On the messiness of evidence-based medicine

I'm about a week late on this one.

In fact, it wouldn't surprise me if some of my readers were wondering why I hadn't weighed in on this story when it broke late last week. (Either that, or no one was wondering, and I'm just displaying some of my surgeon's ego for all to see.) Part of the reason was perhaps because Dr. Charles had handled this whole study well, and I didn't see any need to weigh in. Another part of the reason is because the study came out right when I had to come up with another Your Friday Dose of Woo for last Friday. But, the more I thought about it, the more I thought that this is a perfect example of something that I should have talked about a while ago: the messiness of evidence-based medicine (EBM). I'm referring, of course, to the abstract that statistician Donald Berry, Ph.D. of the University of Texas M.D. Anderson Cancer Center presented to the San Antonio Breast Cancer Symposium last week:

In 2003, breast cancer incidence in the United States dropped sharply, and this decline may largely be due to the fact that millions of older women stopped using hormone replacement therapy (HRT) in 2002, according to a new analysis led by researchers at The University of Texas M. D. Anderson Cancer Center.

At the 29th annual San Antonio Breast Cancer Symposium, the investigators report that there was an overall 7 percent relative decline in breast cancer incidence between 2002 and 2003, and that the steepest decline - 12% - occurred in women between ages 50-69 diagnosed with estrogen receptor positive (ER-positive) breast cancer. This is the kind of breast cancer that is dependent on hormones for tumor growth.

From this, the researchers conclude that as many as 14,000 fewer women were diagnosed with breast cancer in 2003 than in 2002, a year in which the American Cancer Society estimates 203,500 new cases of breast cancer were diagnosed.

"It is the largest single drop in breast cancer incidence within a single year I am aware of," says Peter Ravdin, M.D., Ph.D., a research professor in the Department of Biostatistics at M. D. Anderson.

"Something went right in 2003, and it seems that it was the decrease in the use of hormone therapy, but from the data we used we can only indirectly infer that is the case," he says.

"But if it is true, the tumor growth effect of stopping use of HRT is very dramatic over a short period of time, making the difference between whether a tumor is detected on a mammogram in 2003 or not," says Ravdin.

The study's senior investigator, Donald Berry, Ph.D., professor and head of the Division of Quantitative Sciences at M. D. Anderson, says he was, at first, very surprised by both the magnitude and the rapidity of the decline in incidence, but adds "it makes perfect sense" if you consider that use of HRT may be an important contributing factor to breast cancer development.

"Incidence of breast cancer had been increasing in the 20 or so years prior to July 2002, and this increase was over and above the known role of screening mammography," he says. "HRT had been proposed as a possible factor, although the magnitude of any HRT effect was not known. Now the possibility that the effect is much greater than originally thought all along is plausible, and that is a remarkable finding."

I'm a little wary of this study, mainly because, like Dr. Charles, I'm not yet entirely convinced that this isn't a one year statistical fluke. However, if it isn't, and breast cancer incidence either keeps decreasing or remains at the new, lower level, then this is huge. Whether the cause for this decrease is indeed the decrease in HRT that resulted from the publication in 2002 of the Women's Health Initiative study that demonstrated that hormone replacement therapy resulted in increases in heart disease and cancer is, of course, another matter.

Of course, what confuses both patients and even many doctors is the messiness of the whole HRT story. How on earth could medicine have gotten things so wrong for so long? Let's take a trip back in time to the early 1990's, when the WHI study was conceived and designed. At the time, the widespread belief among medical professionals that HRT had a cardioprotective effect was based on largely retrospective studies and animal studies. For example, there was retrospective data that strongly suggested a decrease in risk for cardiovascular events in women who took HRT that was as high as 40% or 50% compared to postmenopausal women who did not take HRT. Additional studies seemed to show a positive effect on blood lipid levels. Meanwhile the evidence of adverse outcomes, particularly in terms of breast cancer, was conflicting. Put yourself in the position of a gynecologist or primary care physician (the two specialties most likely to be prescribing HRT). Nothing is more effective in relieving menopausal symptoms than replacing the hormones themselves, and the evidence seemed to suggest that HRT had the additional benefit of decreasing the risk of heart disease. Do you offer it to your patients who are beginning to have hot flashes? I bet you probably would recommend a drug that not only relieved distressing symptoms, but also appeared to protect against heart disease and osteoporosis without good evidence that it increased the rate of adverse outcomes like breast cancer. Certainly, patients wanted it, and there didn't seem to be much, if any, downside.

