All medications are a double-edged sword with risks

Menopause: The Journal of The North American Menopause Society Vol. 14, No. 5, pp. 1/14 DOI: 10.1097/gme.0b013e31802e8508 * 2007 by The North American Menopause Society REVIEW ARTICLE Postmenopausal hormone therapy in clinical perspective Howard N. Hodis, MD, and Wendy J. Mack, PhD Abstract Although many of the risks and benefits of postmenopausal hormone therapy are known, only recently has the magnitude of these effects and their perspective to other therapies become more fully understood. Careful review of randomized controlled trials indicates that the risks of postmenopausal hormone therapy including breast cancer, stroke and venous thromboembolism are similar to other commonly used agents. Overall, these risks are rare (less than 1 event per 1,000 women) and even rarer when initiated in women less than 60 years of age or within 10 years of menopause. In addition, the literature indicates similar benefit of postmenopausal hormone therapy, in women who initiate hormone therapy in close proximity to menopause, to other medications used for the primary prevention of coronory heart disease in women. Key Words: Hormone therapy Y Statin therapy Y Cardiovascular disease Y Breast cancer Y Stroke Y Venous thromboembolism. All medications are a double-edged sword with risks and benefits. Most medications enter the marketplace and become standard therapy without formal risk-benefit analyses. Hormones for postmenopausal hormone therapy are no exception. Putting medications and standard therapies into clinical perspective is perhaps the most common approach to understanding overall utility and reasonable acceptance of risks and benefits. The benefits of hormone therapy are well appreciated. The risks of most concern are breast cancer, stroke, and venous thrombosis. Any single randomized, controlled trial does not provide complete information for determination of risks and benefits. This is especially true for hormones because certain effects are similar for most postmenopausal hormone therapies, whereas other effects depend on specific medications, doses, regimens, and routes of administration. This fact is apparent in regard to the divergent effects of hormone therapy on breast cancer, in which case oral daily continuous combined conjugated equine estrogens (CEE) + medroxyprogesterone acetate (MPA) was associated with an increased risk of breast cancer 1 and oral CEE was associated with a decreased risk of breast cancer. 2 Received July 17, 2006; revised and accepted November 9, 2006. From the Departments of Medicine and Preventive Medicine and the Atherosclerosis Research Unit, Keck School of Medicine, University of Southern California, Los Angeles, CA. Funding/support: Funded by the National Institute on Aging (R01-AG24154). Financial disclosure: None reported. Address correspondence to: Howard N. Hodis, MD, Keck School of Medicine, Atherosclerosis Research Unit, 2250 Alcazar Street, CSC 132, Los Angeles, CA 90033. E-mail: athero@usc.edu. After the initial sensationalism of the first few randomized, controlled trials of hormone therapy and coronary heart disease, 3 more tempered critical reappraisals of the cumulating randomized, controlled trial data in relation to the totality of data have emerged. 4 This apparent Bflip-flopping^ is partly due to the fact that assessment of risks and benefits is a dynamic process with very few unambiguous certitudes. As such, viewing the cumulated randomized, controlled trial data of coronary heart disease benefit and potential side effects of postmenopausal hormone therapy in light of other therapies, such as those for the primary prevention of coronary heart disease, is both important and enlightening. CORONARY HEART DISEASE As they are for men, lipid-lowering medications, predominantly 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins), are the mainstay for primary prevention of coronary heart disease in women. 5,6 However, the cumulated data across six randomized trials and 11,435 women do not provide strong support for the use of these medications for primary prevention of coronary heart disease in women 7 : relative risk (RR) = 0.87 (95% CI: 0.69<1.09) for coronary heart disease events; RR = 0.61 (95% CI: 0.22<1.68) for nonfatal myocardial infarction; RR = 0.95 (95% CI: 0.62<1.46) for total mortality; and RR = 1.07 (95% CI: 0.47<2.40) for coronary heart disease mortality. In the final analysis, data supporting the use of lipid-lowering medication for the reduction of coronary heart disease in women and on which to base recommendations for primary prevention are limited compared to that of men. 7 Recommendations for using lipid-lowering medications in the primary prevention of coronary heart disease in women are Menopause, Vol. 14, No. 5, 2007 1

HODIS AND MACK predominantly extrapolated from data derived from men and from secondary prevention trials in women. 5,6 In contrast, the cumulated data across 23 randomized, controlled trials of 39,049 women followed for 191,340 patient-years indicate a 32% (odds ratio [OR] = 0.68, 95% CI: 0.48<0.96) reduction of coronary heart disease in women younger than 60 years old or less than 10 years since menopause when randomized to hormone therapy relative to placebo. 8 This compares to an OR for coronary heart disease of 0.99 (95% CI: 0.88<1.11) for all women and 1.03 (95% CI: 0.91<1.16) for women more than 60 years old or more than 10 years since menopause when randomized to hormone therapy relative to placebo. 8 Hormone therapy is associated with significantly lower relative risk of coronary heart disease events in younger women compared to older women (OR = 0.66, 95% CI: 0.46<0.95). 8 In addition, the cumulated data indicate a 39% (OR = 0.61, 95% CI: 0.39<0.95) reduction in overall mortality in women younger than 60 years old who were randomized to hormone therapy relative to placebo. 9 Oral daily CEE 0.625 mg therapy under primary prevention conditions in the Women s Health Initiative (WHI)- estrogen (E) trial reduced several composite coronary heart disease outcomes by approximately 34% to 45% in 3,310 postmenopausal women younger than 60 years old 10 (Table 1). In addition, both the Heart and Estrogen/progestin Replacement Study (HERS) (P for trend = 0.009) and the WHIestrogen + progestin (EP) trial (P for trend = 0.02) indicate that increasing duration of oral daily continuous combined CEE 0.625 mg + MPA 2.5 mg therapy reduces the risk of coronary heart disease. 