Heart and Stroke Foundation of Canada Position Statement

HORMONE REPLACEMENT THERAPY (HRT) AND HEART DISEASE AND STROKE

Hormone Replacement Therapy (HRT) and Heart Disease and Stroke

FACTS

  • Cardiovascular disease (heart disease and stroke) is the leading cause of death and a major cause of disability for Canadian women.1
    • In 2001, approximately 35% of all deaths among Canadian women were due to heart disease and stroke (37,751 deaths).1
    • In 2001, more Canadian women died from heart disease and stroke than from all cancers combined.1
  • A woman’s overall risk of heart disease or stroke is determined by ALL of her risk factors. We can control some of these risk factors but not all of them.
    • Risk factors that we can control include smoking, high blood pressure, high blood cholesterol, diabetes, physical inactivity, and obesity.
    • Risk factors that we cannot control include age, gender, family history, and ethnicity.
  • Menopause is a time when a woman stops having menstrual cycles and her overall risk of heart disease may increase due to the reduction in the hormones estrogen and progesterone produced by her body. After menopause she may experience:
    • An increase in total blood cholesterol, low density lipoprotein cholesterol (LDL or ‘bad’ cholesterol) and triglyceride levels.2
    • A decrease in high density lipoprotein cholesterol (HDL or ‘good’ cholesterol).2
    • A tendency toward higher blood pressure.2
    • Symptoms related to the reduction in estrogen levels such as severe sweating or sleep disturbances.3
  • For women, the number of deaths due to heart disease and stroke increases after menopause and continues to increase with advancing age.4 It is not clear whether the increase in the number of deaths is caused by lower estrogen levels or is due to the aging process.5
  • Reduced estrogen levels increase a woman’s chance of developing risk factors for heart disease or stroke including high blood pressure, diabetes, and obesity. Reduced estrogen levels also increase central body fat6 and have harmful effects on the way blood clots2 and the way the body handles sugar.2
  • Hormone Replacement Therapy (HRT) refers to different types of estrogen and progestin (usually in pill or patch form) that a woman may take to ease some of the symptoms related to menopause.
  • Randomized controlled clinical trials have found that hormone replacement therapy does not reduce the risk of heart disease or stroke, or prevent future heart disease or stroke.11-14,16,17

RECOMMENDATIONS

The Heart and Stroke Foundation of Canada recommends that:

Women

  1. Do not begin to use nor continue to use hormone replacement therapy (HRT), either estrogen alone or combined estrogen-progestin, for the sole purpose of preventing heart disease or stroke.
  2. Discuss all health risks and benefits associated with HRT, their preferences in relation to HRT, and the goals of treatment with their healthcare provider to guide their decision regarding HRT use.
  3. Prevent and reduce the risk of heart disease and stroke by:
    • Becoming and remaining smoke-free.
    • Achieving and maintaining a healthy body weight.
    • Being physically active for at least 30 minutes a day, preferably every day of the week.
    • Maintaining a normal blood pressure through lifestyle changes (such as increased physical activity) and, when needed, through medication.
    • Eating a healthy diet that is lower in fat, higher in fibre, and includes foods from each of the four food groups in Canada’s Food Guide.
    • Using medications to reduce the risk of heart disease and stroke as prescribed by their healthcare provider, for example medications for high blood pressure, high blood cholesterol and diabetes, or other medications like acetylsalicylic acid (ASA commonly referred to as Aspirin™).

Primary Healthcare providers

  1. Counsel all women about lifestyle changes to reduce or prevent heart disease and stroke, especially those at high risk (those with heart disease, who have had a stroke, have high blood pressure, or have diabetes).

Research Funding Agencies

  1. Increase funding for research related to the prevention of heart disease and stroke for women.

BACKGROUND INFORMATION

Estrogen is a hormone that produces female physical traits and helps regulate a woman’s menstrual cycle. In women, estrogen is produced in varying amounts throughout the menstrual cycle, mainly by the ovaries. When a woman’s estrogen level reaches a low enough point she stops having monthly menstrual periods (menopause).