Still, even while the WHI study was going on, there were rumblings. Smaller studies appeared that suggested that all was not well with HRT, that the risk of blood clots and strokes were higher, but this somewhat conflicting evidence came against fairly consistent evidence that HRT delays osteoporosis and decreases hip fractures, and decreases the risk of colorectal cancer slightly. The WHI was the first really large randomized trial, and its results showed an increased risk of stroke, pulmonary embolus, and breast cancer, to the point where the HRT arm of the study was halted early, leaving the average followup at only 5.2 years.(Ironically enough, in the very same issue of JAMA in which the WHI study appeared, there was also a study demonstrating that long term use of estrogen-only HRT significantly increased the risk of ovarian cancer, while estrogen-progestin HRT, the kind studied in the WHI, did not.) The results were widely publicized; medical practice over the last couple of decades was overthrown and changed almost overnight. Those of us in the breast cancer business faced breast cancer patients torturing themselves over whether they had caused their cancer by taking HRT and other patients asking us whether they should stop their HRT or whether they had increased their odds of getting breast cancer.

Yes, EBM sometimes bites its advocates on the behind.

The point is, physicians who recommended HRT to their patients pre-2002 were practicing EBM just as much as those who now do not recommend HRT except in the cases of highly refractory menopausal symptoms, where the patient is willing to accept the increased risk. It also points out a truism in medicine that giving a medication or using an intervention in a healthy population has to be held to a very high standard in which the benefits of the intervention far outweigh the risks of the intervention. Clearly the WHI shows that HRT does not meet this standard for long term use to prevent heart disease and osteoporosis.

But practicing EBM can be even more messier than that. Let's look at the M.D. Anderson study. Assuming this one year decline in breast cancer incidence is not a fluke, even though the results of this study are consistent with the WHI showing that HRT increases the risk of breast cancer, it's difficult to determine whether this decline was due to decline in the use of HRT that occurred in 2002 after publication of the WHI study. For one thing, 2003 seems as though it would be too soon for such a decline to occur, given that breast cancer generally takes years to develop from normal breast duct linings into frank cancer. Here's another reason to wonder if it's more than just HRT, straight from the M.D. Anderson press release itself, which shows that breast cancer incidence had been leveling off for five years before 2003:

They examined rates of breast cancer in the United States from 1990 to the end of 2003 and found that while incidence increased at 1.7% per year from 1990 to 1998, it began to decrease, relative to other years, 1% each year from 1998 to 2002. When that 1% increase was adjusted for age in each of those years, incidence from 1998 to 2002 stayed about the same, Ravdin says. "There were more cases of breast cancer being diagnosed, but that was because women were getting older and entering the higher risk pool."

But by the end of 2003, there was a 7%, age-adjusted decrease in the number of breast cancer cases diagnosed. With further analysis, the researchers discovered that decline in incidence was far greater in ER-positive breast cancer (8%) compared to ER-negative breast cancer (4%). And when they looked at women 50-69 years old, the decline in ER-positive cancer was 12%, compared to 4%t in ER-negative breast cancers. After adjusting for age, the researchers concluded that there was an absolute decline of about 14,000 fewer women diagnosed with breast cancer in 2003 than in 2002.

Again, correlation does not equal causation. It may, but it may not. And, as Dr. Charles pointed out, there are other confounding factors. One that I'd like to mention is the increasing use of raloxifene (Evista) for the prevention of osteoporosis. The STAR trial showed Evista to decrease the risk of breast cancer in high risk patients, and the CORE trial showed a 59% decrease. The number of women taking Evista is not large enough to account for the drop, but if the 2003 numbers were a fluke and the 2004 and 2005 numbers level off, rather than continuing to decline, I would begin to wonder if this is one of the major factors responsible for the decline, an effect augmented by the plummeting of HRT use that occurred after 2002.

