Assessing benefits and risks of hormone therapy in 2008: New evidence, especially with regard to the heart

HORMONE THERAPY IN CLINICAL PERSPECTIVE

Comparative effects of lipid-lowering therapy and HT

Examination of the evidence regarding lipid-lowering therapy for prevention of CHD, as well as its effects on breast cancer risk and coronary artery calcium scores in women, can add some much-needed perspective and context to the HT data reviewed above.

CHD prevention. Walsh and Pignone examined six randomized controlled trials (N = 11,435) of primary prevention with lipid-lowering medication in women and found no significant effect on CHD events, nonfatal myocardial infarction, CHD mortality, or total mortality.³⁴ In eight randomized controlled trials of secondary prevention (N = 8,272), lipid-lowering therapy in women resulted in significant reductions in CHD end points but had no effect on total mortality.³⁴

Breast cancer risk. In the WHI and in HERS, randomization to EPT resulted in nonsignificant increases of 20%¹⁴ and 30%,²⁸ respectively, in the risk of breast cancer compared with placebo, and randomization to ET in the WHI was associated with a nonsignificant 18% reduction in breast cancer risk²² (Table 4). In randomized controlled trials of statins published to date,³⁵ the risk of breast cancer in the women randomized to a statin relative to placebo ranged from a reduction of 25% (Heart Protection Study [HPS])³⁶ to a 12-fold increase (Cholesterol and Recurrent Events [CARE] trial)³⁷ (Table 4). In three meta-analyses of statins and cancer risk,^38–40 statin therapy was associated with a nonsignificant increase in breast cancer risk relative to placebo (HRs ranging from 1.04 to 1.33), accounting for 2 to 7 additional breast cancer cases per 10,000 women per year of statin use. These data suggest similar magnitudes of risk for HT and statins in terms of breast cancer diagnosis.³⁵

Atherosclerosis progression. In three randomized controlled trials, 1 to 4 years of statin therapy had no effect on the progression of coronary artery calcium compared with placebo.^41–43 Among 1,064 women 50 to 59 years old who participated in a WHI substudy called the WHI Coronary Artery Calcium Study (WHI-CACS), those who were randomized to ET had significantly less coronary artery calcium at year 7 compared with those assigned to placebo.⁴⁴ The mean Agatston coronary artery calcium scores were 83.1 with ET versus 123.1 with placebo (P = .02).

Comparing risk of HT with risk of other therapies

The magnitude and types of risk associated with HT are similar to those associated with other commonly used therapies, such as vitamin supplements,⁴⁵ calcium supplements,⁴⁶ statins,⁴⁷ aspirin,^48,49 fibrates,⁵⁰ oral antidiabetic medications,⁵¹ and selective estrogen receptor modulators⁵² (Table 5). For example, the risk of stroke associated with HT is less than that of fatal stroke with raloxifene⁵² and the excess risk of hemorrhagic stroke with atorvastatin in secondary prevention of stroke.⁴⁷ Although comparing risks between therapies is imprecise because risk estimates are obtained from studies of different populations, it does serve to provide a perspective of the accepted magnitude of risks and reassurance concerning the safety of HT.

Other comparisons yield similar conclusions.³⁵ For instance, a comparison of the ET arm of the WHI randomized trial with raloxifene in the Raloxifene Use for the Heart (RUTH) trial⁵² reveals similar effects on CHD, stroke, VTE, pulmonary embolism, deep vein thrombosis, and breast cancer, with the only large difference being a greater reduction in bone fracture risk with ET compared with raloxifene.³⁵ Finally, in putting the risk of VTE with HT into perspective, consider that the risk of thromboembolic events with selective estrogen receptor modulators⁵² and with the fibric acid derivative fenofibrate in diabetics⁵⁰ is of similar magnitude as the risk with HT.

Risk must be viewed in light of age at HT initiation

Figure 2 presents the risks and benefits (in terms of CHD, stroke, VTE, breast cancer, and overall death) with ET (relative to placebo) in the WHI randomized trial according to age at enrollment.^11,12 Notably, ET recipients in the youngest age group (50 to 59 years) experienced a reduction in the risk of all outcomes except VTE. In contrast, ET recipients in the oldest age cohort (70 to 79 years) had an increase in the risk of all outcomes except, unexpectedly, breast cancer. The final column, which presents a “global index” for the cumulative events, shows that among women enrolled between ages 50 to 59, ET was associated with approximately 20 fewer events per 10,000 women per year of therapy compared with placebo. A null effect is observed among women enrolled at ages 60 to 69, and an excess of approximately 45 events is observed with ET among women enrolled at ages 70 to 79.

CONCLUSIONS FROM RANDOMIZED TRIALS

HT’s effects on CHD and mortality: Timing is everything

Cumulative data from randomized trials indicate that in the overall population of women studied, HT, aspirin, and lipid-lowering therapy each have a null effect on the incidence of CHD and mortality. However, within this overall null effect, early initiation of HT (in terms of time from menopause [< 10 years] and age at initiation [< 60 years]) is associated with reductions in total mortality and CHD incidence. Additionally, a duration of HT use beyond 5 years is associated with a reduction in the incidence of CHD.^{9,10,20,28,29} These effects of the timing and duration of therapy are unique to HT. Unopposed ET may have an advantageous profile relative to EPT for reducing the incidence of CHD and mortality in postmenopausal women.

Gaining perspective on risks

The risks of stroke and VTE associated with HT are low for women overall and lower still for women who are within 10 years of menopause or younger than age 60 when they start HT. With respect to stroke, fewer cases of stroke developed in users of ET compared with placebo in women who started HT before age 60. The risks of EPT are comparable to those of other medications commonly used in this population of women. More broadly, the magnitude and types of risk associated with HT are similar to those associated with other commonly used therapies.

In addition, the underappreciated benefits of HT, such as potential prevention of diabetes mellitus (15 fewer cases of incident diabetes per 10,000 women per year with EPT and 14 fewer cases with ET), need to be recognized and discussed with our patients. These data are consistent in both observational studies and randomized trials.

The bottom line

As data from randomized trials of HT accumulate, the results are clearly similar to those from the more than 20 observational studies indicating that young, symptomatic postmenopausal women who use HT for long periods have lower rates of CHD and total mortality compared with postmenopausal women who do not use HT. Consistent with these data, the American Association of Clinical Endocrinologists issued a position statement in 2008 concluding that for symptomatic menopausal women under the age of 60, the benefits of HT exceed the risks.⁵³

Nevertheless, the bottom line remains that the estrogen-cardioprotective hypothesis has yet to be studied, since randomized trials have not been conducted in the same population of women from which the hypothesis was generated. This hypothesis will be directly evaluated, however, in the ongoing Early versus Late Intervention Trial with Estradiol (ELITE). This randomized trial, funded by the National Institute on Aging, is designed to determine the effects of 17β-estradiol on the progression of atherosclerosis, cognition, and other postmenopausal health issues in recently menopausal (< 6 years) and remotely menopausal (≥ 10 years) women with no history of cardiovascular disease or diabetes. Until data from trials like ELITE emerge, guidelines such as those from the North American Menopause Society⁵⁴ (reviewed in the next article in this supplement) are reasonable for clinical practice.