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Women's Health

Postmenopausal hormone replacement therapy for primary prevention of cardiovascular and cerebrovascular disease: Recommendation statement from the Canadian Task Force on Preventive Health Care

Recommendations
• The Canadian Task Force on Preventive Health Care concludes that there is fair evidence to recommend against the use of hormone replacement therapy (HRT) for the primary prevention of myocardial infarction and death from cardiovascular disease in perimenopausal women without established coronary artery disease (CAD) (grade D recommendation). There is insufficient evidence to make a recommendation on the use of HRT for the primary prevention of stroke and death from cerebrovascular disease. However, because stroke is a major cause of morbidity and death among Canadian women, other beneficial preventive measures, such as aggressive treatment of hypertension, should be used rather than HRT.
  
• To maintain good heart health, women should be advised to adopt other effective preventive strategies, such as lifestyle changes that include increased exercise, lower fat diets, smoking cessation, and blood pressure assessment and control.
  

Coronary artery disease (CAD) is a leading cause of morbidity and death among North American women.^1,2 Each year, 4 of every 10 deaths of women in Canada,³ and up to 3.8 million days in hospital,⁴ are due to heart disease and stroke. Prevention of cardiovascular disease through modification of various risk factors (e.g., lowering of lipid levels, control of hypertension) has been shown to decrease morbidity and mortality among both men and women.⁵

A unique risk factor among older women is the hypoestrogenemic, postmenopausal state. Until recently, hormone replacement therapy (HRT) was postulated to have a role in the primary prevention of cardiovascular disease in women without established CAD. Results of early observational and cohort studies showed promise for the cardioprotective role of HRT in general. This was later tempered by the results of the HERS⁶ and ERA⁷ trials, which showed no benefit from HRT in the reduction of death or coronary events over 4 years among women with established CAD.⁶ An observational cohort study involving women at high risk of recurrent coronary events showed similar results.⁸ Large randomized trials, including the Women's Health Initiative (WHI), were designed to assess the long-term effect of various HRT regimens on CAD and non-CAD outcomes among women without a history of CAD. Initially scheduled for completion in 2005, the WHI was stopped early in July 2002, and the data regarding the use of HRT for primary prevention of cardiovascular disease and other chronic diseases is now more clear.^9,10

Manoeuvres

• Combined estrogen and progestin therapy

• Estrogen-only therapy (for women without an intact uterus)

Potential benefits

• Reduction in cardiac disease outcomes, including incidence of myocardial infarction and cardiovascular-related mortality

• Reduction in cerebrovascular disease outcomes, including stroke incidence and mortality

Potential harms

• Thromboembolic events; hypertriglyceridemia

Evidence and clinical summary
• Before the WHI, 17 studies meeting our inclusion criteria were published (1 small randomized controlled trial¹⁶ and 16 prospective cohort studies^{17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32}). Most observed lower rates of death among women using HRT than among those not using HRT, largely from a reduction in CAD. The summary relative risk of these studies has been calculated previously to be 0.5 (95% CI 0.43– 0.56)³³ and 0.65 (95% CI 0.59– 0.71).³⁴ However, the observational nature of these studies left open the question of whether certain confounding variables were at play, in particular the fact that healthier women tend to take HRT.
  
• Women in the WHI estrogen-plus-progestin trial^9,10 had an increased risk (6 more cases per 10 000)¹⁰ of nonfatal myocardial infarction and death from coronary disease. This was seen early on, within the first year of treatment, and remained elevated over the ensuing years. The WHI also found an excess risk of stroke (8 more cases per 10 000), which persisted throughout the trial, and a doubling of risk of venous thromboembolism (18 more cases per 10 000). This translates into an increased relative risk of an adverse outcome from cardiovascular disease of 22% (hazard ratio 1.22; adjusted 95% CI 1.00–1.49), or 25 more events per 10 000 person-years of HRT use (157 v. 132 events per 10 000), with a risk of early harm from acute myocardial infarction and a risk of continuing harm from stroke and venous thromboembolism with the use of this combined HRT regimen.
  
