American College of Physicians: Internal Medicine — Doctors for Adults ®

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Monday, July 29, 2013

The 'lethal placebo' and clarifying hormone replacement outcomes

Everyone seems to love a riveting conspiracy theory, except, of course, the victims of it. We enjoy the gathering momentum of our collective outrage and casting our passionate aspersions at some malefactor in the military industrial complex. In my world, that malefactor is often Big Pharma. Everyone loves to hate the harms that drugs do and the profits they generate along the way. Denigrating Big Pharma is a cultural pastime, and rollicking good fun.

And in the larger context of health care, it even makes sense. The prime directive of medicine, after all, is primum non nocere. Medicine becomes a legitimate target for scorn when it is a purveyor of net harm.

But what truly matters here is not the means, but the ends, the harm itself. What matters is life lost from years, and in the more extreme cases, years lost from life. And I have just such a tale to tell, but the means are peculiar. It's not the drug that's killing people, it's the placebo.

My Yale colleague, Dr. Phil Sarrel, has devoted his career in large measure to a detailed knowledge of the overall health effects, and in particular the vascular effects, of ovarian hormones. Ovarian hormones, estrogen and its metabolites, and progesterone, profoundly influence a woman's health from menarche to menopause, and then influence a woman's health some more by disappearing.

Dr. Sarrel was in the vanguard of those who saw serious problems with the large, randomized clinical trials, published just at the turn of the millennium, that refuted our prior faith in the disease-preventing potential of hormone replacement therapy. The HERS trial, and the massive and massively influential Women's Health Initiative (WHI), purportedly showed that we had been wrong about the advantages of hormone replacement, and that the practice resulted in net harm.

Even I was among those who noticed right away that the net harm was very, very slight, and grossly exaggerated in media headlines. But Dr. Sarrel was among those with the expertise to induce bigger worries.

Both trials had used the exact same form of hormone replacement, so-called "Prempro," a combination of Premarin and medroxy-progesterone acetate. Premarin is estrogen derived from the urine of pregnant horses, and thus not native to humans. Medroxy-progesterone acetate is a synthetic progesterone, not native to any species, and many times more potent than human progesterone. Most experts, including my colleague, had long preferred other forms of hormone replacement, considering Prem/Pro a dubious choice.

But when HERS and the WHI tarred the practice of hormone replacement, it was with a broad brush. The news was not that Prem/Pro, one questionable approach to hormone replacement, resulted in benefits for some women and harms for others, with a very slight net harm at the population level. The news was: hormone replacement therapy harms women!

We already had potentially serious problems at this point, but the plot thickens considerably. Dr. Sarrel was also among those to note that these clinical trials administered Prem/Pro to women a decade after menopause. They did this to be sure the women were not just merely but most sincerely post-menopausal. But we had cause to suspect then, and abundant reason to know now, that the benefits of ovarian hormone replacement accrue right at the time of menopause, and in the decade that follows. Timing is often crucial in medicine, as in life. Administer, for instance, a potent diuretic while a patient is fluid overloaded, and it can be lifesaving. Give just the same drug after they have already eliminated that excess fluid, and the result is apt to be hypotension and even death. Timing matters, and the hormone replacement trials got it seriously wrong.

All of this suggests that many women who might have benefited from good hormone replacement administered with good timing have missed out on those benefits because of the headlines engendered by HERS and the WHI. But the story does not end here, either. It ends, as noted, with a lethal placebo.

Quite a few months ago, Dr. Sarrel and I had the first of our recent intense flurry of meetings at my lab. He had brought me a paper published in JAMA in 2011, reporting on one particular subgroup included in the WHI: women who had undergone hysterectomy. The only reason to include progesterone in hormone replacement is to protect the uterine lining from overgrowth, so women who have had a hysterectomy are prescribed (or were, back in the days when hormone replacement was not the bogeyman) estrogen only.

Dr. Sarrel's read of this paper was that the younger women, those age 50 to 59 and therefore just on the far side of menopause, had a considerably higher mortality rate when given placebo, rather than when given estrogen. I am formally trained in biostatistics and epidemiology, so my colleague asked me to verify this impression, which I did. Our project, and the resulting publication of our paper in July in the American Journal of Public Health, grew from there.

