ÐÏࡱárs for CHD, and a small subset of women (n=400) reported conditions at baseline that would have made them eligible for the HERS study. Data from studies in non-human primates80a and in postmenopausal women80b suggest that early initiation of hormone therapy may prevent the development of atherosclerosis. 80c Data from Clarkson, Hodis and others suggest that early initiation of hormone therapy, in newly menopausal women, can prevent the development of atherosclerosis. [cite Clarkson, the EPAT study, and the recent Hodis article (NEJM 8/7/03) that draws this distinction] Thus, it is not known whether the results of the WHI are applicable to healthy, younger, postmenopausal women. Given the low background rate of CHD in early postmenopausal women, the same relative risk would be expected to yield a substantially lower absolute risk in this population. Coronary Heart Disease Mortality Of those observational studies that evaluated mortality,63, 68, 70-74, 77, 81-87 most show a lower mortality due to CHD among postmenopausal hormone therapy users. In these studies the observational period ranged from 1.3 to 20 years, with an apparent trend toward a reduction in cardiovascular mortality in postmenopausal hormone therapy users (RRs ranged from 0.17 to 1.94). Furthermore, a modest decrease in mortality remains after adjusting for SES. A recent meta-analysis that adjusted for SES80, 88 reported a summary relative risk for current users of postmenopausal hormone therapy of 0.64 (95% CI, 0.44–0.93) and 0.62 (95% CI, 0.40–0.90) for CVD and CHD mortality, respectively. In the WHI there was no significant difference in CHD mortality between the treatment groups, although the overall number of events was small.26 The overall mortality was not affected by CEE/MPA therapy during the trial.26 Stroke While tThe majority of observational studies and clinical trials did not observe an increased risk of stroke.,89 However, an increased risk of stroke, with a relative risk generally less than 2.0, has been found in some studies; the relative risk reported in those studies was generally less than 2.0. In studies where the type of stroke was evaluated, the increased risk was predominantly observed for thromboembolic strokes. A recent meta-analysis,88 which pooled results from 9 observational studies,63, 82, 90-96 reported that the relative risk for overall stroke incidence was slightly increased among ever users (RR, 1.12; 95% CI, 1.01–1.23). Relative risk was elevated for thromboembolic stroke (RR, 1.20; 95% CI, 1.01–1.40), but not for subarachnoid or intracerebral stroke.88 In the WHI trial the overall hazard ratio for stroke (fatal and nonfatal) was 1.41 (95% nominal CI, 1.07–1.85), after an average of 5.2 years of follow-up.26 The increased risk of stroke appeared in year 2 and persisted to the end of the study. When separated into fatal or nonfatal events, the increase in stroke was statistically significant for nonfatal stroke, but not for fatal stroke. The original WHI publication 26 data were recently updated.97 The average follow-up period was extended from 5.2 years to 5.6 years, the stroke events were subjected to central adjudication, and new cases were added (258 vs. 212). The overall hazard ratio for stroke (ischemic and hemorrhagic) reported in the updated study was 1.31 (95% nCI, 1.02-1.68). The increased risk resulted exclusively from an increase in ischemic stroke [HR 1.44; (95% nCI, 1.09-1.90)]. The relative risk of hemorrhagic stroke was slightly decreased [HR 0.82; (95% nCI 0.43-1.56)]. Hormone users had an increased risk for non-fatal stroke, but not for fatal stroke. The adjusted hazard ratios for overall stroke were similar across age groups. Venous Thromboembolism Evidence supports an increased relative risk of deep vein thrombosis (DVT) and pulmonary embolism (PE) with postmenopausal hormone therapy.26, 64, 98-100 Evidence from randomized controlled trials in women with and without established cardiovascular disease,26, 64, 98 supports an association between postmenopausal hormone therapy and an increased risk of VTE (RR range, 2.08 to 2.89). A number of observational studies have examined the risk of venous thromboembolism with postmenopausal hormone therapy. A recent meta-analysis of 12 studies101 found that current use of postmenopausal estrogen was associated with a 2-fold increased risk for VTE (RR, 2.14; 95% CI, 1.64–2.81). Pooled data from 6 studies64, 79, 102-105 QUOTE ""  ADDIN REFMAN ÿ\11\05‘\19\01\00\00\00\00\01\00\00\09W:\5CDWRITE\03\00\05213716Varas-Lorenzo, Garcia-Rodriguez, et al. 2000 21371 /id\006\00  QUOTE ""  ADDIN REFMAN ÿ\11\05‘\19\01\00\00\00\00\01\00\00\09W:\5CDWRITE\03\00\044688"Daly, Vessey, et al. 1996 4688 /id\00"\00  QUOTE ""  ADDIN REFMAN ÿ\11\05‘\19\01\00\00\00\00\01\00\00\09W:\5CDWRITE\03\00\0522535"Jick, Derby, et al. 1996 22535 /id\00"\00  QUOTE ""  ADDIN REFMAN ÿ\11\05‘\19\01\00\00\00\00\01\00\00\09W:\5CDWRITE\03\00\0485959Pérez Gutthann, García Rodríguez LA, et al. 1997 8595 /id\009\00  QUOTE ""  ADDIN REFMAN ÿ\11\05‘\19\01\00\00\00\00\01\00\00\09W:\5CDWRITE\03\00\0532305,Hoibraaten, Abdelnoor, et