11,12 There is also consistency between the WHI observational study and the WHI-EP and WHI-E randomized, controlled trials in that coronary heart disease risk was reduced with more than 5 years of CEE + MPA therapy and CEE therapy, respectively 13,14 (Table 2). Results from the WHI-EP have also shown a reduction (P for trend = 0.036) of coronary heart disease according to time since menopause; women randomized within 10 years of menopause had a reduction in coronary TABLE 1. Number (annualized percentage) of coronary heart disease (CHD) events with conjugated equine estrogens (CEE) or placebo in 50- to 59-year-old women at baseline from the Women s Health Initiative estrogen trial CHD event Placebo (n = 1,673) CEE (n = 1,637) HR (95% CI) CHD (MI or CD) 34 (0.27) 21 (0.17) 0.63 (0.36<1.08) Angina a 35 (0.28) 21 (0.17) 0.59 (0.34<1.02) CABG or PCI 52 (0.42) 29 (0.24) 0.55 (0.35<0.86) MI, CD, CABG, 65 (0.52) 42 (0.35) 0.66 (0.44<0.97) and PCI MI, CD, CABG, PCI, and angina a 70 (0.56) 46 (0.38) 0.66 (0.45<0.96) HR, hazard ratio; CABG, coronary artery bypass grafting; CD, coronary heart disease death; MI, nonfatal myocardial infarction; PCI, percutaneous coronary intervention. a Angina pectoris confirmed with hospitalization for angina and confirmatory stress test or coronary artery disease by angiography. TABLE 2. Hazard ratios for coronary heart disease in the Women s Health Initiative clinical trials and observational study according to duration of use of estrogen + progestin and estrogen alone a Clinical trial Observational study Duration of use (y) Hazard ratio b (95% CI) Hazard ratio c (95% CI) CEE + MPA 13 G2 1.68 (1.15<2.45) 1.12 (0.46<2.74) 2<5 1.25 (0.87<1.79) 1.05 (0.70<1.58) 95 0.66 (0.36<1.21) 0.83 (0.67<1.01) CEE alone 14 G2 1.07 (0.68<1.68) 1.20 (0.49<2.94) 2<5 1.13 (0.79<1.61) 1.09 (0.75<1.60) 95 0.80 (0.57<1.12) 0.73 (0.61<0.84) CEE, conjugated equine estrogens; MPA, medroxyprogesterone acetate. a Adjusted for age, race, body mass index, educational level, smoking, age at menopause, and physical activity. b Relative to placebo. c Relative to nonusers of hormone therapy. heart disease (hazard ratio [HR] = 0.89), whereas women 10 to 19 years beyond menopause (HR = 1.22) and more than 20 years beyond menopause (HR = 1.71) had increased risk. 15,16 These latter results are consistent with the divergent effects seen at the arterial wall level, where oral 17Aestradiol therapy slowed the progression of atherosclerosis in relatively healthy arteries but had no effect on diseased arteries. 17,18 In contrast to lipid-lowering therapy for the primary prevention of coronary heart disease, the cumulated data indicate that in certain women (younger than 60 years old or within 10 years of menopause), hormone therapy reduces coronary heart disease and overall mortality. Initiation of hormone therapy close to rather than remote from menopause seems to be key in the full expression of the cardioprotective effects of hormone therapy. 8,9 Conversely, in specific trials, certain risks of lipid-lowering medications, such as breast cancer, resemble those of CEE + MPA reported from the WHI-EP. BREAST CANCER The breast cancer results from the WHI starkly contrast; CEE alone was associated with a reduction in breast cancer risk, 2 whereas CEE + MPA was associated with an increased risk. 1 In the WHI-EP trial, the RR for breast cancer was increased 24% with oral daily continuous combined CEE + MPA therapy, resulting in nine additional cases of breast cancer per 10,000 women per year of CEE + MPA therapy 1 (Table 3). Overall mortality and mortality due to breast cancer did not differ between CEE + MPA therapy and placebo. A more recent analysis from the WHI-EP with adjustment for breast cancer risk factors indicates a 20% (RR = 1.20, 95% CI: 0.94<1.53) increased risk of breast cancer associated with CEE + MPA therapy. 19 The elevated breast cancer risk in the WHI-EP was limited to those women who used postmenopausal hormone therapy before the WHI-EP trial. 19 In HERS, CEE + MPA therapy (same 2 Menopause, Vol. 14, No. 5, 2007 * 2007 The North American Menopause Society

POSTMENOPAUSAL HORMONE THERAPY IN CLINICAL PERSPECTIVE TABLE 3. Comparison of absolute and relative risks of breast cancer in randomized, controlled trials of postmenopausal hormone and statin therapies Study No. of breast cancers (annualized %) Placebo Therapy RR 95% CI No. of additional breast cancer cases per 10,000 women per year of therapy Statin PROSPER 20 11 (0.23) 18 (0.38) 1.65 0.78<3.49 15 AFCAPS/TexCAPS 22 9 (0.35) 13 (0.50) 1.44 0.62-3.36 15 4S 10-y follow-up 23 5 (0.11) 7 (0.17) 1.44 0.46<4.52 5 CARE 21 1 (0.07) 12 (0.84) 12.17 2.48<59.80 77 LIPID 25 10 (0.22) 10 (0.22) 1.00 0.42<2.42 0 ALLHAT-LLT 26 37 (0.30) 34 (0.28) 0.93 0.58<1.48 j2 HPS 27 51 (0.40) 38 (0.30) 0.75 0.49<1.13 j10 CEE + MPA WHI-EP 1 150 (0.33) 199 (0.42) 1.24 0.97<1.59 a 9 HERS 11 25 (0.45) 32 (0.57) 1.30 0.77<2.19 12 CEE alone WHI-E 2 161 (0.42) 129 (0.34) 0.82 0.65<1.04 j8 b 17A-E 2 alone WEST 24 5 (0.55) 5 (0.53) 1.00 0.30<3.50 j2 RR, relative risk; Statin, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor; PROSPER, Prospective Study of Pravastatin in the Elderly Risk; AFCAPS/TexCAPS, Air Force/Texas Coronary Atherosclerosis Prevention Study; 4S, Scandinavian Simvastatin Survival Study; CARE, Cholesterol and Recurrent Events Trial; LIPID, Long-Term Intervention with Pravastatin in Ischaemic Disease; ALLHAT-LLT, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial; HPS, Heart Protection Study; CEE + MPA, oral daily continuous combined conjugated equine estrogens (0.625 mg) plus medroxyprogesterone acetate (2.5 mg); WHI-EP, Women s Health Initiative estrogen + progestin trial; HERS, Heart and Estrogen/progestin Replacement Study; CEE alone, oral daily conjugated equine estrogens (0.625 mg); WHI-E, Women s Health Initiative estrogen trial; 17A-E 2, oral daily 17A-estradiol (1 mg); WEST, Women s Estrogen for Stroke Trial. a Adjusted 95% CI describes the variability of the point estimate corrected for multiple outcome analyses. Unadjusted 95% CI describes the variability of the point estimate that would arise from a simple trial for a single outcome; for conjugated equine estrogens + medroxyprogesterone acetate therapy, this interval is 1.01<1.54. b Total breast cancer incidence statistically significantly reduced in conjugated equine estrogens versus placebo in adherent subjects (hazard ratio [HR] = 0.67, 95% CI: 0.47<0.97). Statistically significant reduction of ductal (most common) breast cancer in subjects randomized to conjugated equine estrogens versus placebo (HR = 0.71, 95% CI: 0.52<0.99). See Stefanick et al. 2 hormone therapy as in the WHI-EP) was associated with an increased risk of breast cancer 11 (Table 3). Although these trials show that the risk of breast cancer associated with oral CEE + MPA therapy is rare and, at most, of