• Additional cardiovascular risks from estrogen include a 3-fold increase in thromboembolic events (about 4 per 1000 women-years)⁶ and hypertriglyceridemia.³⁵
  

Recommendations by others

Several groups have issued updated recommendations following the release of the WHI results. The US Preventive Services Task Force recommends against combination estrogen– progestin therapy on the basis of an overall balance of harms versus benefits for chronic disease prevention. It found inconclusive evidence to recommend for or against the use of unopposed estrogen for chronic disease prevention in women who have had a hysterectomy.¹¹ The Society of Obstetricians and Gynaecologists of Canada (SOGC) maintains that the best treatment for distressing menopausal symptoms is combined continuous HRT. However, it also advises that combined continuous HRT should not be recommended routinely for all postmenopausal women, as it does not appear to offer cardio-protection and the slightly increased risk of cardiovascular disease and breast cancer outweigh the benefits in asymptomatic women.¹² The Heart and Stroke Foundation of Canada, in collaboration with the Canadian Cardiovascular Society and the SOGC, states that HRT should not be initiated or continued in women for the sole purpose of preventing future cardiovascular events.¹³

The American College of Obstetricians and Gynecologists also states that HRT is no longer recommended to prevent heart disease in healthy women or to protect women with pre-existing heart disease. It goes further to state that women who take HRT for the management of menopausal symptoms should be encouraged to take it for as short a time as possible and to use the lowest effective dose.¹⁴

The North American Menopause Society, in its recent report on HRT, states that "no estrogen/progestin therapy regimen should be used for primary or secondary prevention of coronary heart disease." It also advises that the use of estrogen/ progestin therapy and unopposed estrogen therapy "should be limited to the shortest duration consistent with treatment goals, benefits, and risks for the individual woman." ¹⁵

In light of the estrogen-only arm of the WHI having recently been discontinued, these recommendations are likely to be updated in the near future.

Footnotes

Contributors: Beth Abramson authored the original systematic evidence review, drafted the current article and made subsequent revisions. The Canadian Task Force on Preventive Health Care critically reviewed the evidence and developed the recommendations according to its methodology and consensus development process.

The Canadian Task Force on Preventive Health Care is an independent panel funded through a partnership of the federal and provincial/territorial governments of Canada.

This statement is based on the technical report: "Postmenopausal hormone replacement therapy for the primary prevention of cardiovascular and cerebrovascular disease: systematic review and recommendations," by Beth L. Abramson, with the Canadian Task Force on Preventive Health Care. CTFPHC Technical Rep no 03-2. London (ON): Canadian Task Force on Preventive Health Care; 2003. [The full technical report is available from the task force at ctf{at}ctfphc.org.]

Competing Interests: None declared.

Correspondence to: Canadian Task Force on Preventive Health Care, 117–100 Collip Circle, London ON N6G 4X8; fax 519 858-5181; ctf{at}ctfphc.org