al. 1999 32305 /id\00,\00  indicated that the risk was highest during the first year of use (RR, 3.49; 95% CI, 2.33–5.59), with a lower increased risk persisting (RR, 1.91, 95% CI, 1.18–3.52) thereafter using different estrogens and progestins.101 The increased DVT risk associated with hormone therapy appears to be dose-dependent and has been seen with multiple regimens.102-104 QUOTE ""  ADDIN REFMAN ÿ\11\05‘\19\01\00\00\00\00\01\00\00\09W:\5CDWRITE\03\00\0522535"Jick, Derby, et al. 1996 22535 /id\00"\00  QUOTE ""  ADDIN REFMAN ÿ\11\05‘\19\01\00\00\00\00\01\00\00\09W:\5CDWRITE\03\00\0485959Pérez Gutthann, García Rodríguez LA, et al. 1997 8595 /id\009\00  Cognitive Functions Global cognitive functions and incidence of probable dementia were evaluated in 4381 postmenopausal women 65 years or older. The study participants were recruited from the WHI Study. Women in the CEE/MPA - treated group did not exhibit as much improvement over time as women in the placebo group exhibited a decline in the Modified Mini-Mental State Examination, a standard instrument used to screen for dementia. for the measurement of global functions. This difference The decline was significant (P = .008) when compared to placebo.106 The incidence of dementia and mild cognitive impairment was reported in another study107 of the above population plus an additional 151 subjects. The hazard ratio for probable dementia in the hormone treated group was higher than in the placebo group [HR 2.05; (n95% CI, 1.21-3.48)]. Alzheimer’s disease was the most common classification of dementia in both study groups. Treatment effects on mild cognitive impairment did not differ between groups. The WHI authors note that these results contrast with prior observational data showing a reduction in Alzheimers disease and dementia for women using hormone therapy. 107 [WHIMS paper, JAMA 5/28/03 at 2659]. Limitations of the WHI Study To date, Wyeth has not had access to the full data underlying the WHI publications, and thus has not been able to analyze that data completely. There are, moreover, a number of factors which limit both the interpretation and generalizability of the WHI results. A non-exhaustive list is set forth below. The WHI26 recruited women of relatively old age (age range at study start: 50-79 years; mean age 63.2 years in the CEE/MPA group and 63.3 in the placebo group). Approximately 66% of the study population was (60 years old. By comparison, the onset of menopause occurs on average at 51 years, an age when hormone therapy is indicated for many women and when the risks associated with hormone therapy can be expected to be substantially lower than observed in WHI. Indeed, the study excluded women with severe severe menopausal symptoms [Design Paper and Protocol], that would have been inconsistent with assignment to placebo.108 Moreover, while only 400 women had previously diagnosed CHD, a number of participants were overweight, smokers (past or current), and being treated for high cholesterol, high blood pressure and diabetes.26 [see Table 1 of 7/02 JAMA paper]. The study thus examined a population unrepresentative of the women for whom the product is principally indicated. The WHI study population included about 25% of prior and current hormone users and therefore had been exposed to potential risk factors associated with hormone therapy for longer than the duration of the study. About 30% of prior and current users had taken therapy for longer than 5 years. Therefore, risk factors ascribed to CEE/MPA therapy in WHI may have been overestimated. A further limitation of WHI is the relatively high rate of unblinding (approximately 40%) and discontinuation (42%) in the active treatment arm, and the relatively high rate of crossover to active treatment in the placebo arm (10.7%). WHI studied only one strength of CEE/MPA. The risk profile observed in WHI may therefore not apply to lower CEE/MPA doses or to other types of hormones. Conclusion The overall benefit of hormone therapy must be evaluated against the overall risk associated with the therapy. The efficacy of postmenopausal hormone therapy to relieve menopausal symptoms, prevent osteoporosis and reduce fractures has been well documented both in observational studies and in the recent WHI study. The CEE/MPA component of the WHI study is by far the largest randomized, placebo-controlled clinical trial to date evaluating fracture risk. Hormone therapy resulted in significant reductions in the risk of both vertebral and hip fractures, and in significant reductions in the risk of colorectal cancer. After a mean follow-up of 5.2 years, the WHI Data and Safety Monitoring Board recommended to discontinue CEE/MPA treatment because the breast cancer rates exceeded the predefined stopping boundary. The board concluded that the overall risks exceeded the benefits, as measured by using the global index. However, the global index was originally intended as a monitoring tool, and not as an overall risk/benefit measure. The index is based on selected risks and selected