borderline significance, these facts do not negate the importance of considering a medication that may cause breast cancer. However, CEE + MPA is not the only commonly used medication associated with a possible increase in breast cancer risk. Such comparisons bring into focus the clinical perspective of the breast cancer risk of oral daily CEE + MPA therapy relative to other commonly used medications and preventive therapies. In the Prospective Study of Pravastatin in the Elderly Risk (PROSPER), a 3.2-year randomized, controlled trial of pravastatin versus placebo in men and women 70 to 82 years old, the diagnosis of new cancer was increased by 25% (HR = 1.25, 95% CI: 1.04<1.51), or approximately 52 additional cancer cases per 10,000 persons per year of pravastatin use. 20 The effect of pravastatin on cardiovascular events in 3,000 women was null (HR = 0.96, 95% CI: 0.79<1.18). The risk of breast cancer was increased 65% (RR = 1.65, 95% CI: 0.78<3.49) in women randomized to pravastatin (18 events) relative to placebo (11 events). This pravastatin-associated breast cancer risk (annualized rate of 0.38%) is similar to the breast cancer risk seen in the WHI- EP (annualized rate of 0.42%), or 15 additional cases of breast cancer per 10,000 womenperyearofpravastatin use (Table 3). The CI for the risk of breast cancer with pravastatin in PROSPER was wider than that in the WHI-EP because the sample size in PROSPER was 5.5 times smaller. The elevated risk of breast cancer associated with the use of pravastatin was reported in an additional randomized, controlled trial of 576 women 59 T 9yearsold treated for 5 years, 21 in 997 postmenopausal women 55 to 73 years old treated with lovastatin for 5.2 years, 22 and in 827 women 60.5 T 6.4yearsoldfollowedfor5yearsafter randomized treatment to simvastatin for 5.4 years. 23 In the Cholesterol and Recurrent Events (CARE) trial, there were 12 cases of breast cancer in women randomized to pravastatin and 1 case in a woman randomized to placebo, or approximately 77 additional cases of breast cancer per 10,000 women per year of pravastatin use 21 (Table 3). In the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS), there were 13 cases of breast cancer in women randomized to lovastatin and 9 cases in women randomized to placebo, or approximately 15 additional cases of breast cancer per 10,000 women per year of lovastatin use 22 (Table 3). In the 10-year follow-up of the Scandinavian Simvastatin Survival Study (4S), there were seven cases of breast cancer in women randomized to simvastatin and five cases in women randomized to placebo, or five additional cases of breast cancer per 10,000 women per year of simvastatin use 23 (Table 3). Because breast cancer events were not reported in the original 5.4-year intervention trial and the subsequent 5-year follow-up period was open-label, the incidence of breast cancer solely due to Menopause, Vol. 14, No. 5, 2007 3

HODIS AND MACK simvastatin exposure cannot be completely determined from the information provided from this study. However, the greater number of breast cancer events in the simvastatintreated versus placebo-treated group in open-label followup suggests a possible residual breast cancer risk from simvastatin. 23 The 15 to 77 additional cases of breast cancer per 10,000 women per year of statin use compares to the 9 additional cases of breast cancer per 10,000 women per year of CEE + MPA therapy in the WHI-EP and the 12 additional cases of breast cancer per 10,000 women per year of CEE + MPA therapy in the HERS (Table 3). The increased absolute risk of breast cancer seen with statin therapy contrasts with CEE alone. In the WHI-E trial, breast cancer was decreased 18% with CEE therapy relative to placebo (HR = 0.82, 95% CI: 0.65<1.04), resulting in eight fewer cases of breast cancer per 10,000 women per year of CEE therapy 2 (Table 3). In subgroup analyses, breast cancer risk was further reduced in women adherent to CEE therapy relative to placebo (HR = 0.67, 95% CI: 0.47<0.97) and in women who developed the most common form of breast cancer, ductal carcinoma (HR = 0.71, 95% CI: 0.52<0.99). In the Women s Estrogen for Stroke Trial (WEST), hormone therapy with 17A-estradiol alone also resulted in a fewer number of absolute cases of breast cancer relative to placebo 24 (Table 3). In addition, the Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) trial showed no difference in breast cancer risk between pravastatin and placebo, 25 the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT) 26 showed 2 fewer cases of breast cancer per 10,000 women per year of pravastatin use, and the Heart Protection Study (HPS) showed 10 fewer breast cancer cases per 10,000 women per year of simvastatin use 27 (Table 3). Unlike the WHI-EP, in which colorectal cancer risk was reduced with CEE + MPA therapy relative to placebo, gastrointestinal cancer risk was increased by 46% with pravastatin treatment relative to placebo in PROSPER (RR = 1.46, 95% CI: 1.00<2.13; 22 additional cases of gastrointestinal cancer per 10,000 persons per year of pravastatin use). 20 In the WHI-EP, colorectal cancer was reduced 37% with CEE + MPA therapy relative to placebo (HR = 0.63, 95% CI: 0.43<0.92), resulting in six fewer cases of colorectal cancer per 10,000 women per year of CEE + MPA therapy. 12 Although lipid-lowering trials other than PROSPER have not shown statistically significant increased risk of cancer overall, the overall absolute cancer risk in the primary prevention trials with statins that have reported cancer incidence is consistently elevated. 22,26 The overall absolute cancer risk specifically determined in women in the primary prevention trial AFCAPS/TexCAPS was elevated, with approximately 15 additional cases of cancer per 10,000 women per year of lovastatin use. 22 In the primary prevention trial ALLHAT-LLT, the overall absolute cancer risk was five additional incident cases of cancer and seven additional cancer deaths per 10,000 persons per year of pravastatin use. 26 Sitespecific cancer incidence, especially breast cancer incidence, has not been reported in all lipid-lowering randomized, controlled trials, and thus the breast canceryrelated risk remains unknown across all lipid-lowering medications. 28,29 A recent meta-analysis reported data from five randomized, controlled trials of statin therapy (PROSPER, CARE, 4S, LIPID, ALLHAT-LLT), indicating a 33% (OR = 1.33, 95% CI: 0.79<2.26) increased risk of breast cancer associated with statin use. There were 81 cases of breast cancer per 27,112 women-years in women randomized to statin therapy and 64 cases of breast cancer per 27,462 women-years in women randomized to placebo, or 7 additional breast cancer cases per 10,000 women per year who used statin therapy. 