An "Absolute" Gamble
With hormone therapy, is the risk relative?
The hormone replacement therapy debate rages on and soon we are going to have to add new scientific data on the treatment of menopause as a risk factor for inducing hot flashes. With respect to treating the symptoms of menopause, today, it seems that no two health care practitioners agree on who should take hormone therapy, for how long and at what specific time point treatment should begin.
Recently, The New York Times ran an excellent roundup on the debate. In that comprehensive overview, however, an important insight was missing, as it almost always is from any story or public debate on the subject of menopause. That is, how an individual woman, given often conflicting information and advice, can intelligently assess her risks and make a decision as to what route is best for her to follow. Adding to the confusion is the fact that medical researchers and doctors most often discuss the effects of treatments in terms of "relative" risk, which is generally very misleading.
As a physician, I am convinced that it is really the "absolute" risk difference rather than the "relative" risk that should be used to help a woman in her decision-making about whether to use a certain treatment. Relative risk quantifies the relative change in the incidence of a disease, comparing people who receive some treatment to others who do not. Absolute risk is the difference in the incidence of the disease between people who receive a treatment and those who do not.
For example, if one heart attack occurs naturally among 1000 40-year-old women every year, and a harmful treatment increases this risk to two in every 1000 women per year, the relative risk is 2.0, or a two-fold relative increase in risk. A two-fold increase in risk of heart attack sounds terrible, but the absolute increase in risk is one additional heart attack per thousand women treated per year. On the other hand, consider the same treatment in 1000 75-year-old women with coronary artery disease, where the risk of heart attack without treatment is about one in five per year.
In these women, a relative risk of 2.0 would indicate that treatment for a year would cause one additional heart attack for every five women treated for a year. So instead of 200 heart attacks per 1000 women treated there would be 400. Two important lessons can be seen in this example. First, relative risk often sounds scary and second, the same relative risk has a very different meaning for different groups of people.
In this day and age of evidence-based medicine, we largely talk about relative risks. For women making a decision about whether or not to use hormone therapy, however, it is really the absolute risk that is a more valuable statistic for decision making. Unfortunately, most patients and many physicians do not understand the differences.
In a recent survey of physicians reviewing the findings of the Women's Health Initiative (WHI) trial, which was halted in 2002, more than one out of every five doctors incorrectly believed that hormone therapy increased the absolute risk for heart disease, stroke, venous thrombosis, and breast cancer by 10 to 30 percent per year. The actual increase in absolute risk for each outcome was closer to 0.1 percent per year.
As has been frequently sited, the average age of the participants in the WHI was approximately 64. However, the peri-menopausal period, when women tend to be most symptomatic with hot flashes and other symptoms, starts on average at age 47. Since the absolute risk for many diseases doubles with each decade of life, a woman at age 47 who decides to take hormone therapy will have an absolute risk increase that is at most half of what was seen in the WHI trial.
For example, the relative risk of having a stroke was 41 percent higher for women who were in the hormone group (Prempro) compared to those who were in the placebo group. That number sounds shocking, but in absolute terms, the risk is not so dramatic. For every 10,000 women treated each year with Prempro in the WHI, there were eight more cases of stroke than there would have been otherwise. For an individual woman, this additional risk is about less than one in 1000 per year of treatment.
Now, apply that to a peri-menopausal woman who decides to take combination hormone therapy beginning at age 47, and the increase in absolute risk would be reduced by at least half, with the absolute risk increase being less than four additional cases of stroke per 10,000 women treated annually. For one year of treatment, this risk is very small, especially if treatment results in the relief of hot flashes, night sweats and insomnia. On the other hand, this small risk is cumulative because it is present during each year of treatment. For example, if hormone therapy is continued for ten years, the estimated risk for stroke is 40 per 10,000 or one in 250 women.
Of concern is the risk of developing any of the potentially fatal conditions associated with hormone therapy. The investigators from the WHI study calculated the net effect of combination hormone therapy by assuming that all of the side effects or potentially fatal diseases affected by hormone therapy are weighted equally, and found that combination therapy resulted in two serious adverse conditions per 1,000 women treated each year.
As noted above, this risk is about half as great in 50-year-old women, or about one per 1,000 per year for developing heart disease, stroke, pulmonary embolism or breast cancer. However, many menopausal women experience symptoms for about five years, and use hormones for that whole duration. With five years of hormone use, risk increases to about five potentially fatal conditions per 1,000 women treated, or one in 200.
So the bottom line for a woman who has hot flashes is, does hormone therapy provide enough relief from your symptoms that are you willing to gamble that you'll be one of the 999 women out of 1,000 each year who have no serious adverse side effects from the treatment? If you continue therapy for five years, are you willing to gamble that you will be one of the 199 out of 200 women who have no serious adverse effect? Or are you too nervous about these risks to take the hormones?
The trade-offs with hormone treatment are not unique. Although we wish to have treatments that are effective without any associated risk, this is hardly ever the case. Only by knowing the absolute risk of a treatment can a person make an informed judgment as to whether the benefit of treatment is worth the risk.
I encourage everyone, especially those whose life, or quality of life, may be at stake, to look at the numbers with a deeper, more critical eye. At the same time, drug researchers and manufacturers should be encouraged to report the relative risk and absolute risk so physicians can improve their recommendations and consumers can make more informed decisions. Above all, we need to find new ways to treat the symptoms of menopause since no matter how you look at the statistics, what preparation you use, or when you start using hormone therapy, these drugs, at a bare minimum, will increase one's risk for blood clots and breast cancer.
Dr. Mary Tagliaferri is co-founder of Bionovo, Inc., and author of The New Menopause Book and Breast Cancer: Beyond Convention.