benefits and not on all risks and all benefits. For example, it includes hip fractures but not vertebral fractures or menopausal symptoms. Vertebral fractures are associated with substantial rates of disability, morbidity and mortality; and menopausal symptoms can be debilitating and detrimental to everyday life. The global index does not contain a measure of quality of life (less disability) associated with reduced rates of vertebral fractures, menopausal symptoms and other factors. Therefore, the global index, as used in the WHI, does not truly represent a comprehensive measure of risks vs. benefits that is applicable to the general population of postmenopausal women receiving estrogen/progestin treatment. It is important to offer different treatment options to physicians and patients. Hormone therapy represents an important option for use in relieving menopausal symptoms and concomitant prevention of osteoporosis in women with high risk of osteoporosis/fractures but without significant risk factors for cardiovascular disease or breast cancer for whom alternative therapies to prevent osteoporosis cannot be used or have not been effective. Postmenopausal hormone therapy is the only intervention that is simultaneously effective in the treatment of menopausal symptoms and the prevention of osteoporosis. The use of postmenopausal hormone therapy for the treatment of menopausal symptoms should be limited to the lowest dose and shortest duration consistent with treatment goals and risks for the individual woman. When using hormone therapy solely for the prevention of postmenopausal osteoporosis, therapy should be considered only for women at significant risk of osteoporosis, and non-estrogen medications, such as alendronate, risedronate or raloxifene, should be carefully considered as a first-line treatment option. For older women, use in combination with a progestin should only be considered for women who failed on, or were intolerant of, non-estrogen medication. Potential long-term risks of postmenopausal hormone therapy should be evaluated when using this therapy for the prevention of osteoporosis. The decision regarding therapy should take into account the individual woman’s underlying risk factors for cardiovascular disease and breast cancer. Because individual treatment goals and risks change over time, the use of postmenopausal hormone therapy should be periodically re-evaluated. These re-evaluations are especially important when longer durations of therapy, particularly greater than 5 years, are considered. The adverse effects associated with alternative therapies, such as esophageal ulceration, gastrointestinal symptoms, lower extremity cramping or vasomotor symptoms should be carefully evaluated and should be balanced against the risks associated with hormone therapy. Studies evaluating long-term use are either lacking or limited for alternative therapies; therefore, conclusions regarding long-term safety cannot be made. Alternative therapies may also have limitations regarding their efficacy. Fracture reduction studies of alendronate or risedronate therapy have been conducted primarily in osteoporotic women. However, the National Osteoporosis Risk Assessment (NORA) study identified nearly 40% osteopenic (i.e., non-osteoporotic, non-symptomatic) women among its study population, indicating that there are large numbers of women with osteopenia in the general population. The NORA study found substantial fracture rates associated with osteopenia. The WHI study was conducted in non-osteoporotic women and thus the significant reduction of fracture risk observed in the WHI study may be more relevant to the general population than the observations from trials of alternative therapies conducted in osteoporotic women. Moreover, the efficacy of risedronate to protect against hip fractures may be limited. The WHI study was conducted largely in an older population of postmenopausal women who are not typical hormone therapy users. Patient counseling is an essential part of any treatment decision. When making decisions about initiating or continuing postmenopausal hormone therapy, counseling women about the potential benefits and risks is particularly important. Healthcare providers who counsel women about postmenopausal hormone therapy should be familiar with the differences between relative risk and absolute risk so that treatment decisions can be based on the individual patient’s benefit/risk profile. Women should participate in the decision-making process with an understanding of the potential risks and benefits of postmenopausal hormone therapy, and they should be reassured that their choice of therapy will be periodically reevaluated. References National Osteoporosis Foundation. America’s Bone Health: The State of Osteoporosis and Low Bone Mass in Our Nation. Washington, DC: National Osteoporosis Foundation; 2002:1-55. Melton LJI, Chrischilles EA, Cooper C, et al. Perspective: How many women have osteoporosis now? J Bone Miner Res. 1992;7:1005-1010. 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