28 A previous meta-analysis reporting data from seven randomized, controlled trials of statin therapy (Table 3) showed a 4% (RR = 1.04, 95% CI: 0.81<1.33) increased risk of breast cancer associated with statin use. There were 132 cases of breast cancer cases per 42,412 women-years in women randomized to statin therapy and 124 cases of breast cancer per 42,757 women-years in women randomized to placebo, or 2 additional breast cancer cases per 10,000 women per year who used statin therapy. 29 Although the oncogenicity of statins and other lipid-lowering medications is complex, incompletely understood, and controversial, there is biological plausibility for induction of cancer in general and for breast cancer specifically. 30<32 In the final analysis, the cumulated data indicate that the absolute risk of breast cancer associated with statin therapy and oral daily continuous combined CEE + MPA therapy as seen in the WHI-EP and HERS is low and similar: j1 to 7.7 additional breast cancers per 1,000 women per year of statin therapy versus 0.9 to 1.2 additional breast cancers per 1,000 women per year of CEE + MPA therapy (Table 3). In contrast to the limited effect of lipid-lowering therapy in reducing coronary heart disease under primary prevention conditions, 7 early initiation of CEE + MPA within 10 years of menopause and duration of CEE + MPA therapy of more than 5 years reduced the risk of coronary heart disease. 8,9,11,13,15,16 Statin and CEE + MPA therapies contrast with oral CEE alone, which was associated with a reduced breast cancer risk in the WHI-E 2 and, in certain women (younger than 60 years old), a reduced risk of coronary heart disease. 8<10 STROKE Although WEST has been the only randomized, controlled trial of hormone therapy designed with stroke as the primary trial outcome, 24 HERS and WHI have also provided information concerning hormone therapy and stroke as an additional trial outcome. WEST was a randomized, controlled trial designed to test whether oral 17A-estradiol 1 mg/day reduces the combined outcome of nonfatal stroke or all-cause mortality in 664 postmenopausal women who were, on average, 71 years old and approximately 20 years postmenopausal at baseline. 24 The women had a documented nondisabling stroke or 4 Menopause, Vol. 14, No. 5, 2007 * 2007 The North American Menopause Society

POSTMENOPAUSAL HORMONE THERAPY IN CLINICAL PERSPECTIVE transient ischemic attack within 90 days of randomization into the trial. As such, WEST was a trial that assessed the effect of 17A-estradiol on the secondary prevention of stroke. Deaths from all causes or nonfatal stroke occurred in 99 participants in the estradiol group and in 93 participants in the placebo group (RR = 1.1, 95% CI: 0.8<1.4). There were 51 nonfatal strokes in the estradiol group and 52 nonfatal strokes in the placebo group (RR = 1.0, 95% CI: 0.7<1.4) and 12 fatal strokes in the estradiol group and 4 fatal strokes in the placebo group (RR = 2.9, 95% CI: 0.9<9.0). There were 48 deaths from all causes in the estradiol group and 41 deaths in the placebo group (RR = 1.2, 95% CI: 0.8<1.8). There were no increased rates of venous thromboembolism (VTE) or breast cancer in the estradiol compared to the placebo group (Tables 3 and 7). The cumulated randomized, controlled trial results concerning stroke and hormone therapy are mixed (Table 4), consistent with previous observational studies that show decreased risk, 13,14,33<36 no effect, 37<40 and increased risk, at least among smokers. 41 WEST showed that oral 17Aestradiol had a null effect on the secondary prevention of nonfatal stroke and nonfatal and fatal stroke combined. 24 HERS showed that oral daily continuous combined CEE + MPA had little effect on nonfatal stroke in postmenopausal women with established coronary heart disease. 42 The WHI- EP 12,43 and WHI-E 44,45 showed that nonfatal stroke was positively associated with oral CEE + MPA and CEE alone (Table 4). Combined stroke followed the same pattern as nonfatal stroke in both the WHI-EP 12,43 and WHI-E. 44,45 The case numbers of fatal strokes in these trials were small and thus difficult to interpret. Although the cumulated data do not conclusively indicate that hormone therapy significantly increases stroke relative to placebo, the randomized, controlled trials do indicate a consistent increase in the point estimate of risk with hormone therapy relative to placebo. The number of additional cases of stroke associated with hormone therapy is greater in women with preexisting coronary heart disease or stroke (ranging from 27 to 56 additional cases per 10,000 women per year of hormone therapy use across randomized, controlled trials) than in women in whom the majority did not have preexisting cardiovascular disease (ranging from 7 to 12 additional cases per 10,000 women per year of hormone therapy use across randomized, controlled trials) (Table 4). In the WHI-EP, the number of additional cases of stroke per 10,000 women per year of CEE + MPA therapy was lower for women younger than 60 years old versus older than 60 years old (4 vs 22 additional cases of stroke per 10,000 women per year of CEE + MPA therapy) and lower for women randomized within 5 years of menopause than for those randomized more than 5 years after menopause (3 vs 22 additional cases of stroke per 10,000 women per year of CEE + MPA therapy). For women randomized within 5 years, between 5 and less than 10 years, between 10 and less than 15 years, or more than 15 years since menopause, the number of additional cases of stroke were rare, with less than one additional stroke per 1,000 women per year of CEE + MPA therapy 43 (Table 5). In the WHI-E, the number of additional cases of stroke per 10,000 women per year of CEE therapy was lower for women younger than 60 years old versus older than 60 years old (1 vs 39 additional cases of stroke per 10,000 women per year of CEE therapy) and lower for women randomized within 10 years of menopause than for those randomized more than 10 years after menopause (15 vs 25 additional cases of stroke per 10,000 women per year of CEE therapy). For women younger than 60 years of age when randomized, the number of additional cases of stroke was rare, with less than one additional stroke per 10,000 women per year of CEE therapy 45 (Table 5). The age- and time-related stroke data from the WHI are important in that they indicate that the number of additional cases of stroke is rare (less than one per 1,000 women per year of hormone therapy) for CEE + MPA therapy in women less than 5 years from menopause and for CEE therapy in women younger than 60 years old (Table 5). Data from the Nurses Health Study indicate that stroke risk associated with hormone therapy may be a function of estrogen dose. 46 Prophylactic use of aspirin for primary prevention of coronary heart disease is a common medical practice and recommended by major health organizations. 