Recent headlines splashed across the nation's newspapers have thrown into doubt the use of hormone replacement therapy (HRT) for treatment of menopause, citing the Women's Health Initiative (WHI) study indicting HRT as causing increased heart disease and breast cancer. As a result of these findings – which brought a halt to the study – HRT has come under a large microscope and will remain the subject of debate for some time. For most experts commenting on the issue, the bottom line is not abandonment of HRT therapy, but close consultation between women and their doctors and consideration of various therapeutic issues.
One of those issues was highlighted by a researcher looking specifically at the time HRT therapy is begun, saying that the major question "may not be if estrogen helps, but when is the optimum time to begin therapy." Shortly before news of the WHI trial halt broke, Dr. Thomas Clarkson issued a report at the third World Congress on Controversies in Obstetrics, Gynecology & Infertility in Washington, saying that HRT has a beneficial role in cardiovascular disease after menopause. Clarkson, of the Baptist Medical Center at Wake Forest University (Winston-Salem, North Carolina), cited "mounting evidence" supporting the prevention of heart vessel disease "if the therapy begins around the time that the body stops making its own estrogen."
A professor of comparative medicine, Clarkson had reviewed studies that evaluated the cardiovascular effects of HRT, including four large trials of postmenopausal monkeys conducted at Wake Forest over the past 12 years. When estrogen replacement was administered at the onset of estrogen deficiency – which compares to the postmenopausal transition in women – there was a 70% inhibition of fatty build-up in the arteries. In contrast, when estrogen replacement was delayed for a period comparable to six years in women, there was no benefit on the heart's arteries.
Clarkson emphasized the importance of avoiding prescribing practices based on one or two studies of older women, but rather, on evaluating all available data. After reviewing recent clinical trials, Clarkson concluded that mounting evidence supports the probability that estrogen therapies can serve as a primary prevention against cardiovascular disease. He cited, for example, the Estrogen in the Prevention of Atherosclerosis Trial (EPAT), conducted by Howard Hodis, MD, at the University of Southern California (Los Angeles, California), which showed that estrogen slows the progression of atherosclerosis in younger postmenopausal women.
"Many studies ranging from cell biology to studies of monkeys and women have found strong evidence supporting estrogen's role in inhibiting the progression of atherosclerosis," Clarkson said. "The best results in slowing the build-up of plaque in blood vessels have been seen in women who begin estrogen replacement as soon as estrogen deficiency begins during the perimenopause transition or at menopause."
Two studies examining heart disease in older women also have raised questions about the cardiovascular benefits of HRT. In particular, the Heart and Estrogen/progestin Replacement Study (HERS) and the Estrogen Replacement Atherosclerosis (ERA) Trial evaluated the effect of HRT on older women with pre-existing heart disease. Both HERS, with patients who were 67, and ERA, with patients who were 64, found HRT to have no effect on cardiovascular health. However, these study populations are not the average HRT user – younger women who begin HRT at the onset of menopause. Like others, Clarkson emphasized the importance of women discussing their health histories with their physicians, adding, "Treatment decisions should not be made on the basis of those studies whose participants may not represent the average younger patient taking HRT."
Despite the broad negative publicity in the U.S., HRT is being supported in both Britain and France. In Britain, scientists last month recommended continuation of a 22,000-patient HRT trial. The Women's International Study of Long Duration Oestrogen after Menopause (WISDOM) study in the UK is directed toward learning whether HRT lowers or increases the chances of developing certain diseases, such as heart disease, breast cancer, osteoporosis and dementia.
The U.S. experience also may not greatly impact the use of HRT in France, where an estimated 30% of women considered appropriate for the therapy receive estrogen supplements either orally or with a patch. Gerard Breart, a director at the French national medical research institute, said the majority of these women continue the therapy indefinitely, with the aim of reducing or eradicating the most unpleasant symptoms of menopause. He noted, however, that in Europe synthetic hormone replacements are used, in contrast to the general use in the U.S. of estrogen of equine origin.
CABG linked to longer-term mental problems
Data reported last month at the eighth International Conference on Alzheimer's Disease and Related Disorders in Stockholm, Sweden, point to an increase incidence of stroke, short-term memory loss and longer-term cognitive changes as a result of coronary artery bypass grafting (CABG) procedures. Guy McKhann, MD, and colleagues at Johns Hopkins School of Medicine (Baltimore, Maryland), collected data on 3,300 patients undergoing CABG between 1997 and 2001 and found that after this type of surgery, 2.6% of patients suffered stroke and 6.8% developed acute confusion or short-term memory problems. Additionally, there was an increased association with longer hospital stays and death. Overall, the researchers identified a 50% increase in the probability of acute confusion for each hour that a patient was on a bypass pump.
