Case Study 11: Hormone Replacement Therapy

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Case Study 11:

Hormone Replacement

Therapy

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Scenario

Ann McDonnald is a successful 55 year old business executive. She starts her first consult with you by saying. “I’m getting hot flushes. It’s only a hormone transition and I’m strong, I got through puberty so I can get through the menopause. But a friend has suggested I take HRT for prevention. I had a small heart attack last year but my angina is OK now. My mother aged 80 is making a good recovery from a fractured hip. My father died of a heart attack at 45. One of my cousins aged 50 has just been diagnosed with breast cancer which has deeply upset the whole family. I have read conflicting reports that HRT may do good or harm. Doctor what do you think? How sure are you?”

Inside

Summary page 3

Results & Expert commentary

Dr Peter Mansfield and Professor Paul Glasziou page 4

Fractures page 5

Cardiovascular events page 7

Deep venous thrombosis and pulmonary embolism page 11

Breast cancer page 13

Gallbladder disease page 15

Options recommended for Ann page 17

Appendix page 20

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Summary

Ann is a 55 year old woman with a past history of a myocardial infarction who has hot flushes but does not want treatment for them. She requested information about

whether hormone replacement therapy (HRT) is beneficial or harmful for life threatening events such as fractures, heart attacks and breast cancer.

The respondents were asked about their certainty regarding whether use of HRT is likely to increase or decrease Ann’s risk of fractures, cardiovascular events, breast cancer, thromboembolism, and gallbladder disease. The level of certainty was measured on a scale of ‘completely unknown’, ‘very uncertain’, ‘probably known’, ‘very certain’ and ‘completely certain’. Most respondents were ‘very certain’ that HRT has an effect on the risk of fractures, thromboembolism and breast cancer whereas the experts considered these risks as ‘probably known’ and ‘very uncertain’ based on the currently available evidence. Most respondents also considered that evidence was ‘very uncertain’ for the risk of a cardiovascular event and gallbladder disease which was consistent with experts’ comments.

The respondents were also asked to indicate their knowledge of harmful or beneficial effects of HRT on the risk of fractures, cardiovascular events, breast cancer,

thromboembolism, and gallbladder disease. The level of harm or benefit was

measured on a scale from ‘extremely harmful’ to ‘extremely beneficial’. The majority of respondents indicated that HRT was likely to offer a ‘neutral benefit’ to ‘mildly harmful’ in prevention of a cardiovascular event, thromboembolism, breast cancer and gallbladder disease whereas the experts stated HRT to be ‘mildly harmful’ to ‘very harmful’. In terms of risk of fractures, both the respondents and the experts agreed HRT is ‘mildly beneficial’ to ‘very beneficial’.

The experts consider that on balance, the risks of harm from HRT outweigh the uncertain benefits for Ann. They also raised concerns that the use of HRT may be harmful by diverting attention from more beneficial interventions. Their

recommendations for management supported by strong evidence include a

Mediterranean diet, aspirin, and a beta-blocker. If Ann can find a physical activity that she enjoys then it would be worthwhile. The use of a “statin” was also suggested if Ann’s total cholesterol level was >5 mmol/L.

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Results & Expert commentary

Dr Peter Mansfield

General Practitioner (Aldinga Beach, South Australia)

Director, MaLAM (Medical Lobby for Appropriate Marketing)

Professor Paul Glasziou

School of Population Health, University of Queensland

This case study is designed to enable you to compare your responses to the case study with other participating GPs and with our efforts to provide evidence-based feedback. There are no clear correct answers because the interpretation of the options given is subjective. We would be happy with any answers near ours. One of us wrote the case scenario and questions. We were not authors of any other part of NPS News 12: Hormone Replacement Therapy.

Some doctors believe that the menopause is a disease like thyroid failure that always requires “replacement” therapy. Others believe that the menopause is a normal life transition like puberty. Therapy recommendations should be based on evidence about whether or not benefit exceeds harm regardless of such personal beliefs. We consider the term “Hormone Replacement Therapy” is a promotional rather than a neutral name for postmenopausal oestrogen and progestogen.1_{However we will use the term}

HRT for consistency with NPS publications.

