The SOGC Statement on the WHI Report On Estrogen and Progestin Use in Postmenopausal Women

THE

SOGe

STATEMENT ON THE

WHI

REPORT ON ESTROGEN

AND PROGESTIN USE IN POSTMENOPAUSAL WOMEN Jennifer M. Blake, MD, FRCSC,John A. Collins, MD, FRCSC, Robert L. Reid, MD, FRCSC, Donna M. Fedorkow, MD, FRCSC,Andre B. Lalonde, MD, FRCSC EXPERT REVIEW GROUP

on behalf of the SOGe jennifer M. Blake, MD, FRCSC, Toronto ON jan Christilaw,MD, FRCSC,White Rock BC john A Collins, MD, FRCSC, Mahone Bay NS Donna M. Fedorkow, MD, FRCSC, Hamilton ON Michel Fortier. MD. FRCSC. Quebec QC Claude Fortin. MD. FRCSC. Lachine QC Elaine E. jolly. MD. FRCSC. Ottawa ON Andre. B. Lalonde. MD, FRCSC, Ottawa ON Andre Lemay, MD, PhD, Quebec QC Terry O'Grady, MD, FRCSC, St john's NF Robert I. Reid, MD, FRCSC, Kingston ON Thirza E. Smith, MD, FRCSC, Saskatoon SK

with Janet Cooper, BSc(Pharm), Canadian Pharmacists Association, Ottawa ON John M. Maxted, MD, CCFP, College of Family Physicians of Canada, Mississauga ON Kathleen O'Grady, PhD(c), Canadian Women's Health Network, Montreal QC Michele ATurek, MD, FRCPC, Heart and Stroke Foundation, Ottawa ON This will serve as an update to the SOGC Guideline No. 108, Canadian Consensus on Menopause and Osteoporosis, approved by the Executive and Council of the Society of Obstetricians and Gynaecologists of Canada (SOGC).

Abstract: The recent Women's Health Initiative study report evaluated the long-term benefits and risks of hormone replacement therapy among healthy postmenopausal women. The report showed that the risk-benefit profile of continuous combined hormone replacement therapy was not consistent with the primary prevention of coronary heart disease. The Women's Health Initiative study of continuous combined hormone replacement therapy is a landmark study and the results provide valuable information for patients and clinicians. However, the most common indication for hormone replacement therapy is menopausal symptoms, for which it is effective, not prevention of disease, and the most common use is for less than three years. Nevertheless, even short-term use has small effects on some outcomes. This statement discusses how the findings of the Women's Health Initiative study can be applied to reach appropriate clinical decisions.

J Obstet

Gynaecol Can 2002;24( I 0):783-7.

Key Words Hormone replacement therapy, coronary heart disease, breast cancer, venous thromboembolism, fracture, colon cancer

JOGC •

The Society of Obstetricians and Gynaecologists of Canada (SOGC) has brought together an advisory committee made up of nationaJ experts on menopause to assist the SOGC in reviewing the findings of the Women's HeaJth Initiative (WHI) study, one arm of which was haJted on July 9, 2002. This WHI study arm was designed to define the risks and benefits of the estrogen-progestin combination, conjugated equine estrogen (0.625 mg/d) and medroxyprogesterone acetate (2.5 mg/d) administered in continuous combined fashion in healthy postmenopausal women with a uterus. Primary outcomes were coronary heart disease (CHD) and breast cancer. Secondary outcomes were stroke, venous thromboembolism (VTE), osteoporotic fractures, and colorectaJ cancer. The study excluded women with severe menopausaJ symptoms and enrolled women up to age 79 as long as they were healthy. The average age at entry of the women in the study was 63.2 years old. The age breakdown for this study was as follows: 33% of women were 50-59 years of age, 45% were 60-69 years, 21 % were 70-79 years. The safery monitoring board of the WHI recommended premature cessation of the combination Premarin/Provera arm in June of 2002 because OCTOBER 2002

the risks of breast cancer and cardiovascular disease, although small, outweighed potential benefits (reduced incidence of osteoporotic fracture and possibly of colorectal cancer) in these asymptomatic subjects. The authors concluded that continuous combined hormone replacement therapy (HRT) was not effective for the primary prevention of heart disease. Extensive reporting of the WHI findings in the media has resulted in confusion and uncertainty about the appropriate use of, and appropriate counselling regarding, continuous combined HRT. The SOGC has prepared the following statement to assist health care professionals in counselling menopausal women about health promotion and disease prevention in the postmenopausal years. This statement is restricted to comments on the recent WHI publication regarding cessation of the estrogen-progestin arm of the WHI study. 1 The estrogen-only arm of the WHI for women who have undergone a hysterectomy is continuing and information on risks and benefits in this population has not yet been released. Important lifestyle approaches to health promotion as well as alternative therapies have been reviewed recently by the SOGC and other professional bodies and are discussed in the Canadian Consensus on Menopause and Osteoporosis document available on-line at . OVERVIEW OF WHI STUDY RESULTS

