Apropos of yesterday’s post on the unproven efficacy of ivermectin for Covid-19, I talked to my GP, Dr. Alex Lickerman, about the drug (he’s read the studies). I learned not only that there is no publication of high-quality controlled double-blind tests needed to show that ivermectin is effective against Covid-19 (there’s a big one that should be published by the end of the year), but also, surprisingly, nearly half of the medical drugs and procedures we use have not been subject to these tests. Very often the outcomes of clinical practice are just assumed to be efficacious without any rigorous tests with placebos and so on. Sometimes some people improve, but there is no randomized control group to compare them to. This is also true for some operations, in which “sham operations”—procedures that mimic real operations without the real surgical manipulation—have shown to be no better than the placebo procedures.
This is all summarized in a 2015 book shown below (click screenshot to go to Amazon link), and in a 2011 paper below that written by the same two physicians (Vinay Prasad and Adam Cifu, the latter from University of Chicago Medicine). What they mean by “medical reversal” is that later and better tests often show that drugs or procedures are either not helpful or could be harmful, so there’s a reversal of opinion and—if doctors are aware of this!—the procedure is abandoned or modified. We will soon know whether ivermectin is such a case.
If you want a shorter read on medical reversal (I haven’t read the book), see the paper below by Prasad and Cifu from the Yale Journal of Biological Medicine. It gives lots of examples, including both drugs and surgery, and describes why medical reversal is important. It’s not detected as often as it should be because double-blind randomized tests with controls are time-consuming, expensive, and hard to do for surgery. Neverthetless, I was surprised to find out that roughly 40% of procedures or drugs prescribed by doctors have been shown to be either unnecessary or harmful. Now I’m not a doctor, but I recommend you at least scan the paper below (click on screenshot) or listen to the audio link below that.
If you prefer listening to reading, you can find an hourlong conversation with Dr. Cifu on econtalk in which he summarizes “medical reversal” and gives examples.
Here are a couple of excerpts from the paper:
The second phenomenon is reversal: A medical practice falls out of favor not by being surpassed, but when we discover that it did not work all along, either failing to achieve its intended goal or carrying harms that outweighed the benefits. Although this phenomenon should be rare in the age of evidence-based medicine, it is ubiquitous. Common use of avandia , ezetimibe , atenolol , hormone replacement therapy , and the class 1C antiarrhythmic agents  all stopped when trials showed they were either ineffective or harmful. Reversal not only affects medications. Previously accepted indications for surgical and medical procedures also have been abandoned. In 2009, stenting for renal artery stenosis was shown to be ineffective for many patients by the Angioplasty and Stenting for Renal Artery Lesions (ASTRAL) trial , and in 2007, the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE)  trial found no benefit to support percutaneous coronary intervention (PCI) (versus optimal medical therapy) in most patients with stable coronary artery disease. In these cases, reversal does not mean that for every indication and purpose the therapy in question was shown not to work, but simply that it was contradicted for key indications.
. . . Reversal differs from replacement in that it produces three perils. First, reversal implies mistake or harm to patients cared for under the old model. The abandoned practices were ineffective or harmful. The cases of CAST and Avandia demonstrate harms, while COURAGE and Atenolol suggest only the harm of misplaced financial and social resources.
. . . Second, removing a once-commonplace practice can be more difficult than imagined. Adherence to the contradicted claim furthers malfeasance. The idea that beta-carotene could diminish cancer gained popularity in the early 1980s . By the mid-1990s, however, three randomized controlled trials overturned the claim [26,27,28]. However, nearly a decade passed before counterarguments were uncommon in the literature .
. . . Third, reversal undermines trust in the medical system. In the case of hormone replacement therapy (HRT) — once thought to be beneficial for reducing a woman’s risk of heart disease while treating menopausal symptoms and contradicted by the Womens’ Health Initiative — patients report feeling “furious” with doctors who “pushed” therapy upon them .