Australian doctors have received conflicting messages about HRT. Important new results were published during 2000 without much publicity. The case scenario and questions were based on the HERS trial because it is the largest randomised controlled trial of HRT published so far.2_{HRT is effective for menopausal symptoms. However,}

we chose to focus on the outcomes measured in the HERS trial such as prevention of fractures, cardiovascular disease and breast cancer rather than the impact of HRT on menopausal symptoms. There has been controversy about how to interpret the findings of the HERS trial. Consequently it is no surprise that the responses to this case study include a wide range of views. Differing beliefs often result from different ways of reaching conclusions. For the benefit of GPs with a special interest in HRT and/or evidence based medicine we will explain the approach that we have used to evaluate the evidence and discuss some of the controversy about the HERS trial in the Appendix.

1. National Women’s Health Network. Taking Hormones & Women’s Health. 5th edition 2000. Available from: URL: http://www.womenshealthnetwork.org

2. Hulley S, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998;280(7):605-13.

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Fractures

Results:

45% of 1155 respondents indicated that the impact of HRT on increasing or decreasing the risk of fractures was very certain.

.

Percentage of respondents

Level of certainty re fractures

. . 10 20 30 40 1155 respondents completely unknown very uncertain probably known very certain completely certain

58% of 1153 respondents indicated that regarding fractures, HRT was likely to be very beneficial.

.

Fractures: harm or benefit

. . 20 40 60 1153 respondents mild harm neutral mild benefit very benefit extreme benefit

There was a significant positive correlation between respondent’s level of certainty and their estimate of benefit. (Spearman’s rho = 0.563, P<0.0001) In other words, those who felt more certain were more likely to believe that HRT had a beneficial effect on fracture rates.

3. Spearman’s rho: 0 = no correlation, +1 = 100% “straight line” correlation where if A increases then B increases, -1 = 100% “straight line” correlation where if A increases then B decreases.

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Our comment:

The impact of HRT on fracture rates is probably known and may be mildly beneficial.

Explanation:

All of the evidence from randomised controlled trials (RCT) is consistent with the belief that long term HRT reduces fracture risk but the benefit may be small. One RCT has suggested that in women with established osteoporosis, HRT may reduce the rate of lower vertebral fractures.4 However, hip fractures are more important for patients. We are not aware of any direct evidence from RCTs of a reduction in hip fractures from HRT even in women with osteoporosis.

Benefit is harder to demonstrate in those without established osteoporosis. Reports of two trials of HRT for women without osteoporosis claim lower rates of non-vertebral fractures of borderline statistical significance. However the first of these trials used questionable statistical “adjustments”.5 The second trial found significantly less

forearm fractures in the HRT group but there was no significant difference in the total number of fractures.6 Most of the participants in this trial were not randomised and there was no placebo so the results are not reliable. The HERS trial is the largest completed trial of HRT. It found no significant difference in the rate of fractures.7 Ten percent of women in the placebo group had fractures vs 9.4% in the HRT group (P = 0.7).

HRT does reduce loss of bone density.8 However, bone density is only a modest predictor of who is or is not at high risk of fractures, as shown in the graph below.9 We should also remember that fractures result from many causes and bone density is just one factor along with balance, environment, sedating medications, etc.

Bone density is not a good test for distinguishing between high and low fracture risk because there is so much overlap between the curves for women who will have hip fractures versus those who will not.9

4. Lufkin EG, et al. Treatment of postmenopausal osteoporosis with transdermal estrogen. Ann Intern Med 1992; 117(1):1-9.

5. Komulainen MH, et al. HRT and Vit D in prevention of non-vertebral fractures in postmenopausal women; a 5 year randomized trial. Maturitas 1998;31(1):45-54.

6. Mosekilde L, et al. Hormonal replacement therapy reduces forearm fracture incidence in recent postmenopausal women - results of the Danish osteoporosis prevention study. Maturitas 2000;36(3):181-93.

8. Lindsay R, Hart DM, Forrest C, Baird C. Prevention of spinal osteoporosis in oophorectomised women. Lancet 1980;2:1151-1153.