References

1. Mosca L, Manson JE, Sutherland SE, Langer RD, Manolio T, Barrett-Connor E. Cardiovascular disease in women. A statement for healthcare professionals from the American Heart Association. Circulation 1997;96:2468-82.[Free Full Text]
2. Eaker ED, Chesebro JH, Sacks FM, Wenger NK, Whisnant JP, Winston M. Cardiovascular disease in women. Circulation 1993;88:1999-2009.[Free Full Text]
3. Nault F, Wilkins K. Deaths 1993. Health Rep 1995;7:51-60.[Medline]
4. Heart and Stroke Foundation of Canada. Heart disease and stroke in Canada 1995. Ottawa: The Foundation; 1995.
5. Gotto AM Jr. Lipid lowering, regression, and coronary events. A review of the Interdisciplinary Council on Lipids and Cardiovascular Risk Intervention, Seventh Council meeting. Circulation 1995;92:646-56.[Free Full Text]
6. Hulley S, Grady D, Bush TL, Furberg CD, Herrington DM, Riggs B, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998;280:605-13.[Abstract/Free Full Text]
7. Herrington DM, Reboussin DM, Brosnihan KB, Sharp PC, Shumaker SA, Snyder TE, et al. Effects of estrogen replacement on the progression of coronary-artery atherosclerosis. N Engl J Med 2000;343(8):522-9.[Abstract/Free Full Text]
8. Grodstein F, Manson JE, Stampfer MJ. Postmenopausal hormone use and secondary prevention of coronary events in the Nurses' Health Study: a prospective, observational study. Ann Intern Med 2001;135(1):1-8.[Abstract/Free Full Text]
9. 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 2002:288:321-37.
10. Manson JE, Hsia J, Johnson KC, Rossouw JE, Assaf AR, Lasser NL, et et al; Women's Health Initiative Investigators. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med 2003;349(6):523-34.[Abstract/Free Full Text]
11. US Preventive Services Task Force. Postmenopausal hormone replacement therapy for the primary prevention of chronic conditions: recommendations and rationale. Rockville (MD): The Task Force; 2002. Available: www.ahrq.gov/clinic/3rduspstf/hrt/hrtrr.htm (accessed 2004 Mar 01).
12. Short-term HRT is a safe and effective option for the treatment of distressing menopausal symptoms: SOGC [press release]. Ottawa: Society of Obstetricians and Gynaecologists of Canada; 2004 Jan 13. Available: www.sogc.org/SOGCnet/sogc_docs/press/releases2004/pdfs/HRT_remains_safe_Jan_12_2004.pdf (accessed 2004 Apr 1).
13. Abramson BL, Derzko C, Lalonde A, Reid R, Turek M, Wielgosz A. Hormone replacement therapy and cardiovascular disease: a joint statement. Can J Cardiol 2002;18(7):723-4. See also updated statement at www.ccs.ca/download/HRT_Statement_2.pdf (accessed 2004 Apr 1).[Medline]
14. American College of Obstetricians and Gynecologists. Statement on the Estrogen plus Progestin Trial of the Women's Health Initiative [ACOG news release]. Washington: The College; 2002 July 9. Available: www.acog.org/from_home/publications/press_releases/nr07-09-02.cfm (accessed 2004 Mar 1).
15. North American Menopausal Society. Amended report from the NAMS Advisory Panel on Postmenopausal Hormone Therapy [review]. Menopause 2003;10(1):6-12.[Medline]
16. Nachtigall LE, Nachtigall RH, Nachtigall RD, Beckman ME. Estrogen replacement therapy II: a prospective study in relationship to carcinoma and cardiovascular and metabolic problems. Obstet Gynecol 1979;54:74-9.[Medline]
17. Cauley JA, Seeley DG, Browner WS, Ensrud K, Kuller LH, Lipschutz RC, et al. Estrogen replacement therapy and mortality among older women. Arch Intern Med 1997;157:2181-87.[Abstract/Free Full Text]
18. Falkeborn M, Persson I, Adami H, Bergstrom R, Eaker E, Lithell H, et al. The risk of acute myocardial infarction after oestrogen and oestrogen-progestogen replacement. Br J Obstet Gynaecol 1992;99:821-828.[Medline]