Progesterone is a steroid hormone that is also produced in the ovary. Progesterone is released by the ovaries during the second half of the menstrual cycle, and prepares and maintains the uterus for pregnancy. At the time of menopause, the level of progesterone declines.

Progestin is the term used to describe any substance that affects a woman's body in the same ways as the hormone progesterone. Progestin can be natural or man-made (synthetic).

The evidence that estrogen protects you from developing heart disease is based on over 30 long-term observational studies conducted over the last 20 years. These studies show that women who were using estrogen alone or combined estrogen-progestin hormone replacement therapy had a 40% reduction in the risk of heart disease compared to women who had never used these hormones.7 However, these types of observational studies cannot completely control other factors that may affect the study results, including the fact that women who take HRT tend to be healthier in general and follow their doctors’ advice.8 Based on these studies, randomized controlled clinical trials of HRT were planned to more clearly understand if HRT could be used in the prevention and treatment of chronic diseases such as heart disease and stroke. Scientifically, randomized clinical trials are considered the best method to assess the impact of a treatment such as HRT.

The Heart and Estrogen/Progestin Replacement Study (HERS) was one of the first randomized controlled clinical trials of HRT in women with heart disease.9 This study was designed to investigate the effects of one formulation of HRT (combined estrogen-progestin). The researchers did not find an overall benefit after 4 years of treatment with combined estrogen-progestin. Of concern, for women using this formulation of HRT there was an increase in the risk of heart attack or death due to heart disease in the first year, and an approximate three-fold increase in the risk of blood clots. On average, this risk decreased over the study period. The women in the HERS study were followed for a further 2.7 years in the HERS II study.10 HERS II did not find any health benefits for women with heart disease who were using HRT (estrogen alone or combined estrogen-progestin).

The Estrogen Replacement and Atherosclerosis (ERA) trial, another randomized controlled clinical trial using a similar regimen of combined estrogen-progestin or estrogen alone, was conducted in a group of women similar to those studied in HERS study. The ERA trial found no difference in the progression of atherosclerosis of the coronary arteries for those women using combined estrogen-progestin or women using estrogen alone compared to placebo.11 Another randomized controlled trial assessing estrogen alone in women with a previous stroke showed no reduction in the risk of another stroke after almost 3 years of treatment.12 Other trials using various types and doses of estrogen, with or without progestin, in women with heart disease, have confirmed that HRT does not prevent future heart disease or stroke.13,14

The above randomized controlled clinical trials only included women with existing heart disease or stroke. The U.S.-based Nurses’ Health Study observed women over time without heart disease or stroke using HRT. The Nurses’ Health Study was not a randomized controlled clinical trial. In these women, HRT use (estrogen alone or combined estrogen-progestin) seemed to show a benefit in preventing heart disease or stroke.15 Researchers questioned whether results from randomized controlled clinical trials on women with existing heart disease or stroke would be the same for women without heart disease or stroke. A study called the Women’s Health Initiative (WHI) was carried out to answer this question.16

The WHI trial of HRT (combined estrogen-progestin) involved approximately 16,000 women between the ages of 50 and 79 years who had not had a hysterectomy. Although the trial was scheduled to be completed in 2005, the trial was stopped early after 5 years of follow-up. The trial was stopped due to a small increased risk of invasive breast cancer (8 cases/10,000 women). For women in the study at the time it was stopped, there was an increased risk (7 cases/10,000) of heart attack and death due to heart disease (especially seen in the first year of treatment). There was also a small but important increased risk of stroke (8 cases/10,000), and as is seen with other estrogen studies, an increase in blood clots. There was a suggestion of benefit for prevention of hip fractures and colorectal cancer but overall, women using HRT were more likely to have harm than benefit. Based on this study, it was calculated that one hundred in 10,000 women using HRT treatment will experience an adverse event. The excess risk is small but important given that this therapy has been suggested for disease prevention. The part of the study that looked at estrogen alone in women with prior hysterectomy was also stopped early because no overall benefit was seen.17 Although there was no increased risk of heart disease, there was an increased risk of stroke and blood clots.

Side effects other than heart disease or stroke-related outcomes must be considered when deciding whether to use HRT in the short term (for a few years or less). The WHI trial has shown an increased risk of breast cancer with long-term use (more than five years) of continuous-combined estrogen-progestin HRT, although this was not found in the estrogen-alone arm of WHI.