9. Green CJ, et al. Bone Mineral Density Testing: does the evidence support its selective use in well women. BCOHTA 97:2T, Vancouver, Dec 1997 www.chspr.ubc.ca

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Cardiovascular events

Results:

44% of 1154 respondents indicated that the impact of HRT on increasing or decreasing the risk of cardiovascular events was probably known.

.

Level of certainty re CV events

48% of respondents indicated that regarding cardiovascular events, HRT was likely to be neutral in terms of benefit or harm.

.

CV events: harm or benefit

. . 20 40 60 1151 respondents extreme harm very harm mild harm neutral mild benefit very benefit extreme benefit

There was a significant positive correlation between respondent’s level of certainty and their estimate of benefit. (Spearman’s rho = 0.26, P<0.0001) In other words, those who felt more certain were more likely to believe that HRT had a beneficial effect on cardiovascular event rates.

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Our comment:

The impact of HRT on cardiovascular events is very uncertain in this patient but may be very harmful in the short term but neutral for survivors in the medium term.

Explanation:

The hypothesis raised by observational studies that using surrogate measures such as cholesterol that HRT would have cardiovascular benefits has been overturned by recent RCT results.10

We have identified four sources of RCT data. Ann has had a myocardial infarction so the first two studies listed below are most relevant for her. The last two are more relevant for women who do not have coronary disease.

1. The HERS trial (August 1998) compared 4.1 years of conjugated equine oestrogen plus medroxyprogesterone acetate (n=1380) vs placebo (n=1383) for postmenopausal US women aged 55 to 79 years with pre-existing coronary disease. 11 The primary research question for the trial was: Does HRT reduce cardiovascular events (coronary deaths plus non-fatal myocardial infarction)?

There was no significant difference in the rate of coronary deaths plus non-fatal myocardial infarction at 4.1 years (12.7% in the placebo group vs 12.5% in the HRT group, P = 0.99).

However there were significantly more coronary deaths plus non-fatal myocardial infarctions in the HRT group at one year (2.7% in the placebo group vs 4.1% in the HRT group, P = 0.046) but this difference became non-significant after the first year.

10. Blakely JA. The Heart and Estrogen/Progestin Replacement Study revisited: Hormone replacement therapy produced net harm, consistent with the observational data. Arch Intern Med 2000;160:2897-2900.

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The graph below shows a trend for more non-fatal myocardial infarcts initially in the HRT group but that trend disappeared after the third year. Please note that after 4.1 years the numbers of women followed drops to 113 so the suggestion of a late trend for benefit is not reliable.

---Placebo

____{Oestrogen-Progestogen}

Follow-up in years (no. remaining in trial)

Incidence of non-fatal myocardial infarction in the HERS trial

The graph below shows a trend for more coronary deaths in the HRT group that did not disappear with time. One interpretation of the two graphs is that some women on HRT had fatal infarcts rather than the non-fatal infarcts they would have had on placebo.

--- Placebo

____{Oestrogen-Progestogen}

Follow-up in years (no. remaining in trial)

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2. The ERA trial(August 2000) compared 3.2 years of treatment with oestrogen plus progestogen (n=104) vs oestrogen alone (n=100) vs placebo (n=105) for

postmenopausal US women aged 42 to 80 with pre-existing coronary disease. 12 There was no significant difference in the progression of coronary atherosclerosis.

3. The Hemminki and McPhersonstudy(February 2000) pooled data from 28 RCTs that compared HRT (n=2206) vs a comparator (n=1278) for up to three years.13 The aim was to support or question the reduced rate of cardiovascular events on HRT seen in observational studies.14

The pooled data showed an increased rate of cardiovascular events on HRT (odds ratio 1.78, 95% confidence interval 0.7-4.52) that was not statistically significant. This could be because the difference was only due to chance, inadequate reporting of adverse events or the low frequency of the adverse events. However the findings do suggest that the chance of positive benefit seen in observational studies being correct is very small (3 in 100). This result suggests that the findings of the observational studies arise from confounding e.g. the “healthy woman effect” (see Appendix).

4. The ongoing Women’s Health Initiative trial is comparing oestrogen plus progestogen or oestrogen alone for women without a uterus (n>13550) vs placebo (n>13550) for healthy postmenopausal US women aged 55 to 79.