I asked my doc about hormone replacement therapy (HRT), as of course it’s still being widely used (check the internet). However, it was long thought, without any real tests showing it, that HRT, among other benefits, would also help postmenopausal women prevent the development of heart disease. A controlled test of that claim showed it was wrong: if anything, HRT increases the risk of heart disease. The problem may have been, as Cifu mentions in the podcast, that women seeking HRT could have been younger, thinner, and healthier (conditions that help prevent heart disease) than those who didn’t seek HRT. The “control” group was the latter, but it wasn’t a randomized trial: the “controls” may have been a nonrandom sample more likely to develop health disease. The upshot is that HRT, which used to be given to all symptomatic post-menopausal women, is not given to women with heart conditions, and patients are (or should be) informed about the slightly increased risk of heart disease. (See the Mayo Clinic’s advice here.)
Dr. Lickerman added this (quoted with permission):
If you’re a post-menopausal woman with post-menopausal symptoms and known heart disease, you probably shouldn’t get it. If your risk of heart disease is otherwise average and your post-menopausal symptoms are severe, it’s a tool that can be used. Think of it like using Advil to treat arthritis. There are definitely risks, but we judge them against the benefits in each individual case. What we no longer do is give HRT to all post-menopausal women because our original thinking was it would benefit them all as a preventative. Now we know better. We no longer use it for prevention; only for treatment when benefits outweigh risks.
Most of what we do in medicine is done based on observational studies. Prospective, placebo-controlled randomized trials are very expensive and time-consuming. My colleague, Adam Cifu, co-wrote a book called Ending Medical Reversal in which he did a survey of the literature and estimated that ultimately 35-40% of medical practices, when finally prospective studies are conducted, are found to be useless or even harmful. It’s quite shocking. This is why I focus so much on evidence.
The lesson, as Cifu says in the podcast, is to interact with your doctor, and ask for evidence if you’re dubious or unclear, for a patient doctor relationship is just that—a relationship. A doctor who is imperious or who won’t even talk about evidence isn’t worth having.
Finally, a couple of quotes from the New York Times‘s 2015 review of Ending Medical Reversal:
The incremental progress of ordinary science is one thing, as individual treatments are progressively replaced by better variants. We all happily accept that kind of revision. But medical reversal, the authors’ sober term for sudden flip-flops in standards of care, unnerves and demoralizes everyone, doctors no less than their patients.
Dr. Vinayak K. Prasad and Dr. Adam S. Cifu, of Oregon Health & Science University and the University of Chicago, have set themselves the task of figuring out how often modern medicine reverses itself, analyzing why it happens, and suggesting ways to make it stop. If this short list of objectives explodes into a breathless and somewhat unwieldy critique of all of Western medicine, you still have to appreciate both their ambition and their argument.
An old saw has long held that 50 percent of everything a student learns in medical school is wrong. Actual calculations suggest that number is not too far off base — Dr. Prasad and Dr. Cifu extrapolate from past reversals to conclude that about 40 percent of what we consider state-of-the-art health care is likely to turn out to be unhelpful or actually harmful.
Recent official flip-flops include habits of treating everything from lead poisoning to blood clots, from kidney stones to heart attacks. One reversal concerned an extremely common orthopedic procedure, the surgical repair of the meniscus in the knee, which turns out to be no more effective than physical therapy alone. The interested reader can plow through almost 150 disproved treatments in the book’s appendix.
. . . What could make more sense, after all, than finding some cancers early, fixing a piece of torn cartilage, closing a hole in the heart, and propping open blood vessels that have become perilously narrow? And yet not one of these helpful interventions has been shown to make a difference in the health or survival of patients who obediently line up to have them done.
. . . Dr. Prasad and Dr. Cifu offer a five-step plan, including pointers for determining if a given treatment is really able to do what you want it to do, and advice on finding a like-minded doctor who won’t object to a certain amount of back-seat driving. Of course, there are no guarantees that their tips will endure forever, but they probably have a longer shelf life than most medical advice.
h/t: Alex Lickerman