In the end, practicing EBM is not straightforward, contrary to the caricature of EBM that alties often paint, of physicians slavishly devoted to nothing but double-blind, placebo-controlled trials. Back in the 1980's and 1990's, there were no such high quality studies, and we were forced to synthesize the existing evidence as well as we could. Also, physicians do not act in a vacuum; we influence society, and society influences us. There was lots of hype about how great hormones are, a hype that continues even after the WHI trial in the form of self-proclaimed "experts" like Suzanne Somers advocating huge doses of "bioidentical hormones," which, in the magic that is altie world, are claimed on the basis of little or no evidence to be able to preserve a woman's youth and health while at the same time supposedly avoiding the harmful consequences of HRT of the type used in the WHI trial. (Never mind that prolonged exposure to endogenous estrogen, the very same hormones whose benefits the "bioidentical" hormone mavens tout, in the form of early menarche, late menopause, and nulliparity has been recognized as a risk factor for breast cancer for decades.) Then, in 2002, when a very large and well-designed randomized, placebo-controlled trial showed that the risks of the extended use of HRT outweighed the potential benefits, we were forced by the evidence to change. Disconcerting, yes, and not everyone was convinced right away. The transition from widespread use of HRT to only selective use was messy and disconcerting to both patients and their doctors, and the WHI and M.D. Anderson studies raise as many questions as they answer. But I'll take this over certain kinds of "alternative" medicine any day, where in the concepts and treatments haven't changed for decades, if not centuries, if not millennia. The key difference between scientific medicine and so-called "alternative" medicine is that scientific medicine eventually corrects its mistakes and improves the efficacy and safety of its therapies using the scientific method. The process is all too often messy and slower than we would like, but at least it has such a process.

Alternative medicine does not.

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I'm also skeptical about this. It seems to me to be more of a "Just So Story" -- an after-the-fact explanation of an observation -- than EBM. It is worth noting that the Women's Health Initiative Study did not report a big increase in breast cancer. Another recent report also fails to find such an increase.

This brings up another issue, which is that while the increased emphasis on evidence is welcome (the fact that the term "evidence based medicine" is not redundant is a somewhat sad commentary on the state of modern medicine), a lot of people in the profession don't really seem able to understand how to interpret this sort of statistical information. Too many doctors want to boil it down to a bottom line of "indicated" or "not indicated" without really weighing risks and benefits.

Before the Women's Health Initiative study, many doctors were browbeating women patients into HRT. Now, some of the same doctors are refusing to prescribe it under any conditions, even to patients who request it. Certainly, if one was taking HRT for health reasons, the WHI result was a good reason to stop. But a lot of women were taking HRT to relieve other symptoms of menopause. And while the risks of HRT sound high when expressed in terms of % increase in cancer incidence, they are not actually that high on an absolute basis. A reasonable physician would explain the risks and benefits to the patient, and let the informed patient make the choice of whether the benefits justify the risk.

Even more absurdly, I've seen cases of physicians switching patients to things like the estrogen patch, apparently on the "what you don't know can't hurt you" theory that since this type of HRT was not tested and found to be harmful by the WHI, it must be OK.

I would differ in the conclusion that promoting HRT for cardiovascular benefits was EBM. There was a considerable body of experimental evidence suggesting possible harm and certainly no clinical evidence on people to support such usage.

I would agree that promoting HRT was done on the basis of inadequate evidence in the 1980's and into the 1990's, but the cardiovascular benefits were not the only benefit touted. Certainly preventing osteoporosis was and is a benefit that is well-supported by the data, and there epidemiological data suggesting a cardiovascular benefit. Also, EBM is not necessarily limited to just evidence in people on clinical trials. Epidemiological evidence can be considered, as can animal studies.

You're also incorrect to say there was no evidence in humans. The article reporting the WHI study cited, for example, epidemiological studies by Stamfer and Colditz, as well as Grady et al.

It was retrospective, observational evidence, which is sometimes all we have to go on. Coupled with the known benefits with regards to osteoporosis and the paucity of evidence 20 years ago demonstrating an increased risk of breast cancer, it was not as unreasonable as it sounds today in light of the WHI to recommend HRT. Sometimes we get burned when we are reminded that correlation does not necessarily equal causation.

Finally, some are going too far in the other direction. Although the percent increase in risk was significant, in absolute terms it was small. Women who consider their symptoms so severe that they're willing to take that risk should have that option, as long as they fully understand it.