In April 2000 the investigators informed the participants that “during the first two years there was a small increase in the number of heart attacks, strokes, and blood clots in women taking active hormones compared to inactive (placebo) pills. Over time, these differences seem to get smaller… ”15

Events occurred in “less than 1%” of women and the difference did not reach

statistical significance16 so it may be only due to chance. However in healthy women, if the difference is real, then even infrequent harm may be clinically important if it is severe e.g. heart attacks, strokes and pulmonary emboli.

Conclusions:

Current RCT evidence is consistent with initial cardiovascular harm during the first one or two years. The harm is not frequent but is severe. There is still uncertainty but it appears that harm is more likely for those like Ann who are already at higher risk. The available evidence suggests that there is no cardiovascular benefit during three to four years of HRT. Any benefit after that would have to be very large to make up for the initial harm.

12. Herrington DM, et al, Effects of Estrogen Replacement on the Progression of Coronary-Artery Atherosclerosis. New Engl J Med 2000;343(8):522-9.

13. Hemminki E, McPherson K. Value of drug-licensing documents in studying the effect of postmenopausal hormone therapy on cardiovascular disease. Lancet 2000;355:566-9.

14. Barrett-Connor E, Grady D. Hormone replacement therapy, heart disease, and other considerations. Annu Rev Public Health 1998;19:55-72.

15. URL:http://www.nhlbi.nih.gov/whi/index.html

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Deep venous thrombosis and pulmonary embolism

Results:

56% of 1153 respondents indicated that the impact of HRT on increasing or

decreasing the risk of deep venous thrombosis (DVT) and pulmonary embolism (PE) was very certain.

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Level of certainty re Thromboembolism

. . 20 40 60 1153 respondents completely unknown very uncertain probably known very certain completely certain

74% of 1153 respondents indicated that regarding DVT and PE, HRT was likely to be mildly harmful.

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Thromboembolism: harm or benefit

. . 20 40 60 80 1153 respondents extreme harm very harm mild harm neutral mild benefit very benefit extreme benefit

There was a significant negative correlation between respondent’s level of certainty and their estimate of benefit. (Spearman’s rho = -0.32, P<0.0001) In other words, those who felt more certain were more likely to believe that HRT had a harmful effect on thromboembolic rates.

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Our comment:

The impact of HRT on DVT and PE is very certain and is very harmful.

Explanation:

Again the HERS trial provides the best evidence that is relevant for Ann.17 In the HERS trial the rate of DVT plus PE was 0.87% in the placebo group vs 2.5% in the HRT group (P = 0.004).

Results from the ERA trial and the Hemminki and McPherson study show trends for more thromboembolism but the findings were not statistically significant. As

mentioned above, a trend for harm has been seen in the early results from the Women’s Health Initiative trial also.

Four observational studies have found similar results with relative risks ranging from 2.1- 6.9 (from twice as often to almost seven times as often).18 Differences seen in any observational study may be due to confounding but the fact that RCT data are

consistent increases confidence that the observed harm really is caused by HRT.

17. Grady D et al. Postmenopausal hormone therapy increases risk for venous thromboembolic disease. The Heart and Estrogen/progestin Replacement Study. Ann Intern Med 2000;132(9):689-96.

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Breast cancer

Results:

41% of 1152 respondents indicated that the impact of HRT on increasing or decreasing the risk of breast cancer was very certain.

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Level of certainty re breast cancer

79% of 1148 respondents indicated that regarding breast cancer, HRT was likely to be mildly harmful.

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Breast cancer: harm or benefit

. . 20 40 60 80 1148 respondents extreme harm very harm mild harm neutral mild benefit very benefit extreme benefit

There was a significant negative correlation between respondent’s level of certainty and their estimate of benefit. (Spearman’s rho = -0.36, P<0.0001) In other words, those who felt more certain were more likely to believe that HRT had a harmful effect on breast cancer rates.

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Our comment:

The impact of HRT on breast cancer is very uncertain but could be very harmful.

Explanation:

In the HERS trial the rate of breast cancer was 1.8% in the placebo group vs 2.3% in the HRT group (P = 0.33). Results from ERA are consistent with this but in both studies the numbers were too small to have the power to detect statistically significant differences.