The main findings of the WHI study are shown in the Table. 1. Continuous combined HRT was not effective in preventing cardiovascular disease, and slightly increased the risk of CHD (7 excess CHD cases per 10,000 women per year). 2. Women who took continuous combined HRT had an increased incidence of stroke (8 excess cases per 10,000 women per year). 3. Incidence ofVTE and pulmonary embolism increased from 0.12% to 0.2% (18 excess cases per 10,000 women per year).

4. The risk of breast cancer increased in women who used continuous combined HRT for five years or more (8 excess cases per 10,000 women per year or less than 0.1 % increase per year of use). 5. Continuous combined HRT reduced the risk of hip fractures (5 fewer cases per 10,000 women per year); vertebral and other osteoporotic fractures were also reduced. 6. Continuous combined HRT was associated with a reduction in the risk of colorectal cancer, which failed to reach statistical significance (6 fewer cases per 10,000 women per year). SOGe'S ANALYSIS OF STUDY RESULTS

The Women's Health Initiative is a landmark study providing critical information on a variety of endpoints relating to the risks and benefits of hormone replacement therapy. It is the largest randomized placebo-controlled clinical trial on hormone replacement therapy. Every study has its limitations and the WHI study is no exception. The study did not attempt to quantify quality of life variables related to the use of HRT for control of menopausal symptoms, but rather it examined whether HRT should be given to most menopausal women for prevention of cardiovascular disease and osteoporosis. When interpreted in this context, the WHI report provides important, meaningful information about HRT for individual women, their health care providers, and public health officials. CORONARY HEART DISEASE

The WHI has shown that continuous combined HRT should not be used for the primary prevention of coronary heart disease in a healthy population of largely asymptomatic women spanning the three decades after menopause. In fact, the use of continuous combined HRT in this population was associated with a small but significant risk of adverse cardiovascular events.

ATTRIBUTABLE RISKS FOR DAILY CONTINUOUS COMBINED HRT FROM WHI TRIAL

Total Women: CHD Stroke VTE Osteoporotic fractures Cancers: Invasive breast Colorectal Endometrial

Continuous combined HRT

Placebo

8506 164 127 151 650

8102 122 85 67 788

+7 +8 +18 -5

166 45 22

124 67 25

+8 -6 0

JOGC •

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HRT attributable cases per I 0,000 women per year

-

Deaths due to cardiac disease were equivalent (15 and 13 per 10,000 woman-years in estrogen-progestin and placebo respectively). At present, in the absence of any evidence of cardiovascular protection from continuous combined HRT in clinical trials, primary prevention of coronary heart disease depends on healthy lifestyle choices (smoking cessation, exercise, weight control) and pharmaceutical agents with established value for prevention or treatment of cardiovascular disease, such as lipidlowering agents and anti-hypertensive agents. The WHI investigators deliberately chose not to enrol acutely symptomatic women and, as a result, only one-third of the subjects entered the trial before the age of 59. To date, data published on the 2,839 continuous combined HRT users between the ages of 50 and 59 do not allow definitive conclusions about CHD risks and benefits of continuous combined HRT if started immediately at menopause. Whether the absolute risks reported by the WHI for women from age 50 to 79 apply to symptomatic women in their late forties or early fifties is doubtful; however, these numbers based on a large prospective trial can assist with counselling about risks for symptomatic women who will elect to use HRT. The risks of non-fatal heart attack and stroke reported by the WHI amount to less than 0.1 % per year of use for each of these events. Rates of deep vein thrombosis/pulmonary embolism, which rise with increasing age, doubled from approximately 0.1 % per year to 0.2% per year.