Although there was no clinical evidence that HRT was beneficial for cardiovascular disease, there was a significant amount of epidemiological evidence for estrogen to be a factor in the lower rate of CVD in women in the 40-50 age group compared to men. The relative differences in HDL between men and women and the difference in HDL following menopause certainly made it reasonable to claim that estrogen had a cardioprotective effect.

By natural cynic (not verified) on 21 Dec 2006 #permalink

That is my point. Observational, epidemiological evidence can merely assess associations, not causation.

I would argue that such evidence, without clinical trials to determine causation, is insufficient to base a treatment modality. Countless times, clinical trials have disproven original hypotheses based on epidemiological correlations.

Younger women have higher estrogen levels and lower CVD disease. A correlation. Perhaps it's not estrogen to explain women's lower CVD rate. What if it's merely their age and genetics, something like their naturally higher blood lipid levels, or something else entirely? For years, women were being led to believe by marketing that HRT would keep them youthful and that, I suspect, has a lot more to do with it's popularity in prescriptions than anything.

PS. In a nutshell, what I am saying is that I believe that we should have some evidence of the efficacy (safety and effectiveness) of a drug, on actual health outcomes (versus false surrogate endpoints which are more correlations), before subjecting millions of patients to them.

That's what I, and I suspect most patients believe, is what "evidence" means.

would argue that such evidence, without clinical trials to determine causation, is insufficient to base a treatment modality. Countless times, clinical trials have disproven original hypotheses based on epidemiological correlations.

True enough.

However, for many (if not most) questions in medicine, particularly preventative medicine, epidemiological studies are all we have. Indeed, before the molecular mechanisms of carcinogenesis were worked out, for cigarette smoking all we had was epidemiological evidence that smokers had a risk of lung cancer that was at least 10 times that of nonsmokers. That was more than enough for the surgeon general to issue his warning in 1964. Another example: The relative risk of cancer and other diseases from secondhand smoke from current epidemiological data is probably less dramatic than the benefit claimed for HRT with respect to heart disease in old epidemiological studies used to justify it. Yet, cities are acting to decrease the exposure of workers to second hand smoke. Doing nothing because the evidence is "only epidemiological" is a recipe for paralysis, also known as "RCTmyopia." In some cases, evidence of lesser quality is all we have because doing an RCT would be unethical.

You can certainly argue that it was inappropriate to base a preventative intervention like HRT on relatively weak evidence, but it's not reasonable to declare such an intervention to be "not evidence-based." HRT recommendations were based on the best evidence available at the time, as weak as it may have been, plus hype. Again, the whole point of this post was to point out just how messy EBM can be and how we can have such shifts in thinking.

Ultimately the lesson that I take away from this is that it is despicably easy to torture yourself (or worse, somebody else) with a retrospectoscope.

Health care professionals should not be pilloried for being honest enough to say "Oh shit, we goofed..." so long as they then take steps to find out where and how.

Unfortunately many in the altmed fraternity take the same line on the medical profession that some armchair historians sometimes take on the World War 1 generals - they point only to the mistakes (whether excusable or not), without being bothered to analyse and understand why they happened (and it is not surprising that they then have the same blinkers on when it comes to the defects of their own profession).

By Justin Moretti (not verified) on 21 Dec 2006 #permalink

Younger women have higher estrogen levels and lower CVD disease. A correlation.

There was rather more than that to the evidence supporting benefits of HRT. It was not merely a comparison between young women an older women. Much of the evidence was derived from retrospective studies of age-matched women who did and did not receive HRT. So you need a more subtle confounding factor than age to explain why the retrospective data did not hold up in prospective studies. It remains something of a mystery. One that has been suggested is that receiving HRT might have been a "marker" for receiving better overall health care.

It's all well and good to acclaim randomized double-blind prospective studies as the gold standard. But sometimes there are ethical reasons why the "perfect" study cannot be carried out, and even if they can be, such studies take years, and. So what is to be done in the meantime. The risk of harming people as a result of being misled by a confounding factor in retrospective studies must be balanced against the risk of harming people by withholding a beneficial treatment while waiting for the outcome of the "perfect" study.