5 However, the Women s Health Study (WHS) of 39,876 healthy women randomized to aspirin 100 mg every other day or placebo for 10 years showed a null effect of aspirin on the primary trial endpoint of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death (RR = 0.91, 95% CI: 0.80<1.03). 47 Overall mortality and cardiovascular death from any cause were also unaffected by aspirin. Within the null finding was no effect on fatal or nonfatal myocardial infarction (RR = 1.02, 95% CI: 0.84<1.25) and a 17% (RR = 0.83, 95% CI: 0.69<0.99) reduction in stroke with aspirin relative to placebo, or two fewer strokes per 10,000 women per year of aspirin use. Although ischemic stroke was reduced 24% (RR = 0.76, 95% CI: 0.63<0.93) with aspirin relative to placebo, hemorrhagic stroke was also increased 24% (RR = 1.24, 95% CI: 0.82<1.87) with aspirin relative to placebo (Table 4). Bleeding diatheses, not seen with hormone therapy, were all significantly increased with aspirin versus placebo in the WHS. 47 Any gastrointestinal bleeding was increased 22% (RR = 1.22, 95% CI: 1.10<1.34) with aspirin versus placebo, and gastrointestinal bleeding requiring blood transfusion was increased 40% (RR = 1.40, 95% CI: 1.07<1.83) with aspirin versus placebo. The absolute increased risk of any gastrointestinal bleeding was eight additional cases per 10,000 women per year of aspirin use. The other randomized, controlled trials of aspirin that included women were of smaller size and shorter duration than WHS but showed similar magnitudes of risk with no overall reduction in cardiovascular events (Hypertension Optimal Treatment [HOT]: n = 8,883 women, 3.8 years 48, and Primary Prevention Project [PPP]: n = 2,583 women, 3.6 years 47,49 ). Meta-analyses confirm the same or greater levels of risks of bleeding diatheses and hemorrhagic stroke for men, in whom Menopause, Vol. 14, No. 5, 2007 5

HODIS AND MACK TABLE 4. Comparison of absolute and relative risks of stroke in randomized, controlled trials of postmenopausal hormone therapy and other medications Trial Sample size Mean age, y Cohort Study duration, y No. of additional combined strokes per 10,000 women per year of therapy Combined stroke, RR (95% CI) Fatal stroke, RR (95% CI) Nonfatal stroke, RR (95% CI) Ischemic stroke, RR (95% CI) Hemorrhagic stroke, RR (95% CI) Aspirin WHS 47 39,876 54.6 jcvd 10.0 j2 0.83 (0.69<0.99) 1.04 (0.58<1.86) 0.81 (0.67<0.97) 0.76 (0.63<0.93) 1.24 (0.82<1.87) Tamoxifen NSABP 53 13,388 53 jcvd 5.0 5 1.59 (0.93<2.77) 1.34 a NR 1.63 a NR 1.51 a NR 1.67 a NR Raloxifene RUTH 54 10,101 67.5 TCHD 5.6 9 1.10 (0.92<1.32) 1.49 (1.00-2.24) f NR 1.15 (0.93<1.41) 0.59 (0.33<1.06) CEE + MPA WHI-EP 43 16,608 63.3 jcvd 5.6 7 1.31 (1.02<1.68) b (0.93<1.84) c 1.20 d (0.58<2.50) d (0.32<4.49) d 1.50 d (1.08<2.08) d 1.44 (1.09<1.90) (0.83<2.70) d adjusted NR 0.82 (0.43<1.56) adjusted NR HERS 42 2,763 66.7 +CHD 4.1 27 1.23 (0.89<1.70) 1.61 (0.73<3.55) 1.18 (0.83<1.66) 1.18 (0.83<1.67) 1.65 (0.47<5.72) CEE alone WHI-E 45 10,739 63.6 jcvd 6.8 12 1.37 (1.09<1.73) (0.97<1.99) e 1.13 e (0.54<2.34) e (0.38<3.36) e 1.39 e (1.05<1.89) e 1.55 (1.19<2.01) (0.91<2.12) e adjusted NR 0.64 (0.35<1.18) adjusted NR 17A-estradiol alone WEST 24 664 71 +CVA/TIA 2.8 56 1.10 (0.80<1.60) 2.90 (0.90<9.00) 1.00 (0.70<1.40) 1.00 (0.6<1.4) 1.30 (0.3<6.0) RR, relative risk; WHS, Women s Health Study; NSABP, National Surgical Adjuvant Breast and Bowel Project; RUTH, Raloxifene Use for the Heart; WHI-EP, Women s Health Initiative estrogen + progestin trial; HERS, Heart and Estrogen/progestin Replacement Study; WHI-E, Women s Health Initiative estrogen trial; WEST, Women s Estrogen for Stroke Trial; CEE, conjugated equine estrogens; MPA, medroxyprogesterone acetate; NR, not reported; Combined stroke, nonfatal + fatal stroke; jcvd, no previous cardiovascular disease; +CHD, previous coronary heart disease; +CVA/TIA, previous cerebrovascular accident or transient ischemic attack. a Relative risk (95% CI) not reported. Relative risk calculated from data given in reference. Placebo: 3 fatal strokes, 21 nonfatal strokes, 14 ischemic strokes, 6 hemorrhagic strokes; tamoxifen: 4 fatal strokes, 34 nonfatal strokes, 21 ischemic strokes, 10 hemorrhagic strokes. b Unadjusted CI describes the variability of the point estimate that would arise from a simple trial for a single outcome. c Adjusted CI describes the variability of the point estimate corrected for multiple outcome analyses. d Fully adjudicated data not reported in reference 43. Data shown in table are the original partially adjudicated data from reference 12. e Fully adjudicated data not reported in reference 45. Data shown in table are the original partially adjudicated data from reference 44. f Mosca L, Grady D, Barrett-Connor E, et al. Risk of stroke in the Raloxifene Use for The Heart (RUTH) trial. Circulation 2006;114(Suppl2):444. 6 Menopause, Vol. 14, No. 5, 2007 * 2007 The North American Menopause Society

POSTMENOPAUSAL HORMONE THERAPY IN CLINICAL PERSPECTIVE TABLE 5. Absolute risk of stroke according to age and years since menopause when randomized to the Women s Health Initiative trials Absolute risk no. of strokes per 10,000 women per year Placebo (n = 8,102) WHI-EP 43 CEE + MPA (n = 8,506) No. of additional cases of stroke per 10,000 women per year of therapy Years since menopause G5 7 10 3 5toG10 11 17 6 10 to G15 17 27 10 915 42 48 6 Age, y 50<59 10 14 4 60<69 23 32 9 70<79 48 61 13 Placebo (n = 5,429) WHI-E 45 CEE (n = 5,310) Years since menopause G10 10 25 15 10 to 20 21 34 13 920 35 47 12 Age, y 50<59 12 13 1 60<69 24 41 17 70<79 44 66 22 WHI-EP, Women s Health Initiative estrogen + progestin trial; WHI-E, Women s Health Initiative estrogen trial; CEE, conjugated equine estrogens; MPA, medroxyprogesterone acetate. the data are more substantial because the majority of study participants in the randomized, controlled trials of aspirin have been men. 50 Sudden death was increased in men randomized to aspirin versus placebo. In the Physicians Health Study (PHS) (n = 22,071), there were 22 sudden deaths in the men randomized to aspirin and 12 events in men randomized to placebo (OR = 1.96, 95% CI: 0.91<4.23), or an increased absolute risk of five sudden deaths per 10,000 men per year of aspirin use. 51 Whether aspirin causes sudden death in women is unknown because these data were not reported in WHS, HOT, or PPP. The magnitude of the side effects associated with aspirin resembles those from CEE + MPA and CEE from the WHI. 12,44 Other medications such as tamoxifen and raloxifene are similarly associated with increased incidence of stroke. 