Ending Medical Reversal: Improving Outcomes, Saving Lives 1st Edition

The book reports how/why doctors continue to used medical practices, sometimes for decades, that are later shown to be of no benefit to their patients. Time and again, we 'learn' that a new practice will help extend life, then that it does not. (Estrogen-replacement therapy after menopause, placement of coronary stents to open narrowed/blocked coronary arteries, cupping - topical suction, lobotomy. Vioxx, flecainide, losartan, routine mammography for women in their 40s) The authors assert that while there are instances of good hypotheses failing to live up to expectations - such should happen in a lab/controlled clinical trial - not in clinical medicine. They believe medicine can do a better job recommending practices that actually work.Medical reversal/disbelief is strongest when involving how people feel - eg. vertebroplasty, coronary stents (for the first three years), arthroscopic knee surgery to repair degenerative meniscal tears (700K/year),Seven states in the career of a medical innovation,' pre-Evidence Based Medicine (EBM), per John McKinlay: A 'promising report' in which a medical innovation is publicized based on its promise. 2)The innovation is adopted. 3)Patients and payers accept the innovation as standard. 4)Data begin to become available - however, those supporting the innovation come only from insubstantial studies that support the innovation in the most superficial way. 5)The RCT makes an appearance. 6)Then denial, if its use is not supported - entrenched interests deny the innovation may not be effective. 7)Acceptance.While EBM has filled journals, they often avoid big questions or favor one side such that they are not useful.Surrogate end points are objective ones that can be easily and directly measured (eg. improved bone density vs. fracture rates, lowered blood pressure vs. decreased rate of strokes, antiarrhythmic drugs decreasing the number of premature ventricular contractions but not survival after a heart attack, hospitalization rates). However, they are invisible to the patient.Summarizing to this point, we have seen reversal for practices meant to make us live longer when evidence supporting that practice was weak or flawed - this included times when the evidence relied on surrogate end points. For practices meant to make us feel better, we have also learned how powerful the placebo effect is, and noted reversals when treatments were later tested using appropriate controls, such as sham procedures.Screening recommendations have also be reversed. In many reversals involving screening are the worst kind - they are performed on healthy people and thus affect an enormous number of them who simply want to stay that way. An ineffective screening test can turn millions of healthy people into patients. Recommendations for PSA tests, mammograms for women in their forties, Pap smears, etc. have all been revised.In studies of CT-scan screening for lung cancer in those between ages 55 and 80 with a heavy-smoking history is the only screening test to-date that makes you live longer - and even here am many as 96% of abnormal findings are false alarms. In studies of colorectal cancer with 30 years of follow-up, for every 10,000 people, 192 die of colon cancer in the unscreened arm, vs. 128 in the screened arm. However, looking at overall mortality, 7,109 out of 10,000 die in the unscreened group vs. 7,111 in the screened group - not a significant difference.Most experts agree that all cancer screening leads to some amount of over-diagnosis. When we screen for prostate cancer, we end up treating about 40 cancers for every cancer that will kill. For mammography, the best studies suggest that if a mammogram finds breast cancer and it is treated, there is a 13% chance this will have saved a life.Each year in America, we spend hundreds of billions on screening tests and their downstream costs. In 2011, two articles were published, finding that gown-and-glove precautions did not decrease transmission of VRE or MRSA in ICUs - an intervention generating additional costs w/o benefits. However, gown-and-glove precautions were adopted largely on the basis of 'single-center, before-and-after studies. The proof from such a study tends to be tenuous because that center may be idiosyncratic - a unique demographic of patients or bacteria, or an unusually enthusiastic proponent who changes the culture in ways not reproduced elsewhere. Before-and-after studies are also problematic, and the initial data behind most systems interventions. However, one's intervention is never the only thing changed (Hawthorne effects) - and per the author, we have yet to see a very large, well-done randomized trial confirming that eg. a checklist is truly what makes the differences. Another - rapid-response-teams for cardiac arrests were demonstrated in the 2005 MERIT trial in 23 Australian