In the early hours of July 9, 2002, within an office building overlooking the river somewhere in downtown Chicago, an elite band of lead scientific investigators involved in one of the largest scientific research studies in the US had gathered and were waiting for their boss to arrive and tell them what was going on.
They had all been summoned at short notice, more than half of them without explanation, according to one of those in the meeting. Accordng to one source that meeting was being held in the offices of one of the world’s most pre-eminent medical journals, JAMA. If that was the case, it must have been on the minds of many of those in the room as to why.
On his arrival to the meeting, a senior colleague would explain to the room that a decision had been taken to stop the major clinical trial being conducted by the group into the risks and benefits of combined oestrogen and progestin in healthy menopausal women due to findings of increased risk of invasive breast cancer, coronary heart disease, stroke and pulmonary embolism. The study had been scheduled to run until 2005.
Such a move during clinical trials is not unusual. Many in the room would have been aware that results being monitored by a safety panel had been cause enough for concern for several letters to have been issued to patients as early as two years prior. But for some investigators in the room it was still not clear what the data actually meant. And why the fuss?
The meeting got turned on its head when their boss made his next announcement.
The decision to cease the trial was being aligned with the release of a paper in JAMA outlining the results, and a series of high profile media conferences around the country. Some of the investigators in the room were flabbergasted.
How could their bosses justify writing a paper for a world leading medical journal without consulting them first, and how had JAMA accepted that paper for publication without a sign off from some of the key lead investigators?
At that time in scientific research you could have scores of people acknowledged on a paper so it wasn’t unheard of that investigators weren’t always aware of the publication of research they had been involved in. But to not consult lead investigators of the calibre that were in this room signalled that something was seriously amiss.
Reports from that meeting suggest that within a short period of time some of the investigators had already poked holes in some of the key premises of the JAMA paper. Tempers flared. Some allegedly demanded of those in the know that that they walk down the hallway to the office of the editor and “stop the presses”.
But it was too late. The journal had already been printed for publication on July 17, and was releasing a special early edition of the paper on its website at 9.00am on that day, July 9.
There was also to be a series of high level press conferences being held all over the country with senior leaders of WHI and the NIH announcing the results. It was a done deal.
Some of the investigators in that room believe that they were stitched up. They say were not properly consulted in the decision to cease the trial or to publish the results supporting the decision.
The senior leaders of the WHI and the NIH held a high profile press conference at the National Press Club in Washington that morning that kicked off worldwide panic. They detailed to an ill-prepared consumer press contingent some horrific sounding statistics: 26% increase in risk of breast cancer, 41% increase in stroke risk, 29% increase in heart attacks, 100% increase in blood clots.
Many in the press did not understand the difference between relative versus absolute risk. They reported these increases as though they referred to absolute numbers, suggesting one in four women on HRT were destined to develop breast cancer rather than the 26% increase from 30 to 38 per 10,000 women who developed breast cancer when on HRT. A big difference. Patients around the world were panicked.
Doctors weren’t warned and therefore completely unprepared. If you ask GPs today if they remember the incident, you will get some to give you vivid recollections of the exact day the story hit, like they remembered the day of the death of Princess Diana or John Lennon.
Chaos reigned by the end of the day. Within a week, HRT was damned for a generation, and more.
A massive drop in HRT use followed. The North American Menopause Society estimate that between 2002 and 2009 there was a 71% overall reduction in the prescribing of oestrogen. Correlating with this number, the percentage of women using HRT dropped from 36% to 10%.
Questions immediately erupted in the scientific and medical community about how such a well thought of and universally accepted therapy could be so suddenly tried, found guilty and sentenced to death. But many in the leadership of the WHI dismissed the earliest detractors as likely friends of the pharma industry or having undue buy-in to HRT for other reasons.
There was a growing fraternity of medical experts at the time who believed that although very useful, HRT was being marketed far too aggressively, especially in the US, and was likely being overprescribed. The announcement fell neatly into this narrative. But things were clearly amiss in WHI from the morning of that first meeting with lead investigators.
