This will be a four part, four day post. The first part is background on HRT use before the WHI, then discusses the WHI and its results. Part two addresses the response in the medical community to the findings of the WHI. Day Three will be TBTAM’s Rules for Prescribing HRT, and Day 4 will address the use of bioidentical hormones. So hop on board, the winds are fair and we’ve got a lot to cover…
Those Were the Days
Those were simpler days, the years prior to the publication of the WHI. “Simple” meaning that, for the most part, we had a “one size fits all” approach to managing menopause. You were a woman, you had menopausal symptoms, you had a heart — you got estrogen. It was that easy.
It seemed simple, but we were not stupid. There was more than a little scientific support for our approach to menopause. Dozens of well done, retrospective and cohort studies had all pointed to the same conclusion – women who took HRT had less heart disease than those who did not.
This conclusion made biologic sense. We knew that the onset of menopause was associated with an increase in the incidence of heart disease in women. Moreover, estrogen raised HDL, the good cholesterol, and lowered LDL, the bad cholesterol. Finally, there was indirect and animal evidence that estrogen caused vasodilation.
Turns out that estrogen also appeared to prevent osteoporosis. It was, and still is, is the most effective treatment for the symptoms of the menopause transition – hot flashes, night sweats, and vaginal dryness. Not to mention its effects on the skin, increasing collagen and decreasing wrinkles.
And the risks? Well, estrogen was known to increase the risk of thromboembolism. In addition, it had been known since the 70’s that it could lead to endometrial cancer, but that risk was alleviated if progesterone was added to the mix. Breast cancer, of course, was a persistent concern, showing up as a potential risk in a number of studies. But the results were inconsistent, even in meta-analyses.
Given that heart disease was the number one killer of women, and that the cardiac benefits seemed to be more consistently apparent than the breast cancer risks, there was a real hope in the medical community that the cardiopreventive properties of estrogen would outweigh the risks.
And yet, looking back at the review articles on estrogen written prior to the WHI studies, all the experts were clear that more evidence was needed before recommending HRT for heart disease prevention on a widespread scale. Almost every paper I read was careful to recommend individualized treatment, weighing the risks and benefits for each woman before prescribing.
As for the world of practicing docs, the primary indication for prescribing HRT in those days was still menopausal symptoms, but we had a much lower threshold for prescribing estrogen than we do now. It didn’t take much in the way of hot flashes for us to prescribe HRT, especially for women we thought might additionally benefit from the cardiac effects of estrogen. For some, a high LDL alone was enough reason to use estrogen. (Remember, we did not have the statins then). And more than a few physicians gave all their menopausal patients estrogen, regardless of symptoms. “My doctor said it was good for me.” is what some of my patients would tell me when I asked them at their first appointment why they were taking estrogen.
Overall, I would say that, prior to the WHI, estrogen was something we felt good about prescribing. We liked it and our patients liked it. It was one of those drugs that had a real and visible effect, which for the overwhelming majority of women was positive. Think about it – relief of hot flashes, insomnia, night sweats and vaginal dryness, prevention of osteoporosis, normalization of lipids, and the possibility of heart disease prevention. That’s one heck of a drug.
Big Pharma, as it turns out, also liked estrogen.
Wyeth been the leader in the HRT market for years, spurred on in no small way by the publication in 1996 of “Feminine Forever“, a book which touted the wonders of estrogen in staving off the effects of aging. (The book, as it now turns out, was entirely underwritten by Wyeth. Why am I not surprised?)
Wyeth’s drug was Premarin, a proprietary mixture of conjugated equine estrogens. Equine – that’s a nice way of saying estrogens isolated from horses, specifically from the urine of pregnant mares. (I had read that if you crush the pill , soak it in water, and then sniff, it is clear where it comes from. I did not believe it until I tried it for myself. It’s true.)
I need to say at this point that, having prescribed Premarin extensively in the past and still occasionally now, that it is a very effective estrogen, and despite the smell, I have no real issue with its source. Many women do, however, and so I rarely prescribe it these days since there are numerous alternatives.
For the progesterone component of HRT, Wyeth had Provera, or medroxyprogesterone acetate. (Same stuff as in Depo-Provera, the birth control shot, but at a much lower dose). The two hormones are combined together as Prempro. I did not prescribe Prempro as much as I used Premarin, having moved towards micronized progesterone as soon as it became available, because I found it in general to be better tolerated than Provera.