52 In the National Surgical Adjuvant Breast and Bowel Project (NSABP) trial of 13,388 women, the incidence of stroke increased from 24 events in the placebo group to 38 events in the tamoxifen group (RR = 1.59, 95% CI: 0.93<2.77). 53 This RR equates to 9 cases of stroke per 10,000 women per year of placebo use versus 14 cases of stroke per 10,000 women per year of tamoxifen use, or approximately 5 additional cases of stroke per 10,000 women per year of tamoxifen use. In a 5.6-year clinical trial of 10,101 postmenopausal women, the incidence of stroke increased from 79 events per 10,000 women per year in the placebo group to 88 events per 10,000 women per year in the raloxifene group (RR = 1.10, 95% CI: 0.92<1.32), or 9 additional cases of stroke per 10,000 women per year of raloxifene use. 54 After 3 years of use, raloxifene was associated with an increased risk of fatal stroke compared with placebo (RR = 1.49, 95% CI: 1.00-2.24) (Table 4). The RR of stroke seen with tamoxifen and raloxifene is comparable to that seen with postmenopausal hormone therapy, and, like with postmenopausal hormone therapy, the absolute risk is of small magnitude in the primary prevention setting (Table 4). It is of interest to examine stroke subtypes by various interventions as reported in the literature (Table 6). Under primary prevention conditions, hormone therapy seems to have a pattern of increasing the risk of ischemic stroke while decreasing the risk of hemorrhagic stroke. Whereas ischemic stroke risk was increased 44% in the WHI-EP, hemorrhagic stroke risk associated with oral daily continuous combined CEE + MPA therapy relative to placebo was reduced 18%. 43 TABLE 6. Comparison of absolute and relative risks of ischemic and hemorrhagic stroke among various therapies Trial Therapy Ischemic stroke, RR (95% CI) Hemorrhagic stroke, RR (95% CI) Primary WHI-EP 43 CEE + MPA 44% j18% 1.44 (1.09<1.90) 0.82 (0.43<1.56) WHI-E 45 CEE 55% j36% 1.55 (1.19<2.01) 0.64 (0.35<1.18) WHS 47 Aspirin j24% 24% 0.76 (0.63<0.96) 1.24 (0.82<1.87) HPS 27 Statin j30% j30% 0.7 (0.5<0.8) 0.7 (0.4<1.2) Secondary HERS 42 CEE + MPA 18% 65% 1.18 (0.83<1.67) 1.65 (0.47<5.72) WEST 24 17A-estradiol 0% 30% 1.0 (0.6<1.4) 1.3 (0.3<6.0) SPARCL 55 Statin j22% 66% 0.78 (0.66<0.94) 1.66 (1.08<2.55) HPS 27 Statin j20% 90% 0.8 (0.6<1.1) 1.9 (0.9<4.4) Absolute risk per 10,000 women per year Ischemic stroke Hemorrhagic stroke Primary WHI-EP 43 CEE + MPA 8 j1 WHI-E 45 CEE 13 j2 WHS 47 Aspirin j3 1 HPS 27 Statin j22 j3 Secondary HERS 42 CEE + MPA 18 5 WEST 24 17A-estradiol j37 9 SPARCL 55 Statin j48 19 HPS 27 Statin j28 13 RR, relative risk; WHI-EP, Women s Health Initiative estrogen + progestin trial; WHI-E, Women s Health Initiative estrogen trial; WHS, Women s Health Study; HPS, Heart Protection Study; HERS, Heart and Estrogen/ progestin Replacement Study; WEST, Women s Estrogen for Stroke Trial; SPARCL, Stroke Prevention by Aggressive Reduction in Cholesterol Levels; CEE, conjugated equine estrogens; MPA, medroxyprogesterone acetate; Statin, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. Menopause, Vol. 14, No. 5, 2007 7

HODIS AND MACK TABLE 7. Comparison of absolute and relative risks of venous thromboembolism, deep vein thrombosis, and pulmonary embolism in randomized, controlled trials of postmenopausal hormone therapy and other medications Trial and outcome NSABP 53 Absolute risk events per 10,000 women per year No. of additional cases per 10,000 women per year of therapy RR (95% CI) Placebo Therapy Tamoxifen VTE NR NR NR < DVT 1.60 (0.91<2.86) 8 13 5 PE 3.01 (1.15<9.27) 23 69 46 RUTH 54 Raloxifene VTE 1.44 (1.06<1.95) 25 36 11 DVT 1.37 (0.94<1.99) 16 23 7 PE 1.49 (0.89<2.49) 8 13 5 FIELD a66 Fenofibrate VTE NR NR NR < DVT b NR 20 27 7 PE c NR 13 22 9 WHI-EP 56 CEE + MPA VTE 2.06 (1.57<2.70) 17 35 18 DVT 1.95 (1.43<2.67) 13 26 13 PE 2.13 (1.45<3.11) 8 18 10 HERS 62 CEE + MPA VTE 2.7 (1.4<5.0) 23 62 39 DVT 2.8 (1.3<6.0) 16 44 28 PE 2.8 (0.9<8.7) 7 19 12 WHI-E 64 CEE alone VTE 1.32 (0.99<1.75) 22 30 8 DVT 1.47 (1.06<2.06) 15 23 8 PE 1.37 (0.90<2.07) 10 14 4 WEST 24 17A-Estradiol alone VTE 0.8 (0.2<3.4) 44 32 j12 DVT 0.5 (0.0<5.8) 22 11 j11 PE 1.0 (0.1<7.1) 22 21 j1 RR, relative risk; NSABP, National Surgical Adjuvant Breast and Bowel Project; RUTH, Raloxifene Use for the Heart; FIELD, Fenofibrate Intervention and Event Lowering in Diabetes; WHI-EP, Women s Health Initiative estrogen + progestin trial; HERS, Heart and Estrogen/progestin Replacement Study; WHI-E, Women s Health Initiative estrogen trial; WEST, Women s Estrogen for Stroke Trial; VTE, venous thromboembolism; DVT, deep vein thrombosis; PE, pulmonary embolus; CEE, conjugated equine estrogens; MPA, medroxyprogesterone acetate; NR, not reported. a Cohort comprised 37% (n = 3,657) women. b Increased risk of deep vein thrombosis, P = 0.074. c Increased risk of pulmonary embolism, P = 0.022. In the WHI-E, ischemic stroke risk was increased 55%, whereas hemorrhagic stroke risk was reduced 36% in the oral CEE therapy group relative to placebo. 45 The pattern of hormone therapy in stroke risk contrasts with that of aspirin in the WHS, where a different pattern emerges. Although ischemic stroke risk was reduced 24%, the risk of hemorrhagic stroke was also increased 24% with aspirin therapy relative to placebo. 47 As HPS shows, statins seem to reduce both ischemic and hemorrhagic stroke risk under primary prevention conditions. In individuals with preexisting cardiovascular disease, hemorrhagic stroke risk compared to placebo seems to be elevated regardless of the therapy. In the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial, although ischemic stroke risk was reduced 22%, hemorrhagic stroke risk was increased 66% with statin therapy relative to placebo. 55 In HPS, hemorrhagic stroke risk was increased 90% with statin therapy relative to placebo. 