Danish Study Gives A Boost To Hormone Replacement Therapy Timing Hypothesis

Hormone replacement therapy (HRT) suffered a sharp blow a decade ago when the Women’s Health Initiative failed to show any cardiovascular benefit in women taking HRT. Despite the setback, many researchers theorized that HRT might still be beneficial in women who start HRT close to menopause. Now a new study from Denmark published in BMJ lends strong support to the “timing hypothesis.”

Louise Lind Schierbeck and colleagues analyzed data from 1006 recently postmenopausal or perimenopausal women who were randomized to HRT or no treatment.

After 10 years, there were 16 primary endpoint events (the composite of death, admission to the hospital for heart failure, or MI) in the HRT group compared with 33 in the control group (hazard ratio 0.48, CI 0.26-0.87, p=0.015).

  • Mortality: 15 versus 26, HR 0.57, 0.30-1.08, p=0.084
  • HF: 1 versus 7, HR 0.14, 0.02-1.16, p=0.07
  • MI: 1 versus 40.25, HR 0.03-2.21, p=0.21.

There were no significant differences in the overall rate of cancer or of breast cancer. Women who were under 50 years of age at the start of the trial appeared to enjoy the greatest benefit from HRT.

The authors concluded:

Our findings suggest that initiation of hormone replacement therapy in women early after menopause significantly reduces the risk of the combined endpoint of mortality, myocardial infarction, or heart failure. Importantly, early initiation and prolonged hormone replacement therapy did not result in an increased risk of breast cancer or stroke.

Andrew Kaunitz told Physician’s First Watch that, when “taken together with findings from a subanalysis of younger women from the WHI, these data should reassure clinicians and women that use of hormone therapy in recently menopausal women is safe.”

Here is the BMJ press release:

HRT taken for 10 years significantly reduces risk of heart failure and heart attack

Wednesday, October 10, 2012 – 08:37

Women who take HRT for 10 years following menopause have a significantly reduced risk of mortality, heart failure and heart attack without any increased risk of cancer, DVT or stroke, a study published today on bmj.com suggests.

HRT therapy has been subject to much discussion due to both positive effects (reduced risk of cardiovascular disease) and negative effects (increased risk of breast cancer). A paper published in the BMJ Group’s Journal of Family Planning and Reproductive Healthcare back in January cast doubt on the “unreliable” Million Women Study which associated HRT with an increased risk of breast cancer.

Conflicting results have led clinicians to believe that time since menopause until HRT is initiated can account for differences in cardiovascular outcome. So authors from Denmark carried out a randomised trial over 10 years with additional six years of follow-up to establish whether HRT can reduce cardiovascular risk if it is started early after menopause.

1006 women (504 in HRT group and 502 in non-HRT group) were included in the study and all were white, healthy, recently menopausal and aged 45-58 years old. Women who’d had a hysterectomy were only included if they were aged 45-52. Exclusion criteria were if they had a history of bone disease, uncontrolled chronic disease, previous or current cancer, current or previous use of HRT within the past three months and alcohol or drug addiction. All data on diagnoses or death were taken from the Danish Civil Registration System and National Hospital Discharge Register.  The primary end-point was a combination of death and hospitalisation for a heart attack or heart failure.

After 10 years of randomised treatment the women were encouraged to discontinue the use of HRT due to the results from the Women’s Health Initiative and the Million Women Study. During this period, 26 women in the non-HRT group died and 33 died or experienced a cardiovascular end-point, compared to 15 deaths and 16 deaths or cardiovascular end-points in the HRT group.

The women were followed for another six years. During this time, the primary end-point was seen in 53 women in the non-HRT group (40 deaths, eight heart failures and five heart attacks) and 33 in the HRT group (27 deaths, three heart failures and three heart attacks).

Causes of death were 23 cardiovascular deaths and 17 non-cardiovascular deaths in the non-HRT group and six cardiovascular deaths and 21 non-cardiovascular deaths in the HRT group.

The study also found that women who had undergone a hysterectomy and younger women taking HRT had a significantly reduced risk of death or breast cancer.

The authors conclude that women treated with long term HRT early after menopause “had significantly reduced risk of mortality, heart failure, or myocardial infarction [heart attack], without any apparent increase of cancer, venous thromboembolisms [DVT] or stroke.” However, they stress that “due to the potential time lag longer time may be necessary to take more definite conclusions.”

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