19. Falkeborn M, Persson I, Terent A, Adami H, Lithell H, Bergstrom R. Hormone replacement therapy and the risk of stroke. Arch Intern Med 1993;153:1201-9.[Abstract/Free Full Text]
20. Finucane FF, Madans JH, Bush TL, Wolf PH, Kleinman JC. Decreased risk of stroke among postmenopausal hormone users. Arch Intern Med 1993; 135: 73-9.
21. Folsom AR, Mink PJ, Sellers TA, Hong C, Zheng W, Potter JD. Hormonal replacement therapy and morbidity and mortality in a prospective study of posmenopausal women. Am J Public Health 1995;85:1128-32.[Abstract/Free Full Text]
22. Lafferty FW, Fiske ME. Postmenopausal estrogen replacement: a long-term cohort study. Am J Med 1994; 97: 66-77.[CrossRef][Medline]
23. Schairer C, Adami H, Hoover R, Persson I. Cause-specific mortality in women receiving hormone replacement therapy. Epidemiology 1997;8:59-65.[Medline]
24. Sourander L, Rajala T, Raiha I, Makinen J, Erkkola R, Helenius H. Cardiovascular and cancer morbidity and mortality and sudden cardiac death in postmenopausal women on oestrogen replacement therapy (ERY). Lancet 1998;352:1965-9.[CrossRef][Medline]
25. Sturgeon SR, Schairer C, Brinton LA, Pearson T, Hoover RN. Evidence of a healthy estrogen user survivor effect. Epidemiology 1995;6:227-31.[Medline]
26. Avila MH, Walker AM, Jick H. Use of replacement estrogens and the risk of myocardial infarction. Epidemiol 1990; 1:128-33.[Medline]
27. Bush TL, Barrett-Connor E, Cowan LD, Criqui MH, Wallace RB, Suchindran CM, et al. Cardiovascular mortality and noncontraceptive use of estrogen in women: results from the Lipid Research Clinics Program Follow-up Study. Circulation 1987;75(6):1102-9.[Abstract/Free Full Text]
28. Criqui MH, Suarez L, Barrett-Connor E, McPhillips J, Wingard DL, Garland C. Postmenopausal estrogen use and mortality. Am J Epidemiol 1988; 128:606-14.[Abstract/Free Full Text]
29. Grodstein F, Stampfer MJ, Manson JE, Colditz GA, Willett WC, Rosner B, et al. Postmenopausal estrogen and progestin use and the risk of cardiovascular disease. N Engl J Med 1996; 335: 453-61.[Abstract/Free Full Text]
30. Henderson BE, Paganini-Hill A, Ross RK. Decreased mortality in users of estrogen replacement therapy. Arch Intern Med 1991;151:75-8.[Abstract/Free Full Text]
31. Wilson PW, Garrison RJ, Castelli WP. Postmenopausal estrogen use, cigarette smoking, and cardiovascular morbidity in women over 50: the Framingham Study. N Engl J Med 1985;313:1038-43.[Abstract]
32. Wolf PH, Madans JH, Finucane FF, Higgins M, Kleinman JC. Reduction of cardiovascular disease-related mortality among postmenopausal women who use hormones: evidence from a national cohort. Am J Obstet Gynecol 1991;164:489-94.[Medline]
33. Stampfer MJ, Colditz GA. Estrogen replacement therapy and coronary heart disease: a quantitative assessment of the epidemiologic evidence. Prev Med 1991;20:47-63.[CrossRef][Medline]
34. Grady D, Rubin SM, Petitti DB, Fox CS, Black D, Ettinger B, et al. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med 1992;117:1016-37.
35. Writing Group for the PEPI Trial. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) trial. JAMA 1995;273:199-208.[Abstract/Free Full Text]

This article has been cited by other articles:

				U.S. Preventive Services Task Force* Hormone Therapy for the Prevention of Chronic Conditions in Postmenopausal Women: Recommendations from the U.S. Preventive Services Task Force Ann Intern Med, May 17, 2005; 142(10): 855 - 860. [Abstract] [Full Text] [PDF]

				C. N. Wathen, D. S. Feig, J. W. Feightner, B. L. Abramson, and A. M. Cheung Hormone replacement therapy for the primary prevention of chronic diseases: recommendation statement from the Canadian Task Force on Preventive Health Care Can. Med. Assoc. J., May 11, 2004; 170(10): 1535 - 1537. [Full Text] [PDF]

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