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Menopausal Medicine Update 2002:
The Year in Review

Cardiovascular Disease in Women: What We Have Learned From Recent Clinical Trials

“Results of the Women’s Health Initiative will have a profound effect on clinical practice,” said Brian W. Walsh, MD, Assistant Professor, Obstetrics, Gynecology, and Reproductive Biology, Harvard Medical School, Boston. He added that “we’re now asking ourselves how millions of women were given HRT with the expectation that it would be

This is at least partly due to an observation made by investigators of the Framingham Heart Study who found that women typically develop cardiovascular disease 20 years later than men. “One obvious difference between men and women is their hormones,” said Dr. Walsh. Therefore, it was thought that in premenopausal women, estrogen may be protective against heart disease.

To test this hypothesis, studies looked for biologic plausibility, and several studies found that estrogen does have cardioprotective properties, such as lowering LDL cholesterol, raising HDL, lowering lipoprotein (a) levels, lowering homocysteine levels, and preventing the oxidation of LDL.

The next step was to collect observational data, which was done in several studies that calculated incidence of heart disease in women who had taken estrogen compared to those who hadn’t. “In all but one of these studies, estrogen users had less heart disease than nonusers,” he said.

Based on these data, it became a popular belief that estrogen is cardioprotective. However, “this can be a misleading conclusion because there are inherent biases in observational studies,” said Dr. Walsh. To overcome these biases, several clinical trials have been performed, with data now available.

The Heart and Estrogen/Progestin Replacement Study (HERS) enrolled 2,763 women (mean age 67 years) with established heart disease who were randomly assigned to 0.625 mg conjugated estrogens with 2.5 mg medroxyprogesterone acetate (MPA) daily or placebo for 4.1 years (JAMA 1998;280(7):605-613).

The number of heart attacks among women given estrogen plus progesterone was essentially equal to the number of heart attacks in those given placebo. “This was surprising because everyone expected the study to show cardioprotection,” said Dr. Walsh.

Further analysis of the data revealed that the risk of heart attacks was greatest during the first four months. At two years, incidence of heart attacks was about equal in both groups. However, continuation of the HERS trial for an additional two years failed to show any cardioprotective effect of HRT. One criticism of the trial was that the women in the study had heart disease, and had they been treated with hormones earlier perhaps it would have been prevented.

This was addressed by the Women’s Health Initiative (WHI), a study of 16,000 postmenopausal women (mean age of 63) with an intact uterus who received 0.625 mg conjugated estrogen plus 2.5 mg medroxyprogesterone acetate or placebo (JAMA 2002;288(3): 321-333).

The trial was scheduled to run for 8.5 years, but it was stopped after 5.2 years because of a statistically significant higher number of breast cancers among women taking the hormones.

Dr. Walsh reviewed the three main cardiac endpoints. There was a greater incidence of coronary heart disease (hazard ratio = 1.29), which was statistically significant. Starting at about 1.5 years, there were more strokes in women on HRT (HR = 1.41), and more women taking HRT had pulmonary emboli (HR = 2.13).

Dr. Walsh reframed the results in terms of absolute risk. In a population of 10,000 women, there would be seven additional cases of heart disease, eight strokes, eight breast cancers, and eight pulmonary emboli among women taking the HRT regimen. “That would be a total of 31 women per 10,000 who would have an adverse event,” said Dr. Walsh.

On the benefits side, of 10,000 women, there would be six fewer cases of colon cancer and five fewer hip fractures. So the net harm (31 minus 11) is 20 patients per 10,000 per year. Over 5 years, this equals 100 out of 10,000. “The magnitude of harm is 1%,” said Dr. Walsh, adding that this is an unacceptable risk to take on for a population for prevention. “HRT should be used for treatment of menopausal symptoms only.”

He went on to address the question of how HRT could possibly increase risk for cardiovascular disease, which may be related to C-reactive protein (CRP). CRP is made by the liver in the setting of acute inflammation. The source of chronic low elevations of CRP is not clear, but it’s possible that atherosclerotic vessel walls may be the source.

In a study by Ridker et al., CRP levels were examined in healthy postmenopausal women (Circulation 1998;98(8):731-733). The higher the baseline level of CRP, the greater the risk of developing cardiac disease, and CRP was more predictive of cardiovascular disease than LDL, HDL, triglycerides, plasminogen activator inhibitor-1, homocysteine, and lipoprotein (a).

In a study by Walsh et al. that looked at the effect of raloxifene and HRT on CRP, raloxifene had no effect on CRP, whereas the estrogen/progesterone combination increased CRP levels as much as 80% (J Clin Endocrinol Metab. 2000;85(1):214-218). They also found that raloxifene lowered LDL cholesterol and did not raise triglycerides. It also lowered fibrinogen, homocysteine, and lipoprotein (a) (JAMA 1998;279:1445-1451). “So there is a biologic plausibility that raloxifene could be cardioprotective,” said Dr. Walsh, adding that data from clinical trials are needed.