A reanalysis of 90% of the relevant observational studies found that the risk of having breast cancer diagnosed is increased in women using HRT and increases with

increasing duration of use. The relative risk for women who used HRT for five years or more is 1.35 (95% confidence interval 1.21-1.49). This effect is reduced after cessation of use of HRT and largely, if not completely, disappears after about five years.19 The relationship between increased risk per year of HRT and per year of delayed menopause is very similar.20 On the other hand some observational studies have suggested that breast cancer mortality is unchanged or lower in women using

HRT.21, 22 For all these studies the general rule that any observational finding could be

due to confounding also applies here.

Ann has indicated that she may be particularly concerned about this risk because of her family history. Having a mother or sister who had breast cancer doubles the lifetime absolute risk from the normal average of 8% to 16%. However, having a cousin with breast cancer would only increase Ann’s risk by 1.5 times normal i.e.

12%23, 24 In fact her risk of breast cancer is even less because her history of a

myocardial infarct leads to a higher risk of premature death from heart disease. Many women who have a second degree relative with breast cancer fear that their own risk of breast cancer is higher than it really is. Consequently, Ann may feel reassured by being told that her absolute risk is less than 12% and mammography is beneficial.25 Whether or not Ann’s family history of breast cancer would make HRT more dangerous for her than for women without such a family history is not known.

19. 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 108,411 women without breast cancer. Lancet 1997;350(9084):1047-59.

20. Willett WC, et al. Postmenopausal estrogens: opposed, unopposed, or none of the above. JAMA 2000;283(4):534-5.

21. Yuen J, et al. Hormone replacement therapy and breast cancer mortality in Swedish women: results after adjustment for 'healthy drug-user' effect. Cancer Causes Control 1993;4(4):369-74.

22. Jernstrom H, etal. Hormone replacement therapy before breast cancer diagnosis significantly reduces the overall death rate compared with never-use among 984 breast cancer patients. Br J Cancer 1999;80(9):1453-8. 23. Taylor R, et al. Absolute risk of breast cancer for Australian women with a family history. Aust N Z J Surg 2000 ;70(10):725-31.

24. Pharoah PD, et al. Family history and the risk of breast cancer: a systematic review and meta-analysis. Int J Cancer 1997;71(5):800-9.

25. Larsson LG, et al. The Swedish randomised mammography screening trials: analysis of their effect on the breast cancer related excess mortality. J Med Screen 1996;3(3):129-32.

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Gallbladder disease

Results:

36% of 1140 respondents indicated that the impact of HRT on increasing or decreasing the risk of gallbladder disease was very uncertain.

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Level of certainty re Gallbladder Disease

63% of 1139 respondents indicated that regarding gallbladder disease, HRT was likely to be neutral.

.

Gallbladder disease: harm or benefit

. . 20 40 60 1139 respondents extreme harm very harm mild harm neutral mild benefit very benefit extreme benefit

There was a significant negative correlation between respondent’s level of certainty and their estimate of benefit. (Spearman’s rho = -0.51, P<0.0001) In other words, those who felt more certain were more likely to believe that HRT had a harmful effect on gallbladder disease rates.

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Our comment:

The impact of HRT on gallbladder disease is very uncertain but may be mildly harmful.

Explanation:

In the HERS trial the rate of gallbladder disease was 4.5% in the placebo group vs 6.1% in the HRT group (P = 0.05). Results from ERA are consistent with this but the numbers were too small to have the power to show statistical significance if it exists. The possibility that the difference seen in the HERS trial was only due to chance should be taken seriously because the significance is borderline and so it needs to be verified in other trials. Also if trials measure many secondary endpoints then 5% of the endpoints will have differences of borderline significance (around P = 0.05) just by chance alone. Gallbladder disease is usually not fatal but can be severe.

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Options recommended for Ann

The percentages of respondents who indicated that they would recommend the options listed in the case study were, in order of popularity:

Recommended options Percentage respondents

Physical activity 99 Aspirin 82 HRT 62 Mediterranean diet 58 Beta-blocker 41 “Statin” 41 ACE inhibitor 22 Isoflavins 21

Traditional Japanese diet 16

The three most important issues for Ann were the impact of HRT on the risks of fractures, future myocardial infarction and breast cancer. Yet standard statistical tests show consideration of these factors influenced on 70% of doctors’ decisions.26 Other factors unknown to us were influential in the remainder of decisions.