Some of those investigators and others were immediately suspicious of the manner in which the whole incident unfolded, which they suggested pointed to agendas beyond that of patient safety alone.
For a start, those fronting the various press conferences made some statements to the press that had no basis of evidence from the data that was being published in JAMA. Key among them was a comment from Roussow that the data was relevant to women of all ages taking HRT. This wasn’t true.
The WHI study had focussed on older women taking HRT, in whom the average age was 63 years. There was no evidence upon which Roussow could or should have extrapolated the results to apply to women from the ages of 45 to 60. But Roussow was deliberate and clear in the press conference that the increased risk associated with HRT applied to all women.
Interviewed by The Wall Street Journal’s Tara Parker-Pope for her seminal book on the topic, The Hormone Decision, Roussow actually admitted to her that he and his colleagues were deliberately portraying the findings in such a way as to “shake the medical establishment up”.
However, some of the investigators who worked with Roussow feel that he was also, in part making a political statement. As the then lead of the WHI, his career was definitely in the making and the early cessation of the study because of sensational findings certainly put him on centre stage.
Some have also speculated that there may have been pressure from the research funders who may have had their own reasons for wanting the study stopped early. Pharma-funded researchers get accused of succumbing to bias so the concept of a funder exerting influence is not all that surprising. Money changes behaviour.
Two other pieces of information have emerged from the incident which suggest the motivation behind the press announcements wasn’t entirely altruistic.
Firstly, when some researchers were given a pre-publication copy of the WHI paper, Roussow and others were questioned robustly about the methodology of the data analysis. According to one of these dissenting investigators, the analysis did not use adjusted confidence intervals, a basic error, and if it had, the only statistically significant increased risk was for thrombosis, and even that was very low and only in women aged over 60.
Secondly, the media conferences also managed to implicate all oestrogen therapies, including oestrogen-only therapy for women who had had a hysterectomy, a therapy that was not associated with any increased risk.
The trial that was ceased was a trial of the oestrogen and progestin combination therapy. The media conferences said of oestrogen-only therapy for women without a uterus, that oestrogen trials were at point where the balance of risk and benefits were uncertain.
In the dour atmosphere of the combination trial announcements, oestrogen-only therapy in hysterectomised women was dragged down into the mud as well.
The consequences of this situation were made stark in a paper written by researchers at Yale University in 2011, which calculated that up to 50,000 hysterectomised women may have died early as a result of stopping their oestrogen-only therapy.
The researchers found that before the 2002 WHI study, about 90% of women who had had a hysterectomy would have been commenced on oestrogen. Following the WHI paper the percentage using oestrogen-only therapy fell to a staggeringly low 10%. Based on survival rates the researchers calculated that between 2002 and their study in 2011, about 50,000 US women may have died prematurely.
If they are right, this puts the damage of the 2002 WHI paper and press conferences into stark perspective. If you add in the women who stopped the combination therapy, researchers estimate more than 90,000 women in the US may have died prematurely, well in excess the amount of people estimated to have died as a consequence of Vioxx (60,000).
Though a theoretical calculation only, you would have thought that the WHI investigators would have been keen to atone for their mistakes.
But as the years have rolled by, lead investigators have gone from doing interviews with The New York Times still promoting their 2002 findings a year later to making statements that demonstrate they have now assumed a completely opposite position to that of 2002, but with little or no contrition.
In fact, not a peep was heard from these WHI leads following the recent publication of research that what was perceived as the final nail in the coffin for the 2002 WHI paper. The behaviour seems even stranger given the fact this most recent paper was written by WHI researchers looking at long term WHI data. It largely confirms the safety of combined therapy, even in women over 60.
Cause for an “apology” moment from WHI perhaps? To that generation of women who were denied HRT some of whom suffered terribly as a result, and others of whom may have died prematurely as a result of not receiving the protective effects of oestrogen.
No such luck.
The paper was published with very little fanfare, if any. By JAMA ironically. There didn’t even seem to be a press release from the WHI research team.
