4. Stop long-term, fixed-dose EPT in asymptomatic women
Also eliminate its use for cardiovascular protection. Asymptomatic women do not need—nor will they benefit from—ET/EPT, so there is no reason to use it. EPT’s potential benefit in terms of bone loss and fractures can be achieved with other agents that are FDA-approved for the prevention of osteoporosis but carry less risk of breast cancer, cardiovascular disease, or thromboembolic events.
Overview and implications of Women’s Health Initiative data
During an interim analysis of the Women’s Health Initiative (WHI) estrogen-progestin arm, the data safety monitoring board determined that estrogen and progestin therapy (EPT) had a greater potential for harm than for benefit. So on July 9, 2002, after an average of 5.2 years of observation, that arm was halted.1
The other arm of the trial continued to examine the use of unopposed estrogen in hysterectomized women. The fact that it continues suggests that its global index is still not definitively unfavorable.
At the time the EPT arm was halted, its participants had an increased incidence of 26% for breast cancer, 41% for stroke, 29% for coronary heart disease events, and 110% for thromboembolic events, compared with the placebo group. On the benefit side, they experienced a 37% reduction in colorectal cancer and a 34% reduction in hip fractures. These reductions were not sufficient to offset the increased risk (TABLES 1 and 2). There was no difference in mortality rates between the EPT and placebo groups.
Absolute versus relative risk. Because relative risks are confusing and often misunderstood, the results were also reported in absolute values, expressed in the number of additional events for treated woman-years, which is more meaningful to individual women. Thus, among 10,000 women taking EPT for a year, there will be 8 more cases of invasive breast cancer, 8 more strokes, 8 more pulmonary embolic events, and 7 more myocardial infarctions, but 6 fewer cases of colorectal cancer and 5 fewer hip fractures.
The absolute risk for an individual woman remains quite small (less than 0.1% per year). When this risk was calculated for all events over the 5.2 years of the trial, approximately 100 more women in the hormone group experienced an adverse event than in the placebo group. If this figure is extrapolated to the population at large and to a longer treatment duration, the use of EPT could account for tens of thousands of additional adverse events.
Study excluded women with hot flashes. The WHI did not evaluate the relief of vasomotor symptoms. In fact, women with severe hot flashes were excluded from the study. This means that the major benefits and most common indication for EPT were not considered in the risk-benefit ratio. Had they been included, that ratio might have yielded different results.
Value of the data. Nevertheless, the WHI data do provide important information, which allows us to discuss the benefits and risks of EPT more precisely and more objectively, especially for asymptomatic postmenopausal women.
REFERENCE
1. Writing group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women’s Health Initiative randomized control trial. JAMA. 2002;288:321-323.
- The bisphosphonates—alendronate and risedronate—are safe, effective, convenient (weekly dosing), and not associated with life-threatening side effects.
- Raloxifene, the selective estrogen receptor modulator, is another good alternative for prevention and treatment of osteoporosis in patients not at risk for thromboembolic events. Unlike ET/EPT, raloxifene is not associated with an increased risk of either breast cancer or cardiovascular events. In fact, data from the Multiple Outcomes of Raloxifene Evaluation study suggest that, besides protecting against bone loss and vertebral fractures,7 raloxifene may reduce the risk of breast cancer8 by as much as 75%.9 Nor was raloxifene found to increase the risk or incidence of cardiovascular disease.8 In fact, in a group of 1,035 postmenopausal women at high risk for cardiovascular disease, raloxifene reduced the incidence of all cardiovascular events by 40%.9
5. Annually reassess the ratio of benefit to risk
At every patient’s annual visit, weigh the reasons for hormone therapy against current knowledge of the benefit-risk ratio, which evolves along with the patient’s needs and status. When all the data from the WHI studies are available and reassessed, the benefit-risk ratio is likely to change again, further altering our recommendations. In my practice I explain the current data and remind patients that the most important—if not the only—reason for ET/EPT is to control menopausal symptoms.
To determine whether the menopausal symptoms have resolved or have become more tolerable, I invite the patient to discontinue the therapy for 4 to 8 weeks. If the symptoms recur and are intolerable, or if the patient concludes that the ratio of benefits to risks is positive, we resume therapy. If she feels that ratio is negative, we stop and consider alternatives.