I find some of these arguments disconcerting, especially among skeptical medical professionals.
1. we can't wait for the evidence, we must act now.
2. this can't be studied
3. other people are doing it, acting on even weaker evidence
4. if it can't be explained on a molecular level then we can't prove/disprove causation
5. we can't withhold something that might help people waiting for evidence because the risks are too great

Let me play devil's advocate here. It these were woo modalities, we'd be all over these arguments, but because we "believe" we were right, we believe we can get away with them. Bias can cloud objectivity in how the evidence is considered. And if this were a public health crisis, some of the arguments might have some merit. But the fact is there was not a crisis of women dropping dead of CVD to necessitate emergency action, nothing to indicate that proven and safe interventions couldn't have been just as helpful or moreso; the risks of hormones had/have a pretty hefty body of evidence to suggest they are not benign; and most women being prescribed hormones were not likely to have been told that if the HRT hypothesis proves to be true and might cut their relative risk for CVD in half, that their actual risk of CVD could drop from 0.1% to 0.05%. We do owe our patients a careful determination of the risks and benefits, but we also have a responsibility to be honest about it, even after the fact. I would hope that the FDA in approving drugs, considers clinical trials to be of greater importance, and carefully weighs the risks and benefits in keeping with the seriousness of the health condition being treated.

We are working from very different definitions of evidence and different definitions of how to define a condition requiring medical intervention. But this has been interesting. Thank you for sharing your perspectives.

And yet, some people want us to become "informed users" of health care services to hold down costs.

My gynecologist wanted me to take a hormone drug whose name escapes me now, but one which had a pretty scary side effect of eating out the esophagus. He would not listen to me when I said I had no post-menopausal symptoms so didn't want to take anything more unless I really needed it, because I already take ten different pills for other things. He kept talking about bone density but then said there was no good test for bone density. I said, prove I'm losing bone and we'll talk about it.

After considerable back-and-forth it was easier just to quit going to the gynecologist. I had a bone density scan recently and it was normal for someone my age. I practice defensive driving and try not to trip over the cat. If I break a bone, so be it. At least I'll still have an intact esophagus.

Have there ever been any studies on how the use of HRT became so widespread over the years? It seemed to have started as a treatment for menopausal symptoms, but then morphed into a longterm treatment that was supposed to decrease the risk of a number of conditions, as well as supposedly helping keep a woman 'youthful' forever.

I don't think that doctors were the sole agents driving this whole HRT situation. There was Wyeth and their scare tactic ad compaigns. The one I remember was ~2000, featuring Lauren Huttom, a famous fashion model. She sadly related in the ad how she didn't take HRT, and lost an inch in height - in just one year!. Wyeth also ran another TV ad around the same time, showing a serious gynecologist in the obligatory white coat, quietly explaining to a forty-ish patient that not treating menopause can lead to tooth loss, memory loss, even blindness. (Was there any EBM for these claims?)

With so many women taking HRT and taking it longterm, this put pressure on all women to start taking it at menopause, even if they weren't having problems with menopausal symptoms. Why not take it, when all your friends are on it.

Back in 2002, I remember watching Katie Couric on the Today Show, when the news about the HRT study first came out, interviewing a doctor about this story. Couric plaintively spoke about her mother, who had been taking HRT for years, mainly to decrease the risk of heart disease, amongst other things. Couric looked like she couldn't understand how there could be such a stunning reversal on the recommendations for HRT. One day you should take it to preserve your health, and the next day you should stop taking it to preserve your health.

I hope I can put this diplomatically*, but it is situations like this that make laypersons wonder about the science behind some medical recommendations and practices. Or if there's much of any science behind some recommendations and practices. Yes, it's true that eventually a study like the WHI was carried out to examine the benefits and risks of HRT. However, the HRT train run full speed ahead for at least 3 decades, with no one caring to put the brakes on it. Certainly not the FDA.

*To clarify, I'm not an altie, I've never used alternative medicine, and I think Suzanne Somers is a blithering idiotic celebrity.

1. we can't wait for the evidence, we must act now.
2. this can't be studied
3. other people are doing it, acting on even weaker evidence
4. if it can't be explained on a molecular level then we can't prove/disprove causation
5. we can't withhold something that might help people waiting for evidence because the risks are too great

There are at least three straw man arguments there: Specifically 1, 2, 3, and 4. (Actually, #1 and #5 are virtually the same comment.)