Working with a team from my lab, we devised a very simple formula to translate the excess death rate seen in the estrogen-only arm of the WHI to the entire population of such women in the United States: women in their 50s, who had undergone hysterectomy. Hysterectomy is very common, arguably too common, so this population numbers in the many millions. We then needed to add into the formula the most reliable estimates we could find for the precipitous drop in estrogen prescriptions following the publication of the original WHI results back in 2002.

We, of course, had to run the details of our analysis through the gauntlet of peer review. And our paper now stands, in a highly-esteemed journal, on full display before a jury of peers. So I can spare you the details of our methods, and focus on the punch line.

We estimated that over the past decade, due to a wholesale abandonment of all forms of hormone replacement for all categories of women by both the women themselves and their doctors, minimally 20,000, and quite possibly more than 90,000 women have died prematurely. We were very careful to incorporate only reliably conservative figures into our formula, so the numbers might actually be higher still. Being extremely cautious, we report that over 40,000 women have died over the past 10 years for failure to take estrogen.

This death toll of estrogen avoidance, or better still, estrogen "aversion," represented some 4,000 women every year. Whatever the emotional impact of that figure, it should be greater, because any one of those women could be your spouse, or mother, or sister, or daughter, or friend. And the impact should be greater because the massively over-simplified, over-generalized, distorted "hormone replacement is bad" message continues to reverberate, and rates of all kinds of hormone replacement use continue to decline.

Stated bluntly, we think the mortality toll of estrogen avoidance is not merely a clear, present, and ongoing danger, it is a worsening one. More women are dying from this omission every year. And the next one in that calamitous line could be a woman you love; it could be you.

I write this column as my colleagues and I wrote our paper: with a sense of urgency, and even desperation. My career is entirely devoted to the prevention of avoidable harms and the protection of years of life, and life in years. This is as clear cut a case of preventable harms, and as readily fixable, as we are ever likely to see.

Here, then, are the take-away messages:

1) All forms of hormone replacement for all women at menopause was never right, but nor is NO forms of hormone replacement for NO women at menopause. There was always baby and bathwater here, and we have egregiously failed to distinguish between the two.

2) The millions of women who have undergone hysterectomy are candidates for estrogen-only hormone replacement at menopause, and when that treatment is provided at the time of menopause and for the years that immediately follow, it can both alleviate symptoms AND save lives. It could save the lives of thousands of women every year in the U.S., and no doubt many thousands more around the world where the tendency toward hormone replacement aversion also prevails.

Every woman who has had a hysterectomy should be open to the option of estrogen therapy at menopause and should discuss it with her doctor. Every health care professional needs to know that some forms of hormone replacement for some women at menopause remain potentially life-saving, and needs to address the topic accordingly.

3) Medical news is often translated into provocative headlines that abandon the nuances of the actual findings for the sake of maximal impact. This certainly happened when we learned that one form of hormone replacement resulted in a very slight excess of total net harm for one particular group of women, but is a far more systemic problem; it happens all the time. All of us plying our wares where medicine and the media come together need a bracing reality check: there are lives at stake! When headlines distort the actual state of medical knowledge and take on a life of their own, they can affect patient behavior and clinical practice, and the result can be the very harm medicine is pledged to avoid.

I call upon my colleagues involved in the reporting of medical news to embrace the great responsibility that comes with the great power of the press, and to deliver their headlines accordingly. How many avoidable deaths is a maximally titillating, but misleading, headline really worth?

We've all seen the commercials on television: Drug companies are required to report the various potential harms of their products, as they should be. But no one is required to report the potential harms of placebo. For the past decade, millions of women who might have enjoyed more life in years, and tens of thousands who might have enjoyed more years of life by taking estrogen, were, in essence, taking a "placebo" instead. And in this case, it was the placebo causing the harm. In this case, the placebo was, and all too often remains, lethal.

David L. Katz, MD, FACP, MPH, FACPM, is an internationally renowned authority on nutrition, weight management, and the prevention of chronic disease, and an internationally recognized leader in integrative medicine and patient-centered care. He is a board certified specialist in both Internal Medicine, and Preventive Medicine/Public Health, and Associate Professor (adjunct) in Public Health Practice at the Yale University School of Medicine. He is the Director and founder (1998) of Yale University's Prevention Research Center; Director and founder of the Integrative Medicine Center at Griffin Hospital (2000) in Derby, Conn.; founder and president of the non-profit Turn the Tide Foundation; and formerly the Director of Medical Studies in Public Health at the Yale School of Medicine for eight years. This post originally appeared on his blog at The Huffington Post.