One such clinical trial was the Multiple Outcomes in Raloxifene Evaluation (MORE) trial, which evaluated the effect of raloxifene on osteoporotic fractures (JAMA 1999;281(23): 2189-2197). Although patients were not selected for cardiovascular disease risk, of the 7,700 participants 1,000 had risk factors for heart disease. Among all participants, there were fewer heart attacks among women taking raloxifene (relative risk 0.9, which was not statistically significant). However, among the 1,000 with heart disease risk factors, relative risk was 0.6, which was statistically significant.

A new study has been launched, called Raloxifene Use and the Heart (RUTH), which is enrolling 10,000 women at increased risk for heart disease. Results are expected in 2006.

“Prevention of cardiovascular disease is an important goal,” said Dr. Walsh. “Unfortunately, we can’t use HRT to protect our postmenopausal patients. HRT should be used only for severe hot flashes, and it should be given at the lowest dose for the shortest duration of time. Raloxifene has the promise of being cardioprotective, but we need to wait for the results of the RUTH trial.”

Osteoporosis: New Thoughts and New Therapies

“There have been some interesting changes in the area of osteoporosis in the past year,” said Steven T. Harris, MD, Clinical Professor of Medicine and Radiology, University of California, San Francisco. To begin with, the definition of osteoporosis is changing.

In the past, the definition was based on bone fractures, then more attention was paid to bone density. But the latest definition also refers to compromised bone strength. The finding that the clinical benefit of osteoporosis drugs outstrips the small change in bone density suggests that the drugs also improve bone quality. And therefore bone quality changes may be more important than changes in bone density. Unfortunately, there’s no clinical tool yet available to measure bone quality.

Epidemiologic data clearly show that with age, bone density goes down and fracture rates go up in women. Dr. Harris added that “fractures lead to an increased risk of subsequent fractures.” Fractures of both the hip and spine
are associated with increased risk of mortality.

“There is a distinction between prevention and treatment of osteoporosis, although the line gets blurred sometimes,” said Dr. Harris. Bisphosphonates and raloxifene are approved for prevention and treatment, the nasal spray calcitonin is for treatment only, and HRT is for prevention only.

Most of the current osteoporosis drugs are antiresorptive agents, which decrease bone resorption, reducing breakdown of bone. A bone formation stimulator was recently FDA approved.

“HRT is clearly effective for increasing bone mineral density,” he continued, noting that this is true even for the low dose combination of 0.3 mg conjugated estrogen plus 1.5 mg medroxyprogesterone, though fracture reduction with such low doses has not yet been studied.

In the WHI study, with standard doses of conjugated estrogens and medroxyprogesterone, there was a reduction in all osteoporotic fractures. “However, the decrease in fractures is probably trumped by the other concerns brought out by the WHI study,” said Dr. Harris.

The drug raloxifene was examined in the MORE study, involving 7,705 postmenopausal women under age 80. The study compared calcium and vitamin D to calcium, vitamin D, plus raloxifene to see how much added benefit the drug would confer. Dr. Harris noted that bone density changes were small; for example, spinal density went up 3% and then reached a plateau. However, fracture data were more dramatic. After four years, among women with vertebral fractures at baseline, there was a 34% reduction in the relative risk of new vertebral fractures in the raloxifene group, and among those without baseline fractures the reduction in risk was 49% for those taking raloxifene.

“In terms of number needed to treat, you only need to treat about 30 women with raloxifene over a period of four years to prevent a vertebral fracture,” said Dr. Harris.

The data on nonvertebral fractures showed no overall statistically significant reduction in fractures. However, among high risk women with pre-existing severe compression fractures, there was a 47% reduction in nonvertebral fracture. The number needed to treat is 10 over three years to prevent vertebral fracture and 18 to prevent nonvertebral fracture.

The bisphosphonates alendronate and risedronate have also been shown to reduce vertebral and nonvertebral fractures. The Hip Intervention Program (HIP) prospectively evaluated the effect of antiresorptive therapy on hip fractures as a primary endpoint, using daily risedronate therapy in two groups of patients (N Engl J Med. 2001;344(5):333-340). Group 1 included women in their 70s with low bone density and confirmed osteoporosis. Group 2 patients were women over age 80 who were recruited largely on the basis of non-bone-density risk factors for fracture.

Overall, Group 1 patients had a 40% reduction in hip fracture over the course of three years; the fracture risk reduction was 60% among the Group 1 patients who had radiographic evidence of vertebral fractures at baseline. Among Group 2 patients, most of whom did not have osteoporosis, there was not a statistically significant reduction in fractures.

The newest osteoporosis drugs are bone formation stimulators (anabolic agents) — parathyroid hormone and related fragments (PTH 1-34 and PTH 1-84). Teriparatide (PTH 1-34), which recently received FDA approval, was examined in a study by Neer et al. (N Engl J Med. 2001;344(19):1434-1441). “The daily injection of teriparatide for 1.5 years produced a larger bone density response than we’ve seen with antiresorptive agents,” said Dr. Harris. In addition, there was a reduction in spinal fractures of 65% and reduction of nonvertebral fractures of 53%.