Women should talk to their doctor to discuss specific risks and benefits of HRT related to their personal health history.

NOTE
The Heart and Stroke Foundation of Canada recognizes that the life-long heart health of Canadians is affected by both individual and social factors. Individual factors include genetic make-up, personal health choices and actions, and social support. Social factors include the social, economic and environmental conditions in which Canadians live, work, learn and play.

The Foundation encourages Canadians to make heart-healthy choices and encourages governments and the private sector to develop policies and programs that support healthy communities and reduce inequalities that negatively affect health and well-being.

REFERENCES

  1. Statistics Canada. Canadian Vital Statistics, Death Database, 2001.
  2. Mendelsohn ME, Karas RH. The protective effects of estrogen on the cardiovascular system. New England Journal of Medicine 1999;340:1801-1811.
  3. Freedman RR. Physiology of hot flashes. American Journal of Human Biology 2001;13(4):453-64.
  4. Heart and Stroke Foundation of Canada. The Growing Burden of Heart Disease and Stroke in Canada 2003. Ottawa, Canada, 2003.
     
  5. MacPherson KI. Cardiovascular disease in women and noncontraceptive use of hormones: A feminist analysis. Advances in Nursing Science 2002;14(4):34-49.
  6. Gambacciani M, Ciaponi M, Cappagli B, Piaggesi L, De Simone L, Orlandi R, Genazzani AR. Body weight, body fat distribution and hormonal replacement therapy in early postmenopausal women. Journal of Clinical Endocrinology & Metabolism 1997;82(2):414-417.
  7. Grady D, Rubin SM, Petitti DB, Fox CS, Black D, Ettinger B, Ernster VL, Cummings SR. Hormone therapy to prevent disease and prolong life in postmenopausal women. Annals of Internal Medicine 1992;117:1016-37.
  8. Abrahmson B, Derzko C, Lalonde A, Reid R, Turek M, Wielgosz A for the members of the expert panel. Hormone Replacement therapy and cardiovascular disease. Canadian Journal of Cardiology 2002;18(7):723-724.
  9. Hulley S, Grady D, Bush T, Furberg K, Herrington D, Riggs B, Vittinghoff E for the Heart and Estrogen/Progestin Replacement Study (HERS) Research Group. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Journal of the American Medical Association 1998;280:605-613.
  10. Grady D, Herrington D, Bittner V, et al for the HERS Research Group. Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow up (HERS II). Journal of the American Medical Association 2002;288:49-57.
  11. Herrington DM, Resboussin DM, Brosnihan KB, Sharp PC, Shumaker SA, Snyder TE, et al. Effects of estrogen replacement on the progression of coronary artery atherosclerosis. New England Journal of Medicine 2000;343:522-529.
  12. Viscoli CM, Brass LM, Kernan WN, Sarrel PM, Suissa S, Horowitz RI. A clinical trial of estrogen-replacement therapy after ischemic stroke. New England Journal of Medicine 2001;345:1243-1249.
  13. Herrington DM, Reboussin DM, Brosnihan KB, Sharp PC, Shumaker S, Snyder TE, Furberg CD, Kowalchuk GJ, Stuckey TD, Rogers WJ, Given DH, Waters D. Effects of estrogen replacement on the progression of coronary-artery atherosclerosis. New England Journal of Medicine 2000;24;343(8):522-9.
  14. Manson JE and Martin KA. Postmenopausal hormone replacement therapy. New England Journal of Medicine 2001;345:34-40.
  15. Grodstein F, Manson JE, Colditz GA, Willett WC, Speizer FE, Stampfer MJ. A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease. Annals of Internal Medicine 2000;133:933-941.
  16. 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. Journal of the American Medical Association 2002;288:321-337.
  17. Anderson GL, Limacher M, Assaf AR, Bassford T, Beresford SA, Black H, et al for 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. Journal of the American Medical Association 2004;291:1701-1712.

The evidence contained in this position statement is current as of: NOVEMBER 2004

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Last updated November 2004.