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Blog log

Members of the American College of Physicians contribute posts from their own sites to ACP Internistand ACP Hospitalist. Contributors include:

Albert Fuchs, MD
Albert Fuchs, MD, FACP, graduated from the University of California, Los Angeles School of Medicine, where he also did his internal medicine training. Certified by the American Board of Internal Medicine, Dr. Fuchs spent three years as a full-time faculty member at UCLA School of Medicine before opening his private practice in Beverly Hills in 2000.

And Thus, It Begins
Amanda Xi, ACP Medical Student Member, is a first-year medical student at the OUWB School of Medicine, charter class of 2015, in Rochester, Mich., from which she which chronicles her journey through medical training from day 1 of medical school.

Auscultation
Ira S. Nash, MD, FACP, is the senior vice president and executive director of the North Shore-LIJ Medical Group, and a professor of Cardiology and Population Health at Hofstra North Shore-LIJ School of Medicine. He is Board Certified in Internal Medicine and Cardiovascular Diseases and was in the private practice of cardiology before joining the full-time faculty of Massachusetts General Hospital.

Zackary Berger
Zackary Berger, MD, ACP Member, is a primary care doctor and general internist in the Division of General Internal Medicine at Johns Hopkins. His research interests include doctor-patient communication, bioethics, and systematic reviews.

Controversies in Hospital Infection Prevention
Run by three ACP Fellows, this blog ponders vexing issues in infection prevention and control, inside and outside the hospital. Daniel J Diekema, MD, FACP, practices infectious diseases, clinical microbiology, and hospital epidemiology in Iowa City, Iowa, splitting time between seeing patients with infectious diseases, diagnosing infections in the microbiology laboratory, and trying to prevent infections in the hospital. Michael B. Edmond, MD, FACP, is a hospital epidemiologist in Richmond, Va., with a focus on understanding why infections occur in the hospital and ways to prevent these infections, and sees patients in the inpatient and outpatient settings. Eli N. Perencevich, MD, ACP Member, is an infectious disease physician and epidemiologist in Iowa City, Iowa, who studies methods to halt the spread of resistant bacteria in our hospitals (including novel ways to get everyone to wash their hands).

db's Medical Rants
Robert M. Centor, MD, FACP, contributes short essays contemplating medicine and the health care system.

Suneel Dhand, MD, ACP Member
Suneel Dhand, MD, ACP Member, is a practicing physician in Massachusetts. He has published numerous articles in clinical medicine, covering a wide range of specialty areas including; pulmonology, cardiology, endocrinology, hematology, and infectious disease. He has also authored chapters in the prestigious "5-Minute Clinical Consult" medical textbook. His other clinical interests include quality improvement, hospital safety, hospital utilization, and the use of technology in health care.

DrDialogue
Juliet K. Mavromatis, MD, FACP, provides a conversation about health topics for patients and health professionals.

Dr. Mintz' Blog
Matthew Mintz, MD, FACP, has practiced internal medicine for more than a decade and is an Associate Professor of Medicine at an academic medical center on the East Coast. His time is split between teaching medical students and residents, and caring for patients.

Everything Health
Toni Brayer, MD, FACP, blogs about the rapid changes in science, medicine, health and healing in the 21st century.

FutureDocs
Vineet Arora, MD, FACP, is Associate Program Director for the Internal Medicine Residency and Assistant Dean of Scholarship & Discovery at the Pritzker School of Medicine for the University of Chicago. Her education and research focus is on resident duty hours, patient handoffs, medical professionalism, and quality of hospital care. She is also an academic hospitalist.

Glass Hospital
John H. Schumann, MD, FACP, provides transparency on the workings of medical practice and the complexities of hospital care, illuminates the emotional and cognitive aspects of caregiving and decision-making from the perspective of an active primary care physician, and offers behind-the-scenes portraits of hospital sanctums and the people who inhabit them.

Gut Check
Ryan Madanick, MD, ACP Member, is a gastroenterologist at the University of North Carolina School of Medicine, and the Program Director for the GI & Hepatology Fellowship Program. He specializes in diseases of the esophagus, with a strong interest in the diagnosis and treatment of patients who have difficult-to-manage esophageal problems such as refractory GERD, heartburn, and chest pain.