By 1990, Premarin was one of the most prescribed drugs in the world, and was approved by the FDA not only for the treatment of both hot flashes and vaginal dryness, but also for the prevention of osteoporosis. When studies began to rack up showing that estrogen was also good for women’s hearts, Wyeth asked the FDA to approve Premarin for the prevention of heart disease. Of course, doctors everywhere were already prescribing the drug off-label for that reason. But with a formal FDA indication, Wyeth would be allowed to advertise for the indication, and we all know what Big Pharma advertising does to sales. It was sure to be a slam dunk, and a very profitable one at that, since the prevention market for a drug is absolutely enormous compared to the treatment market.
The problem was that all the data up to this point supporting the cardiac benefits of estrogen were from observational, retrospective or cohort studies. And there were those pesky little problems of breast cancer and blood clots that kept creeping into the study results. The risks appeared relatively small, but they were there nonetheless.
Despite this, the FDA’s advisory committee had actually recommended that Wyeth be given the cardiac indication based on the observational data. But in an unprecendented move, the FDA went against their own advisory commitee’s recommendation and asked for a randomized, placebo-controlled trial. The trial Wyeth would begin was the HERS trail, a study of HRT use in women with pre-existing heart disease, believing, I’m sure, that estrogen’s protective effect would show up quickly in this group at high risk. (It did not, as we found out later.)
At around the same time, feminists at the NIH, FDA and on the Hill were pushing for federal funding for research in Women’s Health. Congress responded by funding the Women’s Health Initiative, a large prospective study of women’s health enrolling over 60,000 women for 15 years. The jewel in the crown of the WHI was a randomized, prospective, placebo-controlled trial of hormone replacement in menopausal women. The study was designed to determine once and for all whether or not estrogen prevented heart disease and treated osteoporosis, and to answer the lurking question about breast cancer risks. Everyone, including the study investigators, expected favorable findings for estrogen in terms of heart disease.
But which estrogen to use? Well, Premarin and Prempro were the most prescribed hormones at that time, so it made sense (although maybe not biologic sense) to use them. And Wyeth? Well, they were more than happy to supply drug for the study. And that’s how Premarin and Prempro became the drugs used in the WHI.
There were two study arms to the WHI – one arm for women with a uterus, who received either Prempro or placebo, and a smaller arm for hysterectomized women, who recieved either Premarin or placebo.
The Bombshell Results
The first sign of trouble came when the HERS study results showed no benefit to HRT use in women with pre-existing heart disease, despite favorable effects on blood lipids. In that study, there was actually an increase in cardiac events in the first year of hormone use, probably due to clotting effects, that disappeared in the subsequent years such that overall, no difference was found in cardiac mortality among users and non-users of HRT.
Then came the results of the WHI, results that came earlier than expected when the Data Safety Monitoring Board decided to stop the study prematurely. Because as we all know now, Prempro did not to prevent heart disease in the WHI. Not only that, it actually appeared to increase that risk, along with that of blood clots and stroke. At least among the women in the Prempro arm of the study, who were on average 10 years post menopausal and 64 years of age at enrollment.
WHI results from the WHI Newsletter
To make things worse, breast cancers were also increased among users of Prempro in the WHI, to the tune of 8 additional cases for every 10,000 women for every year of use. Not a statistically significant increase if you want to get picky. But, since this was a prevention and not a treatment trial, the bar for safety was much higher since subjects were supposedly healthy to begin with. And the Data Safety Monitoring Board was not about to accept an increase in breast cancer if there was no cardiac benefit. Even the benefits in terms of bone and colon cancer were not enough to tip the balance in favor of HRT.
So, they stopped the trial. (The estrogen-only arm was allowed to continue till 2005, when increased stroke risks stopped that study.) Sure makes sense to me.
Whether the whole study design itself made sense in the first place is another story. The study population was deliberately weighted towards older women. Since most cardiac events occurred among older women, benefit would show up earlier in this group. Younger women with menopausal symptoms were specifically excluded from the WHI because it was felt to be unethical to give these women placebo. Of course, this is exactly the opposite of how HRT is prescribed in the real world, and remains the biggest limitation of the WHI in my humble opinion.
Which raises the question – Is an average age of 64 just too late to start estrogen? By that age, arterial plaque is likely to be long-established, and adding in a drug known to increase risk of blood clotting may not be such a great idea. Some experts still believe that if estrogen is given earlier in life, say at the menopause, it may still be preventive for heart disease. Think of it this way – Running is good for you, and can prevent heart disease, but if you are not a runner, have blocked coronaries and try to run a 10K, you might just trigger an MI, which would not be good. It’s an intruiging hypothesis, but at the time of the publication of the WHI, it was just that. An idea.
In 2002, like it or not, the bottom line was that HRT was associated with an increase in the risks of heart disease, stroke and breast cancer. In a disease prevention trial, that just doesn’t hold water, especially when the primary outcome, heart disease, was not prevented anyway.
And that, my dears, is why they stopped the study.
Up next…The Reaction
Category: Second Opinions