Most respondents wanted more information before making recommendations. Many commented that their recommendation for “statins”, ACE inhibitors and HRT would depend on Ann’s LDL cholesterol, blood pressure and bone density test results respectively. Respondents also wanted to check on smoking, alcohol, caffeine, calcium, diabetes, screening mammograms and cervical cytology.

Some respondents commented that they would inform Ann about the “pros and cons” of HRT to enable her to make her own decision. However it is clear that different doctors would tell Ann quite different things about the “pros and cons” of HRT.

Our comment:

We would recommend a Mediterranean diet with canola oil margarine, aspirin, and a beta-blocker. If Ann’s total cholesterol level was >5 mmol/L we would also

recommend a “statin”. We would recommend physical activity if Ann could find an activity that she enjoyed.

Explanation:

The challenge is to get the right balance of RCT evidence, observational evidence, clinical experience and understanding of the unique individual patient so as to provide the best advice. Ideally we would like to see at least two RCTs involving large

numbers of women like Ann who have had a myocardial infarct. In the case of diet and physical activity alone few trials have been done.

One RCT, the Lyon heart diet study, has shown large benefit from a “Mediterranean” diet (more bread, more vegetables, more fruit, more fish, less meat and canola oil margarine instead of alternatives) although the report did not mention how many women participated.27 Observational evidence from the Nurses Health Study supports the belief that good diets are very beneficial for women.28 It can be difficult to

26. Logit multiple regression equation. Intercooled Stata 6.0

27. de Lorgeril M, et al. Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction: final report of the Lyon Diet Heart Study. Circulation 1999;99(6):779-85.

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improve diet and physical activity levels if patients are not motivated. However the results of the Lyon heart diet trial suggest that if patients are motivated (e.g. by personal experience of a myocardial infarct) then benefits can be achieved with lifestyle changes that rival those that could be expected with medication. We could not find any trials of exercise alone post myocardial infarction but four RCTs have found that cardiac rehabilitation that includes physical activity is

beneficial.29, 30, 31, 32 The Nurses Health Study (an observational study) also supports the belief that physical activity may be very beneficial for women.33 We feel that this evidence is not strong enough to justify recommending that Ann spend a lot of time on physical activities if she does not enjoy it. However if she can find an activity that she enjoys then the benefits (including enjoyment) are very likely to justify the time spent.

Meta-analyses of many trials involving men and women have found that aspirin34, 35 and beta-blockers 36 are beneficial post myocardial infarction.

RCTs have shown benefit from “statins”37 for people who have had a myocardial infarct even if their lipid levels are normal although the benefit may be less if the total cholesterol level is less than 5 mmol/L. Patients with existing coronary heart disease are eligible for Pharmaceutical Benefits Scheme subsidised lipid lowering drugs if their total cholesterol is >4 mmol/L.

RCTs have shown benefit from ACE inhibitors but the magnitude of benefit is small so we have given it lower priority.38 If Ann had high blood pressure not controlled by a beta-blocker then an ACE inhibitor would be a good choice.

The hypothesis that traditional Japanese diets are superior to other diets and the hypothesis that isoflavins are better than placebo for the outcomes of interest here have not yet been properly tested.

HRT would reduce Ann’s hot flushes but she has not requested treatment for them. For women like Ann who have had a myocardial infarct, HRT has been shown to be potentially harmful in RCTs of up to 4.1 years duration. The possibility that longer-term use may do more good than harm has not been excluded but any late benefit

29. Dusseldorp E, et al. A meta-analysis of psychoeducational programs for coronary heart disease patients. Health Psychol 1999;18(5):506-19.

30. Dugmore LD, et al. Changes in cardiorespiratory fitness, psychological wellbeing, quality of life, and vocational status following a 12 month cardiac exercise rehabilitation programme. Heart 1999;81(4):359-66. 31. Dorn J, et al. Results of a multicenter randomized clinical trial of exercise and long-term survival in myocardial infarction patients: the National Exercise and Heart Disease Project (NEHDP). Circulation 1999;100(17):1764-9. 32. Jolliffe JA, et al. Exercise-based rehabilitation for coronary heart disease (Cochrane Review). Cochrane Database Syst Rev 2000;4:CD001800.