27 Although hormone and nonhormone therapies tend to have statistically significant effects on the risk of stroke subtypes, absolute additional stroke protection or risk tends to be of a low magnitude, especially in individuals without preexisting cardiovascular disease (Table 6). VENOUS THROMBOEMBOLISM VTE is a disease process comprised of two different outcomes, deep vein thrombosis (DVT) and pulmonary embolism (PE). For DVT, there are two distinct clinical entities classified according to location: calf and other. Calf DVTs are considered clinically benign and typically are not treated because pathophysiologically they are rarely associated with PE. To date, the distinction between calf and other DVT locations associated with randomization in hormone therapy trials of cardiovascular disease have not been published. Although there was a two-fold greater risk of VTE in the CEE + MPA group relative to the placebo group in the WHI-EP, the increase in the absolute risk was small and comparable to that of other medications 56 (Table 7). The elevated absolute risk of VTE was lowest for women who were younger than 60 years old when randomized. For women younger than 60 years old, there were 11 additional cases of VTE per 10,000 women per year of CEE + MPA use versus 51 additional cases of VTE per 10,000 women per year of CEE + MPA use in women older than 60 years old 56 (Table 8). The increased risk of VTE was greatest in the first year after randomization and significantly decreased but remained elevated over time: the HR for VTE was 4.01 (CIs not reported) in year 1 of treatment, 1.97 in year 2, 1.74 in year 3, 1.70 in year 4, 2.90 in year 5, and 1.04 in year 6 and beyond (P for trend = 0.01). 56 This trend in the TABLE 8. Absolute and relative risks of venous thromboembolism in the Women s Health Initiative estrogen + progestin trial by age Age at screening, y Absolute risk per 10,000 women per year HR (95% CI) (relative to 50- to 59-year-old placebo group) 50<59 Placebo 8 1.00 CEE + MPA 19 2.27 (1.19<4.33) CEE + MPA vs placebo 11 a 2.27 b 60<69 Placebo 19 2.31 (1.23<4.35) CEE + MPA 35 4.28 (2.38<7.72) CEE + MPA vs placebo 16 a 1.85 b 70<79 Placebo 27 3.37 (1.72<6.60) CEE + MPA 62 7.46 (4.32<14.38) CEE + MPA vs placebo 35 a 2.21 b HR, hazard ratio; CEE, conjugated equine estrogens; MPA, medroxyprogesterone acetate. a Number of additional cases of venous thromboembolism per 10,000 women per year of conjugated equine estrogens + medroxyprogesterone acetate therapy (difference of age-specific absolute risks). b Hazard ratio within each age group (ratio of age-specific hazard ratios). 8 Menopause, Vol. 14, No. 5, 2007 * 2007 The North American Menopause Society

POSTMENOPAUSAL HORMONE THERAPY IN CLINICAL PERSPECTIVE TABLE 9. Absolute and relative risks of deep vein thrombosis, pulmonary embolism, and venous thromboembolism in the Women s Health Initiative estrogen trial by age Deep vein thrombosis Pulmonary embolism Venous thromboembolism Age at screening, y Absolute risk per 10,000 women per year HR (95% CI) (relative to 50< to 59-year-old placebo group) Absolute risk per 10,000 women per year HR (95% CI) (relative to 50< to 59-year-old placebo group) Absolute risk per 10,000 women per year HR (95% CI) (relative to 50< to 59-year-old placebo group) 50<59 Placebo 8 1.00 6 1.00 12 1.00 CEE 13 1.64 (0.74<3.40) 10 1.54 (0.63<3.77) 16 1.37 (0.70<2.68) CEE vs placebo 5 a 1.64 b 4 a 1.54 b 4 a 1.37 b 60<69 Placebo 17 2.17 (1.06<4.45) 10 1.63 (0.70<3.78) 25 2.16 (1.20<3.89) CEE 23 3.02 (1.51<6.06) 17 2.80 (1.28<6.16) 32 2.82 (1.59<5.01) CEE vs placebo 6 a 1.39 b 7 a 1.72 b 7 a 1.31 b 70<79 Placebo 22 2.94 (1.37<6.30) 16 2.67 (1.12<6.39) 31 2.78 (1.48<5.22) CEE 34 4.54 (2.22<9.31) 14 2.36 (0.96<5.80) 42 3.77 (2.07<6.89) CEE vs placebo 12 a 1.54 b j2 a 0.88 b 11 a 1.36 b HR, hazard ratio; CEE = conjugated equine estrogens. a Number of additional cases of deep vein thrombosis, pulmonary embolism, or venous thromboembolism per 10,000 women per year of conjugated equine estrogens therapy (difference of age-specific absolute risks). b Hazard ratio within each age group (ratio of age-specific hazard ratios). reduction of VTE over time is consistent with those of previous observational studies, the majority of which suggest an early effect of postmenopausal hormone therapy on VTE limited to the first year of therapy and/or a decreasing risk of VTE over time. 13,14,57<61 In HERS, CEE + MPA was associated with a 2.7-fold increased risk of VTE relative to placebo 62 (Table 7). The increase in the absolute risk of VTE from CEE + MPA in HERS was greater than in the WHI-EP due to the greater baseline risk of VTE in HERS, a secondary prevention trial. Similar to the WHI-EP, over 6.8 years of follow-up, the HR for VTE declined from 2.66 during HERS 11,62 to 1.40 during the open-label follow-up of 2.7 years 63 (test for time trend, P =0.08). The results from the WHI-E showed a smaller RR of 1.32 (95% CI: 0.99<1.75) with respect to the risk of VTE with CEE alone relative to placebo 64 (Table 7). The absolute risk of VTE was lowest for women who were younger than 60 years old when randomized. For women younger than 60 years old, there were 4 additional cases of VTE per 10,000 women per year of CEE use versus 18 additional cases of VTE per 10,000 women per year of CEE use in women older than 60 years old (Table 9). Comparison of the results from the WHI-EP (HR = 2.1) and WHI-E (HR = 1.3) suggest that the VTE risk associated with CEE alone is less than the risk associated with CEE + MPA (62% increased risk associated with MPA relative to CEE alone). In the WEST, VTE and DVT were lower in the estradiol group relative to placebo, whereas there was no effect on PE 24 (Table 7). The cumulated data suggest that the increased risk of VTE associated with CEE + MPA is not generalizable to CEE alone or to other forms of estrogen. In a case-control study of 586 incident VTE cases and 2,268 controls, compared to women not currently using hormone therapy, current users of esterified estradiol alone, esterified estradiol + MPA, and CEE alone did not have an increased risk of VTE, whereas current users of CEE + MPA had a two-fold statistically significant increased risk of VTE 65 (Table 10). In combination with MPA, esterified estradiol (OR = 1.08) and CEE (OR = 2.17) had increased RRs of VTE, CEE + MPA was statistically significant (Table 10). The increased risk of VTE associated with CEE + MPA (OR = 2.17) in this casecontrol study was similar to the risk reported from the HERS (HR = 2.7) and WHI-EP (HR = 2.06). The risk of VTE associated with CEE alone (OR = 1.31) in this case-control study was similar to that of the WHI-E (HR = 1.32). Esterified estradiol alone (OR = 0.78) was also similar to estradiol alone in the WEST (RR = 0.8). Most studies of VTE risk in hormone users have been conducted in women using orally administered exogenous hormones. Theoretically, TABLE 10. Risk of venous thromboembolism with current use of different hormone therapies None EE alone EE + MPA CEE alone CEE + MPA No. of participants a Cases 372 39 47 57 64 Controls 1,439 278 237 167 122 OR (95% CI) Reference 0.78 (0.53<1.15) 1.08 (0.75<1.56) 1.31 (0.91<1.88) 2.17 (1.49<3.14) OR 0.80 (WEST) 1.32 (WHI-E) 2.06 (WHI-EP) EE, esterified estrogen; MPA, medroxyprogesterone acetate; CEE, conjugated equine estrogens; OR, odds ratio; WEST, Women s Estrogen for Stroke Trial; WHI-E, Women s Health Initiative estrogen trial; WHI-EP, Women s Health Initiative estrogen + progestin trial. a Excludes 7 case and 25 control subjects who were current users of estrogens other than equine estrogen and conjugated equine estrogens. Menopause, Vol. 14, No. 5, 2007 9