Another study, this one looking at the effect of teriparatide on postmenopausal women taking HRT, found that the combination resulted in spinal density going up an additional 13% over three years (Lancet 1997;350(9077):550-555).

Gynecologic and Breast Considerations: Expect the Unexpected

Vivian M. Dickerson, MD, Associate Clinical Professor, Department of Obstetrics and Gynecology, University of California, Irvine, discussed HRT in relation to gynecologic considerations, such as urinary incontinence and pelvic organ prolapse, and breast cancer.

In addition to other outcomes, the HERS trial assessed urinary incontinence (Obstet Gynecol. 2001;97(1):116-120). Among women taking HRT, 21% had an improvement in urinary incontinence, while 39% experienced a worsening of symptoms. In the placebo group, 26% improved and 27% worsened.

Goldstein et al. evaluated urinary incontinence in an osteoporosis prevention trial (Menopause 2001;8:460 (P-24)), which compared HRT, two doses of raloxifene, and placebo. Among those on placebo 1.3% had new or worsening urinary incontinence, less than 1% of those on either dose of raloxifene did, but 7% of HRT recipients did.

While there are surgical and nonsurgical modalities that have been used to treat stress urinary incontinence, there’s no medical therapy. However, researchers have identified an agent that acts on the serotonergic and noradrenergic pathways, which is being evaluated for treatment of stress incontinence. A Phase II trial of the drug, duloxetine, found that it reduced incontinence episode frequency greater than placebo and had a positive impact on measures of quality of life and patient global impression of improvement.

A Phase III trial of duloxetine found that there was a statistically significant reduction in stress urinary incontinence episodes of almost twice as much as placebo.

On the topic of pelvic organ prolapse, Dr. Dickerson noted the concern that this might be an adverse effect associated with selective estrogen receptor modulators (SERM) arose during a Phase III trial of the SERM levormeloxifene. That trial was suspended in 1998 because of gynecological, gastrointestinal, and genitourinary adverse events, including uterine prolapse.

Subsequently, the SERM raloxifene was subjected to an integrated analysis by Goldstein et al. to see if it too was likely to cause these side effects (Obstet Gynecol. 2001;98(1):91-96). Three studies, with a total of 6,926 women, were analyzed; the rate of pelvic floor surgery in women taking raloxifene was half that of women on placebo.

The authors concluded that “raloxifene does not appear to increase the risk of pelvic organ prolapse.”

“The effects of ERT and HRT on the urogenital system need further study,” Dr. Dickerson said, before turning to a discussion of breast cancer.

One of the reasons the WHI studied was stopped was that the hazard ratio for breast cancer reached 1.26. The increased risk of breast cancer occurred by year 3 and continued through the rest of the study.

“While there was a clear jump in the hazard ratio for invasive breast cancer at 5 to 10 years, there were only 13 women affected,” said Dr. Dickerson. “So the numbers are small, and it’s impossible to make a significant statement about HRT and invasive breast cancer at this time.”

She went on to discuss breast cancer prevention and SERMs, beginning with the Italian Breast Cancer Prevention Trial with Tamoxifen (Lancet 2002;359 (9312):1122-1124). The study included 5,048 hysterectomized women ages 35 to 70, 21% of whom had a family history of breast cancer. They were randomized to tamoxifen 20 mg/day or placebo for 81 months. Participants were given the choice of taking HRT any time during the trial.

Overall, there was a nonstatistically significant reduced risk of breast cancer on tamoxifen. “A further analysis showed that there was a significantly increased cumulative incidence of breast cancer in women in the placebo group who used HRT compared to those taking tamoxifen with or without HRT and those on placebo who did not use HRT,” said Dr. Dickerson.

She went on to describe the International Breast Cancer Intervention Study (IBIS), which enrolled 7,152 women (median age of 51), one-third of whom had had a hysterectomy; 40% were taking HRT at entry and 50% used HRT at some point during the trial. “The only statistically significant finding of the study was that the odds ratio of breast cancers was reduced in the tamoxifen arm by 33%.

The major data on breast cancer and raloxifene come from the MORE trial, which didn’t look primarily at breast cancer but rather at osteoporosis and fractures. Among women with osteoporosis who took raloxifene, there was a 62% reduction in the incidence of breast cancer over four years. “Data on whether these results generalize to the population who don’t have osteoporosis should be forthcoming from the Study of Tamox-ifen and Raloxifene (STAR) trial,” said Dr. Dickerson. No similar data exist from trials of bisphosphonates.

She concluded with aromatase inhibitors and breast cancer prevention. The Anastrozole, Tamoxifen, Alone or in Combination (ATAC) study, which involved 10,000 women, found that recurrence of breast cancer was significantly reduced with the aromatase inhibitor compared to tamoxifen, with a hazard ratio of 0.83. “The combination actually showed less reduction of recurrence than anastrozole alone,” said Dr. Dickerson.

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