Some media outlets did pick it up, but the story was usually tucked away in the inside pages of the major newspapers. The HRT debacle is a forgotten story. Along with a generation of women who have passed through menopause without feeling HRT was an option. The significance of this September WHI paper seems lost on everyone.
And with studies supporting HRT now holding little news value, it’s no wonder prejudice against the treatment still exists.
Some supposedly respectable consumer newspaper outfits still harbour bias against HRT.
Of note was The Guardian’s coverage of this latest WHI study with a headline and intro that said HRT “does not shorten lives, but it still increases the risk of cancer, leaving those suffering symptoms with a tough choice to make”.
The latest research showed that HRT was largely safe in women in women aged 45-60, with only a slight increase in risk of breast cancer associated with long-term use of oestrogen and synthetic progestin. And for hysterectomised women taking oestrogen only, mortality was actually reduced.
It’s hard to see how a paper like The Guardian could continue to make such fundamental errors. While likely seeking to protect women in some way, it is inadvertently hurting them.
There are quite a few clinicians who remain distressed at not only what happened in 2002, but at what continues to happen as a consequence of this “fake news” so many years ago.
Obstetrician and gynaecologist, Professor Rob Baber, of the Sydney University School of Medicine, is unequivocal. “HRT is not for everyone by any means. It never has been. But if you have significant menopausal symptoms it’s the best treatment. And if you use it in your 50s, it’s very safe and far outweighs the risks.”
Over 60, the data is less categorical, but Professor Baber says that like all assessment for HRT it is a matter of a women’s individual situation and their preferences.
Symptoms do go away over time but up to 10% of women have symptoms that persist long term and about 40% of women will still have hot flushes into their 60s.
Professor Baber says that, depending on the situation you can make therapy relative safe for long-term use and for use in women over 60.
“It’s all about perception of risk and absolute risk versus relative risk, and given someone has no clear contraindication. Once explained many women will proceed with HRT”, he said. He senses that as the data extends to include the older cohort, women above 60, the safety will be reinforced. And as more data comes in on some of the newer drugs in the market which act differently, such as the TSECS, the same will occur.
But he remains concerned that the scars caused by the 2002 WHI paper are deep, and many women still will end up suffering unnecessarily.
The scars exist both in patients and in the medical community.
“Some GPs are only just starting to return to idea that [HRT] is not the domain of mad monks anymore”, Professor Baber said.
He sees GP education as critical but says that although many GPs are now well aware of the realities of HRT and the WHI, they aren’t always as well-equipped to deal with menopause patients because these women may take a lot of convincing which can be both frustrating and time-consuming.
On the patient side, he says that with a long consultation and good communication skills, women who come in still quoting old or erroneous media reports can be convinced.
He estimates that of the menopausal women he sees, 8% are using it when they come to see him, but probably at least 20% need it.
“If you spend the time you can get that 8% up to 16%, but there is still 4% left,” he said.
One big issue that remains as a legacy of the WHI 2002 paper says Professor Baber, is the flight to natural therapies and in particular compounding HRT treatments.
He says that most natural therapies are safe even if their common benefit is placebo, but when compounding comes into play, there is no safety protocol and women should be extremely careful.
“A doctor still has to write a prescription for compounding but a lot of doctors are … All of these people charge a lot of money for these services. But worse, they claim that compounding is safer than traditional HRT, and there is no evidence of that. Most complementary medicines can’t harm you. Compounded hormones can.”
Where to from here?
In the late 1990s, HRT was seen almost as a miracle therapy.
That hype and some aggressive pharma marketing were potentially two things that contributed to its very sudden and catastrophic decline. It was an easy target for a scientific community that wanted to make a statement to the medical establishment. And it fell into a community narrative around big pharma and the medicalisation of menopause.
So can trust in HRT be restored?
Prof Baber is mildly optimistic, suggesting the tide has certainly turned, but it is going to take a lot of time still until the patient and medical community again fully trust HRT.
But a miracle therapy?
“It still is for women who have terrible symptoms,” says Professor Baber. “It turns their lives around.”
Professor Rod Baber lecture on the new TSECS HERE