First the obvious ones: No one ever said it "can't be studied." What we said is that you can't do a randomized, double-blinded study on some things. It's not the same thing at all, and we study problems all the time without randomized studies. Just because doing a randomized study might be unethical does not mean we can't study the question! Similarly, I certainly didn't say that if we can't explain something on a molecular level then we can't figure out causation. We use several drugs where the molecular mechanism is unclear, but we know they have a therapeutic effect.

People are acting on weaker evidence. This is true in some cases, but, contrary to your comparison with altie therapies, you'd be hard-pressed to come up with an altie therapy where the evidence for efficacy is scientifically sound enough compared to conventional therapies not to be worthy of castigation. Yes, some conventional medicine is not as evidence-based as we would like, but few alternative modalities reach even the level of the least well-supported conventional therapies.

Finally, yes, there are diseases and conditions for which we can't wait for the definitive evidence to act. There's stroke, MI, cancer, and all sorts of other diseases that won't wait for randomized studies. Using HRT to prevent cardiovascular disease is not among these conditions, as I've mentioned before, because it is a preventative intervention. Moreover, because it is a preventative intervention, the safety standard it must reach is much higher than for diseases that need to be treated--which is why, although its use was evidence-based using the best evidence at the time, the evidence upon which it was based was not of adequate quality to support giving HRT to millions of otherwise healthy women.

I'm with Orac on this one, statistical analysis is not as good as experiment, but sometimes its all you have.

I'm an economist and policy analyst and I can tell you in economics it is generally impossible to conduct a controlled experiment. Econometric analysis is generally the best tool (assuming you can get data).

Also in a policy environment a decision will have to be made now, and waiting isn't an option. When that happens you do the best you can, control for as many confounding factors as possible and try to sort out the possible explanations for your results afterward.

And causality is an even bigger problem as you can't even rely on what happens first being the cause as humans have an annoying habit of trying to predict the future and then act on those predictions, no consideration at all.

If hormone use decline only delays and does not prevent cancers, we'll see a blip up in the expected rate in a few years. How will "EBM" react to that?

Concerning actual preventive health and medical care of people, numbers and statistics are not clinical evidence...certainly insufficient for me to rush my support behind treatments I advocate for my patients and my family. And when there is decades of epidemiological evidence that contradicts many of the treatments being advocated today, or even for the need of certain conditions to be treated, and there are animal studies pointing to harm and lack of efficacy; those are critical to include in the equation. The problem is, many professionals and policy makers get their information from the news and commercial promotions, and they go along with what is popular rather than digging deep and thinking critically. It is sadly common among risk analysts to base their work on incredible clinical premises and research to begin with. Yet, when deciding care for millions of people and diverting $$$billions of public healthcare resources, it is all the more important to carefully include all of the soundest evidence available when balancing risks and benefits.

I agree with Orac that with preventative interventions, the safety and efficacy standards they must reach should be higher than life-and-death situations. Most all medications and treatments can be tested with clinical trials on some credible level. Even the FDA has a mechanism in place for fast tracking drugs that treat life-threatening diseases with low-survival expectations and no other treatment options (AIDS and late-stage cancers). But that is not why many drugs and treatments are rushed to be marketed today -- it's all too often profit potential. Medicalizing normal human conditions and variations and changes like menopause, weight and aging is profitable because so many people certainly can be targeted, but that doesn't make it good medicine.

Most of all, people deserve to know the full story behind the treatments and drugs being recommended to them so that they can make informed choices for themselves, but they almost never do unless they dig it up themselves and then they encounter some of the crazy, fear-driven stuff out there and don't know what to believe. But what else can they do when medical professionals aren't doing the hard work of being skeptics? Besides HRT, cholesterol meds, weight loss meds, certain health screenings, and popular supplements, I have been cautioning my family about the liver problems with tylenol and refusing tylenol products for myself for years. The evidence has been there for a long time to point to significant enough concerns that, being informed, we were able to use to weigh the risks with the benefits and choose other, safer medications or measures when they were available.