cer, so that the total duration of continuous combined HRT use before any increase in the risk of breast cancer was in excess of four years. Frequency of surveillance by mammography was equivalent in both groups. Because there was no significant increase in in situ cancers, it is uncertain whether the reported risk in invasive breast cancer detection in continuous combined HRT users was due to more formation of new cancers. Continuous combined HRT could mediate facilitation ofearly diagnosis of pre-existing cancers or hasten pre-clinical to clinical conversion. In an older population such as that in the WHI study, more pre-existing breast cancer might reasonably be expected. Subgroup analysis by age is critical to understand the attributable risks. The effect from duration of use was virtually the same as the duration effect indicated by the Collaborative Reanalysis published in 1997. 2 Breast cancer risk in the Collaborative study was statistically significantly elevated after five years of use. Figure 1 displays some of the risks for breast cancer, to place them in perspective.

NEW INFORMATION ABOUT STROKE

HOW SHOULD THE WHI STUDY RESULTS

The previous evidence about continuous combined HRT use and stoke was based on numerous epidemiological studies with inconsistent stroke endpoints and definitions of continuous combined HRT use. In considering the results of the WHI it is important to remember that two-thirds of the study population were over 60 years of age. Although the WHI reported that continuous combined HRT appeared to increase the incidence of non-fatal stroke, the absolute risk was very small and not statistically significant after adjusting for multiple testing. The characteristics of the patients who are at greatest risk of stroke may become clear as the investigators continue their evaluation with more explanatory analyses.

BE APPLIED TO INDMDUAL PATIENTS?

BREAST CANCER

Continuous combined HRT was associated with an increase in the incidence of invasive breast cancer. The magnitude of this risk for individual women was very small-less than 0.1 % per year of use (8 more cases per 10,000 women per year) and similar to the risk estimates in previous epidemiological studies. 2-4 A meaningful finding of the WHI study is that breast cancer risk was not significantly increased during use of continuous combined HRT for up to four years. Only women who had used continuous combined HRT prior to enrolment in the WHI study showed this increased incidence of breast canlOGC •

NEW INFORMATION ABOUT OSTEOPOROTIC FRACTURES

The WHI study was the first large continuous combined HRT clinical trial to confirm a reduction in osteoporotic fracture incidence. Accordingly, women who choose to use continuous combined HRT can anticipate protection from osteoporotic fractures.

Further analysis of the WHI results will help to determine the specific risk factors that may be useful to individualize the application of these results. Although more than two-thirds of the women in the WHI study were over 60 years of age, there were 5,522 women aged 50 to 60 years, more than in any previous study and more than the sum of patients in nearly all previous randomized controlled trials. More in-depth analysis of the WHI study will be likely to provide useful information about the baseline risk of cardiovascular disease and cancer in women aged 50 to 59. There are lower baseline risks for thromboembolism, stroke, myocardial infarction, and breast cancer in a younger population since each of these risks increases with age. 5,6 ARE THE RESULTS APPLICABLE TO OTHER FORMSI REGIMENS OF CONTINUOUS COMBINED HRT?

The results of the WHI study do not give any indication of the effects of other hormone doses, routes of administration, formulations, or the use of progestins alone. There are theoretical reasons why different formulations might have different biological effects or greater safety, but there are no data from large clinical trials to support recommendations at this time. OCTOBER 2002

14 / • 2 affected relatives I affected relative obesity young menarche • HRT >S years In child age >30 menopause <49

12/ 10/ 8/

RR

6/

4/ 2/ 0

Risk category Figure I: Relative Risks of Breast Cancer. The greatest single risk factor, after gender and advancing age, is the presence of two or more affected first order relatives. There are a number of commonly experienced risks, including being 20% overweight, delaying childbirth until 30 or older, consuming three glasses of alcohol daily, and lack of regular exercise. Long-term use of continuous combined HRT is of comparable magnitude to this group of risk factors. These risks do not appear to be additive. In the WHI the Gail model for computing and predicting risk of breast cancer did not identify women who were at higher risk for a diagnosis of invasive breast cancer. Any risk below I is protective (Le., menopause before 49).

Lower dosage and alternative delivery methods are promising options, but adverse event profiles for these approaches have not been determined in studies involving large numbers of women.

plasia or cancer; if unopposed estrogen is prescribed, it must be accompanied by rigorous endometrial surveillance. ARE THESE RESULTS APPLICABLE TO WOMEN WITH PREMATURE MENOPAUSE?

