Compliance: Raloxifene vs Hormone Replacement Therapy
D. Hochner-Celnikier
Dept. of Obstetrics and Gynecology
Hadassah University Hospital, Mt Scopus, Jerusalem, Israel
The postmenopausal state is characterized by a decline in the level of circulating plasma estrogens. This fall in estrogen levels is responsible for various symptoms affecting the quality of life of postmenopausal women, such as hot flushes, mood swings and sleep disorders, as well as metabolic changes including cardiovascular disease and osteoporosis. These are the major causes of morbidity and mortality in postmenopausal women. Hormone Replacement Therapy (HRT) given to postmenopausal women relieves the symptoms that accompany the decrease in estrogen levels during the postmenopausal period. This therapy has also been shown to prevent bone loss and to counteract the development of coronary artery disease. Some studies indicate that HRT may reduce the risk and delay the onset of Alzheimer’s disease, as well as improve memory in non-demented postmenopausal women.
All the beneficial effects associated with HRT are achieved only following long term therapy. However, less than 20% of postmenopausal women in the US receive prescriptions for HRT, and of these nearly one third never fill the first prescription. Of the women who commence therapy, less than 40% continue beyond 1 year, and many more discontinue therapy after 3 years. This is insufficient time to reap the long-term benefits associated with HRT, particularly preventing osteoporosis and decreasing the incidence of coronary artery disease. The most common reasons given for discontinuation of treatment are undesirable side effects, such as uterine bleeding and breast pains, and a fear of breast cancer. It must be noted that long term HRT may be associated with an increased incidence of breast cancer. There is, therefore, a need for an “ideal estrogen”, designed to pinpoint desired target tissues such as the bones and liver, while acting as an antiestrogen in reproductive tissues such as the uterus and breast, these being chiefly responsible for the side effects associated with HRT. These unwanted side effects are among the main reasons for discontinuation of therapy.
Selective Estrogen Receptor Modulators (SERMs), are a new class of compounds that bind to and interact with estrogen receptors, acting as estrogen agonists in some tissues and as estrogen antagonists in others.
The prototype of such “designer drugs” is the antiestrogen tamoxifen, which has been used for the treatment of breast cancer for the last 20 years. Tamoxifen has recently been shown to prevent breast cancer in high-risk women, as reported in preliminary results from a large breast cancer prevention trial. While having antiestrogenic effects in breast tissues, it retains estrogenic stimulating effects on the skeletal and cardiovascular systems. However, its estrogenic properties in the endometrium are associated with an increased incidence in endometrial cancer, the most serious of its adverse effects.
Raloxifene hydrochloride, another compound that belongs to the SERMs class, has recently been introduced and shown to preserve the beneficial effects of estrogen, mainly increased bone mineral density and decreased LDL-cholesterol, as well as antiestrogen effects on the breast. However, unlike HRT, the incidence of hot flushes reported among raloxifene patients is 20-30%, similar to that of placebo-treated groups. Unlike tamoxifen, raloxifene has not been shown to stimulate the endometrium.
We have studied the 2-year compliance rate among postmenopausal Israeli women who received various regimens of HRT. Overall 2-year compliance among all the groups studied was 70%. Compliance was highest (80%) in the estrogen-only group, comprised of women who had undergone hysterectomy. In the other two groups, made up of women with intact uteri, compliance was lower, ranging from 63 to 67%, according to the hormonal regimen (continuous vs sequential HRT). In all three groups the dropout rate was highest during the first 6 months of the study (13-23%). There was an additional drop in the second half of the first year (20-27%), and none during the second year.
The most common reason for therapy discontinuation cited among all three groups was that of fear of therapy, particularly fear of breast cancer. Other reasons cited included vaginal bleeding, breast cancer, thyroid problems, general malaise, high blood pressure, weight gain, impaired liver function, vomiting, and increase in fibroid size.
Excessive vaginal bleeding was common in approximately 50% of patients with intact uteri. However, it was an uncommon reason for discontinuation of therapy (3%).
We have found that a woman’s level of education significantly affected her 2-year compliance rate. Since Raloxifene was introduced to clinical use in Israel and in the USA only in January 1998, no real data is available regarding its clinical use.
However, based on early studies it seems that the 3- year compliance to Raloxifene is 78% and does not differ from placebo, which may indicate that higher rates of compliance are to be expected with this drug as compared to HRT. The main reasons given for discontinuation of therapy are hot flushes, leg cramps and thromboembolic disease; none complained nor discontinued therapy due to breast cancer fear.
In addition to the data available from the MORE study indicating a 65-90% reduction in invasive breast cancer among women treated with Raloxifene, compliance rates may be expected to increase further.
Data about the use of Raloxifene in Israel regarding its indications for use, side effects and dropout rates will be presented.