Concerning actual preventive health and medical care of people, numbers and statistics are not clinical evidence

I can't help wonder what you imagine clinical evidence consists of, if not "numbers and statistics?" Anecdotes? Every type of clinical study, even randomized prospective studies, is susceptible to certain types of bias that can potentially lead to incorrect conclusions. For example, it is by no means certain that the women in the WHI study are truly representative of the population receiving HRT. While I would say, based on the current state of knowledge, that HRT should not be used as a routine protective measure, it is worth noting that in addition to identifying risks, the prospective study confirmed some of the benefits reported from previous retrospective studies. For the study population, the net risk outweighed the benefit by a rather small margin, but it still remains possible that the benefits could outweigh the risks for some groups of patients. Moreover, there are many women who would find the risks acceptable given the reduction in postmenopausal symptoms.

Potential sources of biases in clinical studies of any design are a factor that a physician must consider in making decisions. There are risks associated with acting and there are risks associated with failing to act.

It's certainly now possible for a woman to make an informed decision whether she wants to take HRT for relief of menopausal symptoms. I believe the recommendations are that HRT should be taken at the lowest level that is needed to relieve symptoms, and that it's to be taken for a limited time (I think it's about a year).

What was happening prior to 2002 was that women would go on HRT for symptom relief, and then never go off it. Most likely for a number of reasons - their doctors assured them it was safe, and because they heard from both their doctors and the media that HRT had preventative benefits, particularly for heart disease, strokes, and osteoporosis. From what I understand, the only real long term benefit is to reduce the severity of osteoporosis.

One can argue about this whole situation from a distance, as if it is an interesting mental exercise. But it isn't and wasn't - this debacle went on for 3 decades, and affected the health of millions of women. The appropriate use of HRT was never seriously questioned before it became widely prescribed. And once it became widely prescribed, it became the standard practice, making it even harder to 'just say no' to long term use of HRT.

To be frank, I don't see where evidence based medicine was 'messy' in the HRT situation. Evidence-based medicine appears to have been absent from the picture. Perhaps doctors thought they were doing good for their patients by prescribing it long term. Women thought they were taking good care of their health by taking long term. The only evidence I see is that Wyeth made a lot of money.

Despite the apparent risks the fact remains that for some of us HRT makes life worth living. I have been taking HRT since hitting menopause in my early 40s and I am now 56. When I reduced the dose last year, within 3 months I suffered joint pains, frequent migraines, exhaustion, broken sleep, inability to concentrate, severe mood swings. After 8 months with no sign that the symptoms were reducing I went back on HRT and within days felt energetic and lively, the joint pains vanished within 2 weeks and I have not had a migraine since. Despite this, it is a struggle to persuade my GP that for me the risks are far outweighed by the benefits.

By Sally Marshall (not verified) on 22 Dec 2006 #permalink

Evidence-based medicine was by no means absent from the decision to use HRT. Historically, the way it happened is that doctors began prescribing HRT to women to relieve post-menopausal symptoms, which for some women can be a major quality of life issue. And in clinical studies, it was found that women on HRT had a lower incidence of a variety of ills. On the basis of this clinical evidence, HRT was extended to women without major menopausal symptoms. The WHI study, in which participants were randomly given either estrogen or a placebo, confirmed some of these protective effects, but also found risks that on average outweigh the benefits. So both the decision to extend HRT and the decision to curtail it were evidence-based.

On the other hand, the recommendation that HRT for menopausal symptoms be limited to 1 year seems to be arbitrary rather than evidence-based. There is no evidence that post-menopausal symptoms reliably vanish after a year, and considerable evidence that they frequently do not. A rational policy would weigh the severity of the individual patient's symptoms and the impact upon quality of life against the rather modest risks of HRT.

Several weeks ago, an Ob/Gyn ran this series on HRT, with some information on HRT use, both pre- and post-WHI.
From her summary, there appears to have been good evidence of the benefits of HRT for menopausal symptoms and osteoporosis, but less evidence and more suppositions for heart disease prevention.

This doctor does take a balanced approach now to HRT, and seems to have had a somewhat conservative approach to this treatment before 2002. She writes quite well about the mileau surrounding the whole HRT situation, and how Premarin in particular came to be one of the best selling drugs.

I'm not against women taking HRT, particularly for menopausal symptoms. I don't care for the 'one size fits all' treatment approach that was once prevalent.

She also shows some older print ads for Premarin from the 1960's. They emphasize the benefits for men (i.e., husbands) and for doctors (all men).

I'm sorry, but I can't help myself. I found another old Premarin ad, this one entitled 'The Whole Family Likes Premarin':


And, of course, there's 'Women Like Premarin, of Course':