I'm dok
Mike Aref, MD, PhD, FACP, is an academic hospitalist with an interest in basic and clinical science and education, with interests in noninvasive monitoring and diagnostic testing using novel bedside imaging modalities, diagnostic reasoning, medical informatics, new medical education modalities, pre-code/code management, palliative care, patient-physician communication, quality improvement, and quantitative biomedical imaging.

Informatics Professor
William Hersh, MD, FACP, Professor and Chair, Department of Medical Informatics & Clinical Epidemiology, Oregon Health & Science University, posts his thoughts on various topics related to biomedical and health informatics.

David Katz, MD
David L. Katz, MD, MPH, FACP, is an internationally renowned authority on nutrition, weight management, and the prevention of chronic disease, and an internationally recognized leader in integrative medicine and patient-centered care.

Just Oncology
Richard Just, MD, ACP Member, has 36 years in clinical practice of hematology and medical oncology. His blog is a joint publication with Gregg Masters, MPH.

KevinMD
Kevin Pho, MD, ACP Member, offers one of the Web's definitive sites for influential health commentary.

MD Whistleblower
Michael Kirsch, MD, FACP, addresses the joys and challenges of medical practice, including controversies in the doctor-patient relationship, medical ethics and measuring medical quality. When he's not writing, he's performing colonoscopies.

Medical Lessons
Elaine Schattner, MD, FACP, shares her ideas on education, ethics in medicine, health care news and culture. Her views on medicine are informed by her past experiences in caring for patients, as a researcher in cancer immunology, and as a patient who's had breast cancer.

Mired in MedEd
Alexander M. Djuricich, MD, FACP, is the Associate Dean for Continuing Medical Education (CME), and a Program Director in Medicine-Pediatrics at the Indiana University School of Medicine in Indianapolis, where he blogs about medical education.

More Musings
Rob Lamberts, MD, ACP Member, a med-peds and general practice internist, returns with "volume 2" of his personal musings about medicine, life, armadillos and Sasquatch at More Musings (of a Distractible Kind).

Prescriptions
David M. Sack, MD, FACP, practices general gastroenterology at a small community hospital in Connecticut. His blog is a series of musings on medicine, medical care, the health care system and medical ethics, in no particular order.

Reflections of a Grady Doctor
Kimberly Manning, MD, FACP, reflects on the personal side of being a doctor in a community hospital in Atlanta.

The Blog of Paul Sufka
Paul Sufka, MD, ACP Member, is a board certified rheumatologist in St. Paul, Minn. He was a chief resident in internal medicine with the University of Minnesota and then completed his fellowship training in rheumatology in June 2011 at the University of Minnesota Department of Rheumatology. His interests include the use of technology in medicine.

Technology in (Medical) Education
Neil Mehta, MBBS, MS, FACP, is interested in use of technology in education, social media and networking, practice management and evidence-based medicine tools, personal information and knowledge management.

Peter A. Lipson, MD
Peter A. Lipson, MD, ACP Member, is a practicing internist and teaching physician in Southeast Michigan. The blog, which has been around in various forms since 2007, offers musings on the intersection of science, medicine, and culture.

Why is American Health Care So Expensive?
Janice Boughton, MD, FACP, practiced internal medicine for 20 years before adopting a career in hospital and primary care medicine as a locum tenens physician. She lives in Idaho when not traveling.

World's Best Site
Daniel Ginsberg, MD, FACP, is an internal medicine physician who has avidly applied computers to medicine since 1986, when he first wrote medically oriented computer programs. He is in practice in Tacoma, Washington.

Other blogs of note:

American Journal of Medicine
Also known as the Green Journal, the American Journal of Medicine publishes original clinical articles of interest to physicians in internal medicine and its subspecialities, both in academia and community-based practice.

Clinical Correlations
A collaborative medical blog started by Neil Shapiro, MD, ACP Member, associate program director at New York University Medical Center's internal medicine residency program. Faculty, residents and students contribute case studies, mystery quizzes, news, commentary and more.

Interact MD
Michael Benjamin, MD, ACP member, doesn't accept industry money so he can create an independent, clinician-reviewed space on the Internet for physicians to report and comment on the medical news of the day.

PLoS Blog
The Public Library of Science's open access materials include a blog.

White Coat Rants
One of the most popular anonymous blogs written by an emergency room physician.

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