33. Manson JE, et al. A prospective study of walking as compared with vigorous exercise in the prevention of coronary heart disease in women. N Engl J Med 1999;341(9):650-8.

34. He J, et al. Aspirin and risk of hemorrhagic stroke: a meta-analysis of randomized controlled trials. JAMA 1998;280(22):1930-5.

35. Antiplatelet Chemoprevention of Occlusive Vascular Events and Death. Therapeutic Initiative Newsletter September/October 2000;37. Available from: URL:http://www.ti.ubc.ca/pages/letter37.htm

36. Freemantle N, et al. Beta Blockade after myocardial infarction: systematic review and meta regression analysis. BMJ 1999;318(7200):1730-7.

37. Ross SD, et al. Clinical outcomes in statin treatment trials: a meta-analysis. Arch Intern Med 1999;159(15):1793-802.

38. Domanski MJ, et al. Effect of angiotensin converting enzyme inhibition on sudden cardiac death in patients following acute myocardial infarction. A meta-analysis of randomized clinical trials. J Am Coll Cardiol 1999;33(3):598-604.

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would have to be very large to make up for the early harm. The best evidence available to date indicates increased thromboembolism and maybe gallbladder disease, possible early cardiovascular harm with no medium term cardiovascular benefit, and uncertainty with regards to impact on breast cancer and fracture. In our clinical experience women are often more concerned about getting breast cancer in their 50s than fractures in their 70s and 80s. On balance, the risks of harms outweigh the uncertain benefits. We are also concerned that use of HRT may divert attention from more beneficial interventions.

Acknowledgements:

We thank Alistair MacLennan, Amanda Newman, Angela Wai, Barbara Mintzes, Elina Hemminki, Joel Lexchin, Judith Mackson, Katrina Allen, Laureen Lawlor-Smith, Peter Lake and Sharon Sanders for their input. However we accept responsibility for any deficiencies in this report.

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Appendix

Comments on evaluation of evidence on HRT risks & benefits.

Randomised Controlled Trials (RCTs) are more reliable than observational studies.

RCTs compare outcomes for people who were randomly allocated to take a therapy with those randomly allocated to a comparator (a placebo or an alternative therapy). If therapy (A) changes the rate of an event (B) in an RCT then we can be confident that using (A) instead of the comparator for similar people causes the difference in the rate of (B). By contrast, observational studies compare outcomes for people who are on a therapy versus those who are not because they decided not to take the therapy or just never decided. Such studies suffer from many biases including the “healthy

volunteer effect”. Consequently, observational studies do not reliably tell us if (A) causes (B). Observational studies can provide very useful information but require careful interpretation.

The study of women that found an association between agreeing to have

mammography and lower heart attack rates is an example of an observational study that requires careful interpretation. In this case (A) does not cause (B). Instead (A) and (B) are caused by factor (C): women who do agree to having mammography are different e.g. they have more conscientious personalities and less depression so they look after themselves better and thus have less heart attacks.39 This is called the “healthy volunteer effect”.

In most (but not all) observational studies it has been observed that women who take HRT have a lower rate of cardiovascular disease. One possible explanation for that association is that HRT causes benefit i.e. (A) causes (B). An alternative explanation is that the association due to confounding by the healthy volunteer effect i.e. healthy women are less likely to have cardiovascular disease and also are more likely to take HRT.40

Another possible explanation is the “healthy survivor effect”. Imagine a therapy that increases death rates during the first year but then makes no difference. That pattern is likely to be detected by long term RCTs but long term observational studies are likely to falsely suggest benefit. This is because subjects are usually not recruited into long term observational studies until after they have been taking the therapy for a year or so. Consequently such studies may miss the initial harm. Also subjects taking the therapy will appear to live longer than those who do not. This is because only lower risk survivors will be recruited into the study because higher risk people will have died early (because of the therapy) before they could be recruited into the study. The disadvantage of RCTs is that the subjects involved may be different, at higher or lower risk, than the patients involved in everyday clinical practice. Consequently there is a need for care when generalising the results of RCTs to your patients.