There is no basis from the WHI results to modify the treatment recommendations for prematurely menopausal women.

HOW LONG SHOULD WOMEN CONTINUE COMBINATION ESTROGEN-PROGESTIN?

Women taking continuous combined HRT for the relief of menopausal symptoms will generally find vasomotor symptoms spontaneously ease within two or three years. Women who are using continuous combined HRT for ongoing symptom relief should re-assess their medication and the route and dosage on a regular basis with their physicians, considering potential risks and benefits, as well as effective alternatives. Further analysis of the younger subgroup of this study may help to redefine riskbenefit estimates. WOMEN TAKING ESTROGEN ONLY

HOW TO STOP CONTINUOUS COMBINED HRT

There is no scientific basis for counselling women on how to stop continuous combined HRT. Practically, women can decrease the dose slowly or use continuous combined HRT on alternate days for a period of several weeks. Women reducing or stopping continuous combined HRT should be advised to anticipate a withdrawal bleed. Physicians may discuss alternate therapies, routes of administration, and different continuous combined HRT combinations.

(POST-HYSTERECTOMy)

The arm of the WHI study of estrogen-only use in women who had previously undergone hysterectomy is continuing. The riskbenefit profile has not been determined for these women. Women who plan to take estrogen-only therapy should undergo standard breast health monitoring. In the absence of data, it is prudent to use the lowest effective dose and duration of estrogen for the treatment objectives. Unopposed estrogen is not recommended for women with a uterus because of the risk of endometrial hyperJOGC •

INFORMED CHOICE

The SOGe recommends that women discuss these issues with their health professional so they can make an informed choice about continuous combined HRT for menopausal symptoms. Figure 2 is a guide for physicians in discussions about risks/benefits/potential harm with their patients.

OCTOBER 2002

FIGURE 2

WHI HRT Study - Effect of HRT on Event Rates ~

S 60

"'~

Risk*

Benefits*

dQ.. so a>~ "'QI

'-c OQl

Additional Events 18 8 8 40 7

~~

30

~E a>O

i§

20

.5

10

0

Reduced Events

Neutral Estrogen + Progestin

o Placebo

5

0 Uncer

'Statistically significant based on 95% nominal Cion hazard ratios. Adapted and printed with permission from Women's Health Initiative, WHI HRT Update. Available at .

CONCLUSION

3.

The best treatment for distressing menopausal symptoms is continuous combined HRT. Alternative therapies are limited in their effectiveness and safety has not been tested in large-scale trials like the WHI study. Continuous combined HRT should not be recommended routinely for all postmenopausal women, as it does not appear to offer cardiovascular protection and the slightly increased risk of CHD and breast cancer outweigh the benefits in asymptomatic women. Short-term use remains an option for osteoporosis prevention, and may be considered in conjunction with benefits, risks, tolerability, and the costs of alternatives. The SOGC has revised its 2000-2001 Consensus document on menopause and osteoporosis? The revised document is available on-line at , and a summary of the modified recommendations are found in the appendix below.

4.

5.

6.

7.

Schairer C, Lubin J,Troisi R, Sturgeon S, Brinton LA, Hoover R. Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk. JAm Med Assoc 2000;283(4):485-91. Ross RK, Paganini-Hill A,Wan PC, Pike Me. Effect of hormone replacement therapy on breast cancer risk: estrogen versus estrogen plus progestin.J Nat! Cancer Inst 2000;92(4):328-32. Farley TMM. Collins JA, Schlesselman JJ. Hormonal contraception and risk of cardiovascular disease: an international perspective. Contraception 1998;57:211-30. Ries LAG, Eisner MP, Kosary CL, Hankey BF, Miller BA, Edwards BK. SEER Cancer Statistics Review, 1973-1998. Bethesda, MD: National Cancer Institute; 200 I. The Canadian Consensus Conference on Menopause and Osteoporosis 20001200 I. September-December 200 I. J Obstet Gynaecol Can 200 I;23(9):829-35. 836-41. 842-48. 849-52; 23( I0):966-72. 973-7.978-88;23(11):1096-1101.1102-4,1105-14; 23( 12): 1198-1203, 1204-13, 1214-20.

REFERENCES I.

2.

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.JAm MedAssoc 2002;288:321-33. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52 705 women with breast cancer and 108 41 I women without breast cancer. Lancet 1997;350: 1047-59.

JOGC

OCTOBER 2002