NephMadness 2016: Normalization of Hemoglobin—The Ultimate Medical Reversal
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Guest Commentator Vinay K. Prasad, MD, MPH shares his provocative take on the rise and fall of ESAs. As with all content on the AJKD Blog, the opinions expressed are those of the author of each post, and are not necessarily shared or endorsed by the AJKD Blog, AJKD, the National Kidney Foundation, Elsevier, or any other entity unless explicitly stated.
If you are looking for a widely recommended, guideline-driven treatment that blew up in our faces, you can’t find a better example than use of ESAs. The story has everything you would want. Early trial data should have provided caution. Enthusiasm for the treatment was driven by a faith that restoring an abnormal oxygen-carrying capacity would yield improved physiologic outcomes. Observational data repeatedly suggested benefits associated with higher hemoglobin. Enthusiasm had a (BIG) helping hand from the pharmaceutical company that stood to make billions. Guidelines were based on inadequate evidence, and written overwhelmingly by those with financial conflicts. Then, a few years later several randomized trials showed that the intervention and targeting normalization of hemoglobin, no matter how much ESA was needed, wasn’t just ineffective, but actually worse than a lesser goal.
The rise and fall of ESAs is an example of a medical reversal—a widespread medical practice that fares no better or worse than a prior or lesser standard in a well-designed clinical trial. Medical reversals are so common, so much the norm that my friend and colleague Adam Cifu and I wrote an entire book on the subject called Ending Medical Reversal.
For at least a couple hundred years (but probably since the dawn of time), doctors have been seduced by mechanistic thinking. We believe we understand why a physiologic process deviates from the norm, and we tell ourselves that “it would make perfect sense” if correcting the abnormality restores outcomes. Yet, this step is merely the hypothesis. It must be subjected to testing in rigorous, unbiased empirical studies; yet often we skip this inconvenience and make the leap to recommending the practice. You would think that, after ESAs, hormone therapy for post-menopausal women, stenting for stable coronary angina, autologous stem cell transplant for breast cancer, and the like, we would wisen up, but not so. Each year it seems two more dubious medical practices come along to replace the one we debunked. Manufacturers demand faster approval and command large market shares, and only years later, in certain cases, do brave investigators put these practices to the test. Sometimes, they don’t work. In our investigations, we put the number at ~40%.
The elephant in the room is the very long reach of money. It took years to change the culture of medicine such that financial conflicts were seen as a problem. Much like the data surrounding the deleterious effects of tobacco smoke, at one point financial COI was considered harmless or the norm. Enjoy that cigarette on your free trip to Hawaii! A few hundred papers later, we learned that financial conflicts lead to more favorable conclusions for sponsors’ products and lead to more brand name (rather than generic) prescriptions. In the last year, the NEJM has sought to re-write the history of conflict (link, link), but it would have trouble handling the case of ESAs. Guidelines sponsored by conflicted groups, and written by conflicted authors, generously recommended ESAs to treat to targets that were not supported by any evidence—one explanation for such a recommendation is if the goal was profits first, and for some, or perhaps many, it may have been.
What’s the grand take away of ESAs? The story tells us we have to roll up our sleeves and try to fix some of the major structural problems in medicine. This is our field after all—our profession. Human beings will always be seduced by something that sounds like it should be better, but we need regulators and guidelines writers and doctors to stop and remember that we have to prove it is better before we leap. The biopharmaceutical industry and the profit motive are capable of great mobilization and ingenuity, but we must be careful that the final arbiter of the effectiveness and use of medical products are un-conflicted doctors trained in recognizing bias. And the grand overarching lesson is that in the absence of randomized trial data showing a given intervention improves an outcome, we are all best to have some humility. Sure, it may, but, you know what, at the same time, it may not.
Vinay K. Prasad MD MPH is a hematologist-oncologist and Assistant Professor of Medicine at the Oregon Health and Sciences University. He holds appointments in the Division of Public Health and Preventive Medicine, and as a Senior Scholar in the Center for Health Care Ethics. He is known for his research on oncology drugs, health policy, evidence-based medicine, bias, public health, preventive medicine, and medical reversal.
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