HODIS AND MACK nonoral routes of administration of hormone therapy should be associated with a lower risk of VTE than oral hormone therapy because of avoidance of the first-pass liver effects on procoagulation. However, the data are mixed, and this hypothesis has yet to be tested. 57,58,61 Although the data remain sparse, the effect of different hormones and regimens on VTE outcomes is intriguing and warrants further investigation. Other commonly used medications are also associated with elevated VTE risk. Both tamoxifen 53 and raloxifene 54 increase VTE by 1.4- to 3-fold. Like postmenopausal hormone therapy, the additional absolute risk tends to be small (Table 7). The added absolute risk of VTE from raloxifene (11 additional cases per 10,000 women per year of use) is similar to that of oral daily continuous combined CEE + MPA (18 additional cases per 10,000 women per year of use) and CEE alone in the WHI (8 additional cases per 10,000 women per year of use) but greater than the risk associated with 17A-estradiol alone (12 fewer cases per 10,000 women per year of use) (Table 7). The relative and absolute risks of PE associated with tamoxifen are greater than those associated with postmenopausal hormone therapy (Table 7). Fenofibrate (a fibric acid derivative used for lipid lowering) has also been shown to increase the risk of DVT and PE relative to placebo in diabetics, with seven additional DVTs per 10,000 subjects per year of fenofibrate use and nine additional PEs per 10,000 subjects per year of fenofibrate use 66 (Table 7). ADDITIONAL CONSIDERATIONS Other commonly used medications and supplements also exhibit risks comparable to or greater than those of postmenopausal hormone therapy. The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study was designed to assess the effect of fenofibrate on cardiovascular disease events in patients with type 2 diabetes mellitus. 66 This trial included 9,795 participants who were 50 to 75 years old; 37% of the participants were women. After 5 years of treatment, the primary endpoint of coronary events was nonsignificantly reduced in the fenofibrate group versus the placebo group (HR = 0.89, 95% CI: 0.75<1.05). This included a reduction in nonfatal myocardial infarction in the fenofibrate versus placebo group of 24% (HR = 0.76, 95% CI: 0.62<0.94) and an increase in coronary heart disease mortality of 19% (HR = 1.19, 95% CI: 0.90<1.57), resulting in seven additional coronary heart disease deaths per 10,000 participants per year of fenofibrate use. 66 Additionally, in the FIELD study, there were nine additional cancers per 10,000 subjects per year of fenofibrate use. In the FIELD study, although total cardiovascular disease events were reduced 11% (HR = 0.89, 95% CI: 0.80<0.99), total mortality was increased 11% (HR = 1.11, 95% CI: 0.95<1.29), resulting in 13 additional total deaths per 10,000 participants per year of fenofibrate use. 66 This same mixed pattern of an overall null effect on the primary endpoint of coronary events with a reduction in nonfatal myocardial infarction but an increase in total mortality of similar magnitude to that of the FIELD study has been reported with vitamin E supplementation in randomized, controlled trials. 67 The increased mortality seen with fenofibrate in the FIELD study and vitamin E in the Cambridge Heart Antioxidant Study (CHAOS) contrasts with certain subgroups receiving postmenopausal hormone therapy. In a meta-analysis of 30 randomized, controlled trials, women younger than 60 years old who were randomized to hormone therapy (a population of women similar to observational studies) had a 39% reduction in overall mortality relative to women randomized to placebo (OR = 0.61, 95% CI: 0.39<0.95), whereas in all women (OR = 0.98, 95% CI: 0.87<1.18) and in women older than 60 years old (OR = 1.03, 95% CI: 0.90<1.18), there was no difference in overall mortality. 9 Other commonly used products also demonstrating elevated risks have received little public health attention. In the Alpha- Tocopherol Beta-Carotene Cancer Prevention Study of 29,133 male smokers randomized for a median of 6.1 years, A-carotene increased the incidence of lung cancer by 18% (RR = 1.18, 95% CI: 1.03<1.36), resulting in nine additional lung cancers per 10,000 subjects per year of A-carotene use. 68 Overall mortality was also increased in the A-carotene group versus placebo group (RR = 1.08, 95% CI: 1.01<1.16) due to 5 additional lung cancer deaths, 8 additional ischemic heart disease deaths, 1.5 additional ischemic stroke deaths, and 1 additional hemorrhagic stroke death, each per 10,000 subjects per year of A-carotene use. 68 In subjects with previous myocardial infarction, fatal coronary heart disease death was increased in the A-carotene versus placebo group by 75% (RR = 1.75, 95% CI: 1.16<2.64), resulting in 146 additional fatal coronary heart disease deaths per 10,000 subjects per year of A-carotene use. 69 The results of the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study were confirmed in a second randomized, controlled trial (40% female) of A-carotene and retinol in 18,314 smokers, former smokers, and workers exposed to asbestos in the Beta- Carotene and Retinol Efficacy Trial (CARET). 70 After a mean follow-up of 4 years, subjects randomized to A-carotene and retinol had a 28% (RR = 1.28, 95% CI: 1.04<1.57) increase in lung cancer compared to the placebo group, resulting in 13 additional lung cancers per 10,000 subjects per year of A-carotene and retinol use. In the A-carotene and retinol group, the risk of death from lung cancer was increased 46% (RR = 1.46, 95% CI: 1.07<2.00) and the risk of death from cardiovascular disease was increased 26% (RR = 1.26, 95% CI: 0.99<1.61) compared to the placebo group. 70 Compared to the placebo group, death from any cause was increased 17% (RR = 1.17, 95% CI: 1.03<1.33) in the A-carotene and retinol group, resulting in 26 additional deaths per 10,000 subjects per year of A-carotene and retinol use. 70 Although conducted primarily in men, these studies demonstrate risk (without benefit) in a population at risk for lung cancer and cardiovascular disease from a commonly used supplement that exceeds that reported with postmenopausal hormone therapy. 10 Menopause, Vol. 14, No. 5, 2007 * 2007 The North American Menopause Society