More Evidence Linking Hormone Therapy To Cardiovascular Harm in Postmenopausal Women

Cardiovascular disease — including heart disease and stroke — remains the leading cause of death worldwide.[1] Most women who develop these conditions do so after menopause, when their natural supply of estrogen dwindles. In fact, postmenopausal women have almost three times the rate of cardiovascular events — such as heart attacks and strokes — as those in the same age group who have not yet experienced menopause.[2]

Such findings served as the basis for Wyeth-Ayerst's request to the Food and Drug Administration (FDA) in 1990 for approval of its estrogen drug (PREMARIN) for decreasing the risk of heart disease after menopause.[3]

However, the FDA rejected the company's request. In fact, the agency required in January 2003 that the labels of all estrogen and estrogen-progestin (a synthetic form of another female hormone) combination drugs be revised to include a black-box warning that these drugs should not be used for the prevention of cardiovascular disease.[4] However, more than 10 years after this decision, a great deal of controversy may still appear to exist about the effectiveness and safety of hormone therapy for the prevention of cardiovascular disease in postmenopausal women.[5]

A recent study again showed that hormone therapy does not protect postmenopausal women against cardiovascular disease and actually can cause harm to the cardiovascular system. This study was conducted for the Cochrane Collaboration — an independent international organization that specializes in health care research — by researchers from the University of Oxford and other research centers in the U.K. and Spain. It was published in March in the Cochrane Database of Systematic Reviews.[6]

About hormone therapy

Hormone therapy is the use of female hormones (either estrogen alone or estrogen in combination with a progestin) in medication form. It is available in a variety of formulations and doses. The effects of hormone therapy can vary depending on the type of the hormone being used and duration of treatment.

Approved formulations of estrogen for postmenopausal women include conjugated estrogens (CENESTIN, ENJUVIA, PREMARIN); esterified estrogens (MENEST); estradiol tablets, patches, gels, creams, nasal sprays or implants (ALORA, CLI­MARA, DIVIGEL, ELESTRIN, ESTRACE, ESTRADERM, ESTRASORB, ESTRING, ESTROGEL, EVAMIST, FEMRING, FEMTRACE, MENOSTAR, MINIVELLE, VAGIFEM, VIVELLE); and estradiol injections (DELESTROGEN, DEPO-ESTRADIOL).

Estrogen-progestin combinations include conjugated estrogens with medroxyprogesterone (PREMPHASE, PREMPRO), estradiol with drospirenone (ANGELIQ) and ethinyl estradiol with norethindrone (ACTIVELLA, COMBIPATCH, FEMHRT). The combination is used to reduce women's risk of endometrial hyperplasia (enlargement of uterine cells). Another estrogen-containing combination drug approved for postmenopausal symptoms is conjugated estrogens with bazedoxifene (DUAVEE), which Public Citizen's Health Research Group has designated as Do Not Use.

FDA-approved uses of hormone therapy are limited to relief of menopausal symptoms (including hot flashes and night sweats), treatment of vaginal or vulvar atrophy, and prevention (but not treatment) of osteoporosis.

The new study

The new study — an update of a similar Cochrane study published in 2013[7] — pooled data from 19 ran­domized, controlled trials published through February 2014. It included six new trials, in addition to another 13 trials that also were included in the earlier Cochrane study. Overall, the new study included more than 40,000 postmenopausal women. About half received oral hormone therapy consisting of estrogen alone or in combination with a progestin, and the remaining half received either a placebo or no treatment. Some of the trials studied women who had no evidence of existing cardiovascular disease upon enrollment (primary prevention trials), and others studied women with evidence of such disease (secondary prevention trials). The trials lasted from seven months to about 10 years, with an average duration of about four years.

The researchers found that hormone therapy does not lower overall death rates and offers no protection against cardiovascular-related death, nonfatal heart attack or angina (chest pain caused by coronary heart disease) in either healthy women or those with existing cardiovascular disease. Conversely, they found an increased risk of stroke, pulmonary embolism (blood clot in the lungs) and deep vein thrombosis (blood clot in deep veins, such as those in the thigh or lower leg) in women receiving hormone therapy.

To test whether the timing of hormone therapy in relation to the onset of menopause influences the drugs' cardiovascular effects, the researchers compared the effect of treatment among women who started therapy less than 10 years after menopause (or before age 60) versus those starting treatment 10 or more years after menopause (or at 60 years of age or older). This analysis showed a very small reduced risk of overall death and death related to coronary heart disease — but no differences in stroke risk — in the group that started hormone therapy less than 10 years after menopause.

On the other hand, the analysis showed strong evidence of increased risk of pulmonary embolism and deep vein thrombosis in both groups.

