two randomised WHI hormone therapy trials: conjugated equine oestrogens (CEE, 0.625 mg/d) plus medroxyprogesterone acetate (MPA, 2.5 mg/d) (n = 8,506) vs placebo (n = 8,102) for 5.6 years (median); or CEE alone (n = 5,310) vs placebo (n = 5,429) for 7.2 years (median). The analysis included postmenopausal women ages 50 to 79 years who were enrolled in the trials between 1993 and 1998 and followed up through 2014.
Among 27,347 women who were randomised, mortality follow-up was available for more than 98%. During the cumulative 18-year follow-up, 7,489 deaths occurred (1,088 deaths during the intervention phase and 6,401 deaths during post-intervention follow-up). All-cause mortality was 27.1% in the hormone therapy group vs 27.6% in the placebo group in the overall pooled cohort. Analyses indicated that CEE plus MPA and CEE alone were not associated with increased or decreased risk of all-cause, cardiovascular, or total cancer mortality. During cumulative follow-up, trends in cause-specific mortality across age groups were not significantly different.
Several limitations of the study are noted in the article, including that only one dose, formulation, and route of administration in each trial was assessed; thus, results are not necessarily generalisable to other hormone preparations.
“In view of the complex balance of benefits and risks of hormone therapy, the all-cause mortality outcome provides an important summary measure, representing the net effect of hormone therapy use for 5 to 7 years on life-threatening outcomes,” the authors write.
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.
JoAnn E Manson; Aaron K Aragaki; Jacques E Rossouw; Garnet L Anderson; Ross L Prentice; Andrea Z LaCroix; Rowan T Chlebowski; Barbara V Howard; Cynthia A Thomson; Karen L Margolis; Cora E Lewis; Marcia L Stefanick; Rebecca D Jackson, ; Karen C Johnson; Lisa W Martin; Sally A Shumake; Mark A Espeland; Jean Wactawski-Wende
A report in The Guardian says that’s good news. Gynaecologists who have been frustrated and dismayed by the bad press HRT has had, leaving them groping in the dark for something else to give the distressed woman in the consulting room who doesn’t want hormones, said this is proof of its safety. The risks are low. Women must be told about them, but they should not be deterred by any thought that HRT could shorten their life.
And yet, the report says, the long-term results from the study are about mortality and in one way they don’t change a thing. HRT still increases the chances that a woman will get breast cancer and ovarian cancer and possibly heart disease and stroke in those over 60 – she just won’t die as a result. Treatment is better these days.
The Women’s Health Initiative (WHI) was a huge study of nearly 162,000 women launched in 1991. The UK-based Million Women Study began in 1996. Both found an increased rate of breast and ovarian cancer. Thousands of women stopped taking HRT. Thousands more were anxious about starting it.
Now, the report says, the pendulum has swung back the other way, with guidance from the National Institute for Health and Clinical Excellence (NICE), in November 2015. Millions of women should no longer have to suffer in silence, it said. An estimated 1.5m women in the UK – 85% of all those going through menopause – suffer common symptoms such as hot flushes, insomnia and night sweats. Yet they don’t always get the help they need to manage the symptoms. HRT worked, Nice said, and should be considered. And now the WHI study has published its long-term findings showing women do not die from taking it.
“Data showing that mortality overall is not increased in all age groups is a very reassuring finding,” said Haitham Hamoda, consultant gynaecologist at Kings College Hospital and spokesperson for the Royal College of Obstetricians and Gynaecologists. Hamoda is also on the medical advisory council of the British Menopause Society which has lobbied for HRT and disputed the risk findings in the past.
Hamoda says the breast cancer risk is not high. The WHI study puts it at one more case in 1,000. The report says he prefers that to the observational Million Women Study, funded by Cancer Research UK, which says it is two women in 1,000. One in 1,000, Hamoda says “in medical and statistical terms is a small number. It is similar to the (breast cancer) risk of drinking a glass of wine a night.” The risk of breast cancer from being overweight is four times higher.
The report says the advice from the UK’s National Health Service (NHS) is that each woman should sit down with her GP and talk through the options, based on what they know of her individual risk. There are no easy answers, it says. Women at high risk of breast or ovarian cancer or those who have had them will not be advised to take HRT.
For everyone else it is something of a guessing game. The odds of cancer are low and reduced if a woman takes the pills for a shorter length of time (no help to those who have symptoms for 20 years), but the risk exists.