We can be more confident about the results of observational studies and RCTs if they are all consistent with each other.

39. Siegler IC, et al. Predictors of adoption of mammography in women under age 50. Health Psychol 1995;14(3):274-8.

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Clinically important events are more reliable than surrogate events.

Studies of clinically important outcomes (e.g. fractures) are more reliable than studies of surrogates (e.g. bone density). This is because surrogates are not always as accurate at predicting clinically important outcomes as hoped.

HRT increases bone density though there is no direct RCT evidence of reductions in rates of important fractures. However, it seems likely that HRT will be beneficial, given that studies of other agents such as bisphosphonates show that they increase bone density and modestly reduce rates of fractures.

Surrogate outcomes may correctly predict whether an intervention is beneficial or harmful but still mislead about the magnitude of the benefit or harm. Although HRT has a large effect on bone density it may or may not have a large effect on fracture rates depending on whether other risk factors, such as poor balance turn out to be more important. Although HRT has a large effect on bone density it does not seem to have a large effect on fracture rates during the first 4 - 5 years.

All good quality RCT results available should be considered to reduce bias.

One form of bias arises from basing conclusions on only those trials that the author likes for whatever reason. The safest way to reduce the risk of that type of bias is to consider all available relevant information from RCTs of reasonable quality that measured the outcome of interest. Consequently, we have included the information available from the Women’s Health Initiative trial despite the fact that it is very incomplete.41

Controversy about the HERS trial.

The HERS trial studied postmenopausal US women with established coronary artery disease aged 55 to 80.42 The average age was 67 years. A total of 1383 women took placebo and 1380 took conjugated equine oestrogen and medroxyprogesterone acetate. The average duration of participation in the trial was 4.1 years.

There has been suggestion that the results of the HERS trial can be dismissed because of various problems with the trial.

One criticism is that the results may not apply to women who do not have established coronary artery disease. This objection is reasonable. However the results of all the RCTs of women without coronary artery disease are consistent with HERS. 43, 44, 45 Consequently, the possibility that the impact will be similar in both groups needs be considered seriously. This case study addresses that criticism by focusing on Ann who has established coronary artery disease and would have met the entry criteria for the HERS trial so the results of that trial are relevant for her.

41. URL:http://www.nhlbi.nih.gov/whi/index.html

42. Hulley S, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998;280:7:605-13.

43. Herrington DM, et al. Effects of Estrogen Replacement on the Progression of Coronary-Artery Atherosclerosis. New Engl J Med 2000;343:8:522-9.

44. Hemminki E, McPherson K. Value of drug-licensing documents in studying the effect of postmenopausal hormone therapy on cardiovascular disease. Lancet 2000;355:566-9.

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Another criticism is that the trial terminated prematurely. This is not true. The trial ended on the scheduled date. The investigators considered extending the trial because the average duration of trial therapy was lower than hoped for because of late

recruitment, however they decided against this.

Yet another criticism arises from the fact that women in the control group used other cardioprotective drugs including “statins” more often than those in the treatment group. This occurred because HRT lowered lipid levels in the treatment group so “statins” were prescribed less often for women in that group. However “statins” were unlikely to have accounted for the differences in cardiovascular events observed during the first year of the HERS because other trials of “statins” have shown that they do not make that much difference to cardiovascular events in the first year. It has been suggested that there may have been unknown differences between the groups at randomisation. However there were no significant differences in any of the many baseline parameters that were tested.

It has been suggested all the endpoints other than the primary endpoint (coronary death plus non-fatal infarct) can be dismissed. It is true that if the treatment really makes no difference and if many endpoints are measured and if the criteria for

significance are set at P<0.05 then on average the findings for 5% of endpoints will be false positives. This applies equally to all endpoints including the primary endpoint. The best response to this is to accept uncertainty about the results of any trial in proportion to the P-value until those results are verified by at least one other trial. If the P-value is very low then a lower level of uncertainty is needed. Healthy flexible scepticism is appropriate. Completely dismissing results is inappropriate given that the trial is rarely powered to measure the difference in secondary endpoints.