Strong evidence of harm

The findings of the new Cochrane study are generally consistent with those of the previous study, which also showed that hormone therapy does not reduce the overall death rate or cardiovascular-related deaths.

Two large trials — called the Women's Health Initiative (WHI) trials — constituted the largest portion of subjects included in the new Cochrane study and deserve special mention. Both studies were funded by the National Institutes of Health.

The first trial evaluated the effects of oral estrogen plus progestin and was terminated in 2002 (three years before its scheduled completion) due to a finding of increased breast cancer in the group given hormone therapy.[8] It precipitated the black-box warning issued by the FDA against using hormone therapy to reduce cardiovascular risk.[9],[10] The key finding of this trial was that the potential harms of long-term hormone therapy in postmenopausal women (including increased risk of nonfatal heart attack, stroke, deep vein thrombosis, pulmonary embolism and invasive breast cancer) outweighed its potential benefits (which were limited to reduced incidence of colon cancer and fractures).[11]

The second WHI study evaluated estrogen-only therapy, and it also showed that the risks of hormone therapy outweighed its benefits. The study was terminated early, in 2004.[12]

A 2013 study that analyzed follow-up data from surviving subjects of the two WHI trials concluded, "Even though hormone therapy is a reason­able option for the management of moderate to severe menopausal symptoms, the risks associated with hormone therapy … preclude a recommendation in support of its use for disease prevention even among younger women."[13]

This advice is consistent with guidance from the American College of Obstetricians and Gynecologists that hormone therapy should not be used for the primary prevention or secondary prevention of coronary heart disease.[14]

What You Can Do

If you are transitioning into menopause or life after menopause, you should not use hormone therapy for prevention of cardiovascular disease — or any other chronic condition, including osteoporosis,[15] for that matter. If you choose to use hormone therapy to control the symptoms of menopause, you should use the lowest dose for the shortest possible period to avoid long-term complications.

References

[1] World Health Organization. Cardiovascular diseases (CVDs): Fact sheet. 2015. http://www.who.int/mediacentre/factsheets/fs317/en/. Accessed July 23, 2015.

[2] Boardman HMP, Hartley L, Eisinga A, et al. Hormone therapy for preventing cardiovascular disease in post-menopausal women (review). Cochrane Database Syst Rev. 2015;(3):CD002229. doi:10.1002/14651858.CD002229.pub2.

[3] Long term hormone replacement therapy (HRT): The demise of a standard of practice. Worst Pills, Best Pills News. September 2002. /newsletters/view/53. Accessed July 29, 2015.

[4] Davis J. FDA approves new HRT warning label. Medscape. 2003. http://www.medscape.com/viewarticle/447629_print. Accessed July 24, 2015.

[5] Brown S. News and views — HRT: No end in sight to the doubts and controversies. Post Reprod Heal. 2014;20(2):45-47.

[6] Boardman HMP, Hartley L, Eisinga A, et al. Hormone therapy for preventing cardiovascular disease in post-menopausal women (review). Cochrane Database Syst Rev. 2015;(3):CD002229. doi:10.1002/14651858.CD002229.pub2.

[7] Main C, Knight B, Moxham T, et al. Hormone therapy for preventing cardiovascular disease in post-menopausal women. Cochrane Database Syst Rev. 2013;4(CD002229). doi:10.1002/14651858.CD002229.pub3.

[8] Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women's Health Initiative randomized controlled trial. JAMA. 2002;288(3):321-333.

[9] Food and Drug Administration. Estrogen and estrogen with progestin therapies for postmenopausal women. 2010. http://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm135318.htm. Accessed July 24, 2015.

[10] Food and Drug Administration. MedWatch Alert: Prempro/Premphase (conjugated estrogens/medroxyprogesterone acetate tablets). January 2003. Available at: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm153358.htm. Accessed August 11, 2015.

[11] Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women's Health Initiative randomized controlled trial. JAMA. 2002;288(3):321-333.

[12] The Women's Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: The Women's Health Initiative randomized controlled trial. JAMA. 2004;291(14):1701-1712.

[13] Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative randomized trials. JAMA. 2013;310(13):1353-1368.

[14] American College of Obstetricians and Gynecologists. Committee opinion: Hormone therapy and heart disease. June 2013. http://www.acog.org/Resources-And-Publications/Committee-Opinions/Committee-on-Gynecologic-Practice/Hormone-Therapy-and-Heart-Disease. Accessed July 24, 2015.

[15] A guide to treatments for osteoporosis. Worst Pills, Best Pills News. May 2015. /newsletters/view/960. Accessed July 24, 2015.