Case Study 11: Hormone Replacement Therapy

Transcription

1 Case Study 11: Hormone Replacement Therapy October 2000

2 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 Comments on evaluation of evidence on HRT risks & benefits 2

3 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 3

4 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 5 th edition 2000 Available from: URL: 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):

5 Fractures Results: 45% of 1155 respondents indicated that the impact of HRT on increasing or decreasing the risk of fractures was very certain 1155 respondents 40 Percentage of respondents completely unknown probably known completely certain very uncertain very certain Level of certainty re fractures 58% of 1153 respondents indicated that regarding fractures, HRT was likely to be very beneficial respondents Percentage of respondents mild harm neutral mild benefit Fractures: harm or benefit extreme benefit very benefit There was a significant positive correlation between respondent s level of certainty and their estimate of benefit (Spearman s rho = 056 3, P<00001) 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 5

6 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 94% in the HRT group (P = 07) 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): 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): Hulley S, et al Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women JAMA 1998;280(7): Lindsay R, Hart DM, Forrest C, Baird C Prevention of spinal osteoporosis in oophorectomised women Lancet 1980;2: Green CJ, et al Bone Mineral Density Testing: does the evidence support its selective use in well women BCOHTA 97:2T, Vancouver, Dec 1997 wwwchsprubcca 6

7 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 1154 respondents 40 Percentage of respondents completely unknown probably known completely certain very uncertain very certain 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 respondents Percentage of respondents extreme harm mild harm very harm neutral CV events: harm or benefit mild benefit extreme benefit very benefit There was a significant positive correlation between respondent s level of certainty and their estimate of benefit (Spearman s rho = 026, P<00001) In other words, those who felt more certain were more likely to believe that HRT had a beneficial effect on cardiovascular event rates 7

8 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 41 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 41 years (127% in the placebo group vs 125% in the HRT group, P = 099) However there were significantly more coronary deaths plus non-fatal myocardial infarctions in the HRT group at one year (27% in the placebo group vs 41% in the HRT group, P = 0046) 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: Hulley S, et al Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women JAMA 1998;280(7):

9 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 41 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) Incidence of coronary heart disease death in the HERS trial 9

10 2 The ERA trial (August 2000) compared 32 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 McPherson study (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 178, 95% confidence interval ) 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 eg 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 significance 16 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 eg 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): Hemminki E, McPherson K Value of drug-licensing documents in studying the effect of postmenopausal hormone therapy on cardiovascular disease Lancet 2000;355: Barrett-Connor E, Grady D Hormone replacement therapy, heart disease, and other considerations Annu Rev Public Health 1998;19: URL: 16 HRT study shows increased heart risk Scrip 2000;2530:22 10

11 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 respondents Percentage of respondents completely unknown probably known completely certain very uncertain very certain Level of certainty re Thromboembolism 74% of 1153 respondents indicated that regarding DVT and PE, HRT was likely to be mildly harmful respondents Percentage of respondents extreme harm mild harm very harm neutral mild benefit extreme benefit very benefit Thromboembolism: harm or benefit There was a significant negative correlation between respondent s level of certainty and their estimate of benefit (Spearman s rho = -032, P<00001) In other words, those who felt more certain were more likely to believe that HRT had a harmful effect on thromboembolic rates 11

12 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 087% in the placebo group vs 25% in the HRT group (P = 0004) 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 (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): MacLennan AH Long term hormone replacement therapy Aust Prescr 2000;23:

13 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 1152 respondents 40 Percentage of respondents completely unknown probably known completely certain very uncertain very certain Level of certainty re breast cancer 79% of 1148 respondents indicated that regarding breast cancer, HRT was likely to be mildly harmful respondents Percentage of respondents extreme harm mild harm very harm neutral Breast cancer: harm or benefit mild benefit extreme benefit very benefit There was a significant negative correlation between respondent s level of certainty and their estimate of benefit (Spearman s rho = -036, P<00001) In other words, those who felt more certain were more likely to believe that HRT had a harmful effect on breast cancer rates 13

14 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 18% in the placebo group vs 23% in the HRT group (P = 033) 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 135 (95% confidence interval ) 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 15 times normal ie 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): Willett WC, et al Postmenopausal estrogens: opposed, unopposed, or none of the above JAMA 2000;283(4): 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): 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): Taylor R, et al Absolute risk of breast cancer for Australian women with a family history Aust N Z J Surg 2000 ;70(10): Pharoah PD, et al Family history and the risk of breast cancer: a systematic review and meta-analysis Int J Cancer 1997;71(5): 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):

15 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 respondents Percentage of respondents completely unknown probably known completely certain very uncertain very certain Level of certainty re Gallbladder Disease 63% of 1139 respondents indicated that regarding gallbladder disease, HRT was likely to be neutral 1139 respondents 60 Percentage of respondents extreme harm mild harm very harm neutral mild benefit extreme benefit very benefit Gallbladder disease: harm or benefit There was a significant negative correlation between respondent s level of certainty and their estimate of benefit (Spearman s rho = -051, P<00001) In other words, those who felt more certain were more likely to believe that HRT had a harmful effect on gallbladder disease rates 15

16 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 45% in the placebo group vs 61% in the HRT group (P = 005) 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 = 005) just by chance alone Gallbladder disease is usually not fatal but can be severe 16

17 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 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): Hu F, et al Trends in the incidence of coronary heart disease and changes in diet and lifestyle in women New Engl J Med 2000;343(8):

18 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 (eg 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 29, 30, 31, 32 beneficial 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 34, 35 Meta-analyses of many trials involving men and women have found that aspirin 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 41 years duration The possibility that longerterm 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): 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): 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): Jolliffe JA, et al Exercise-based rehabilitation for coronary heart disease (Cochrane Review) Cochrane Database Syst Rev 2000;4:CD 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): He J, et al Aspirin and risk of hemorrhagic stroke: a meta-analysis of randomized controlled trials JAMA 1998;280(22): Antiplatelet Chemoprevention of Occlusive Vascular Events and Death Therapeutic Initiative Newsletter September/October 2000;37 Available from: URL: 36 Freemantle N, et al Beta Blockade after myocardial infarction: systematic review and meta regression analysis BMJ 1999;318(7200): Ross SD, et al Clinical outcomes in statin treatment trials: a meta-analysis Arch Intern Med 1999;159(15): 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):

19 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 19

20 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 eg 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 ie (A) causes (B) An alternative explanation is that the association due to confounding by the healthy volunteer effect ie 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): Barrett-Connor E Hormone replacement therapy BMJ 1998;317:

21 Clinically important events are more reliable than surrogate events Studies of clinically important outcomes (eg fractures) are more reliable than studies of surrogates (eg 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 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 41 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 43, 44, 45 RCTs of women without coronary artery disease are consistent with HERS 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: 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: Herrington DM, et al Effects of Estrogen Replacement on the Progression of Coronary-Artery Atherosclerosis New Engl J Med 2000;343:8: Hemminki E, McPherson K Value of drug-licensing documents in studying the effect of postmenopausal hormone therapy on cardiovascular disease Lancet 2000;355: URL: 21

22 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<005 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 22