The researchers evaluated changes in patients' cognitive function at one month, one year and five years following surgery. In the short term, they found that memory and attention generally improved within one year after surgery. But between one year and five years after surgery, they found cognitive declines, with those having the most severe cerebrovascular disease at baseline most likely to experience this delayed decline. McKhann said that, particularly for the sub-population of those at greatest risk for cerebrovascular disease, "it may be beneficial to consider alternative cardiac interventional techniques in addition to carefully managing diabetes, hypertension and other related risk factors."
In another report released at the Alzheimer's gathering, researchers rolled out data indicating that African Americans with Alzheimer's have high levels of homocysteine, and low levels of vitamin B12, which is essential for maturation of red blood cells and normal functioning of the nervous system. Floyd Willis, MD, and colleagues at the Mayo Clinic (Jacksonville, Florida) collected blood samples from 256 African Americans who had no symptoms of cognitive impairment, and 58 African Americans who had a clinical diagnosis of Alzheimer's. In comparing the two groups, the researchers found homocysteine levels significantly higher and levels of B12 significantly lower in the Alzheimer's group, a finding suggesting increased risk for heart attack and stroke since increased homocysteine in the blood has been linked to damaged arteries.
Various other studies presented at the conference supported the hypothesis that early steps to treat high blood pressure may reduce the risk of developing Alzheimer's. But that finding was not across-the-board. One study by a Swedish researcher, Ingmar Skoog of Goteborg University, found that the use of the antihypertensive medication candesartan vs. a placebo in nearly 5,000 patients showed no significant risk reduction.
Aspirin gets boost in AHA guideline update
Aspirin, though long considered a basic medication for reducing the risk of heart attack, received a bit of an upgrade recently, with the release of updated guidelines from the American Heart Association (AHA; Dallas, Texas) for prevention of cardiovascular disease and stroke. The new guidelines call for the use of low-dose aspirin for people who have an increased risk for coronary heart disease. Additionally, the revised guidelines call for the use of blood-thinning drugs to reduce stroke risk in those with atrial fibrillation.
Thomas Pearson, MD, PhD, chair of the consensus panel that developed the revised AHA guidelines, said, "The U.S. Preventive Services Task Force has always recommended aspirin for secondary prevention in people who already have heart disease, but now recommends low-dose aspirin for primary prevention as well." He noted the risks of aspirin may include gastrointestinal bleeding and bleeding into the brain, but said that these risks are greatly outweighed by the benefits "if a person has a 10-year risk of heart disease that exceeds 10%." He also pointed to recent studies indicating that the use of blood thinners to treat atrial fibrillation reduces the chance of stroke.
Overall, the updated guidelines put increasing emphasis on the evaluation of cardiovascular risk factors at an earlier age. "The updated guidelines incorporate new findings and expert opinion that have emerged since [we] published the recommendations in 1997," the AHA said in releasing the updates. "They reflect recent data on the degree of risk imposed by specific risk factors and the new efforts to categorize people more specifically according to their number and types of risk factors." It added that risk factor screening includes having blood pressure, body mass index, waist circumference and pulse recorded at least every two years and cholesterol profile and glucose testing "at least every five years, beginning at age 20."
Asymptomatic angina and 'syndrome X'
Research published in The New England Journal of Medicine links something called "cardiac syndrome X" to a long-time puzzle of cardiovascular disease: that many people experience chest pain without having any of the classic signs of heart disease. The new report explains this contradiction by pointing to syndrome X and saying that it may be the result of irregular blood flow in microscopic arteries within the heart wall. But the researchers found no evidence that this condition can increase a patient's risk of heart attack or other severe cardiovascular illness.
Conducted at Royal Brompton Hospital (London), the research was conducted by Dudley Pennel, MD, the hospital's chief scientist. It included imaging of 10 healthy patients and 20 patients showing signs of syndrome X with MRI scans, the images revealing blood flow more precisely than angiograms. The result was to reveal poor distribution of blood flow in the syndrome X patients – too little in the inner heart wall and too much in the outer layer.