hospitals to not improve patient outcomes. Yet, gown-and-glove precautions and RRT are widely accepted, despite not working.'Door-to-balloon' time was considered an important objective. A 2013 study found that between 2005 and 2009, door-to-ballon times were significantly reduced across the nation - the number of patients waiting longer than 90 minutes decreased from 40.3% to 16.9^. Mortality, however, was unchanged. Explanations - perhaps we were not targeting the right metric (instead focus on total time), or decreasing door-to-balloon time might be an example of diminishing returns. A final example - in 2001 a single-center unblinded RCT found that lowering blood-sugar levels to normal levels could improve survival in a SICU. (A novel strategy because one of the body's responses to critical illness is to raise blood-sugar levels.) This quickly became a new standard until a 2009 multicenter (42 hospitals) RCT found the practice increased deaths by 2.6 percentage points at 90 days.Prasad then points out that while doctors often recommend treatments that do not work, patients also do - on their own. Glucosamine and chondroitin ($700 million in 2004) - a 2006 RCT found no difference in pain; this was followed by a 2010 review of data from 10 different trials that reached the same conclusion. Echinacea - nearly 20% of Americans reported using Echinacea in the past 30 days, mostly to reduce the duration of cold symptoms. A 2005 RCT study concluded it did not reduce symptom duration; this was later supported by 7 randomized trials - only one of which reduced symptom duration compared to a placebo. (The authors also examined 12 studies that looked at Echinacea to prevent colds - none of the studies showed an effect.)Acupuncture is a popular treatment for pain, dating back over 3,000 years. An effort to summarize all research analyzing acupuncture published (Western Chinese, and Korean scientific literature) between 2000 - 2009 concluded there is 'little truly convincing evidence that acupuncture is effective in reducing pain,' and also enumerated a few examples of acupuncture causing real harm.Use of multivitamins in a 2009 study of 161K women found no link to declines in cancer, heart disease, or mortality; a 2013 review of randomized trails found no clear benefit on overall survival, heart disease, or cancer.Recent analyses of randomized trials found that calcium and vitamin D supplementation does not reduce risk of fractures among healthy women, and the U.S. Preventive Services Task Force recommends against the supplements. On the other hand, we've known that calcium and vitamin D supplementation increases kidney stones, and a 2010 group of researchers added heart attacks as another potential side effect.When it comes to dietary habits, studies are less like science and more like an opinion poll. Most diets are never tested in a randomized trial, and when they are, the main outcome of study is usually short-term weight loss. In PREDIMED (an RCT evaluation of the Mediterranean diet, using randomly assigned patients at high risk for a cardiovascular event) found one had to treat about 90 people with the diet for 5 years to prevent one stroke - yet no mortality differences.In 2005 John Ioannidis wanted to measure the proportion of important findings in medicine that were later contradicted. He started with studies referenced over 1,000 times published during the years 1990 to 2003. Of those, 45 found a medical intervention effective, and of those 16% were later found ineffective, another 16% less effective than initially believed, 44% supported in future studies, 24% never tested again. The authors did their own research, using articles in the 2009 NEJM - of the 35 studies examining current standards of care, 46% showed current standards as ineffective. They then extended their study to NEJM articles between 2001 and 2010. Reversals were found in 40%, 38% reaffirmed the benefit of a new practice, and 22% were inconclusive. A project of the British Medical Journal Clinical Evidence completed a review of 3,000 medical practices and found 35% effective, 15% harmful/unlikely to be beneficial/tradeoff, and 50% of unknown effectiveness.Tracking citations to three major practices found not to work: beta-carotene to prevent cancer, estrogen to prevent Alzheimer's, and vitamin E to lower cardiovascular risk, researchers found that 10 years passed before the research community stopped referencing the flawed practice.Original analyses of prescribing estrogens for post-menopausal women was cofounded by the self-selected nature of those originally taking the supplements - less likely to have a family history of heart disease, be hypertensive, have diabetes, or smoke; they also were younger, drank more alcohol, and consumed more saturated fats.A 2012 paper titled 'Empirical Evaluation of Very Large Treatment Effects of Medical Interventions' (Pereira, Horwitz, Ioannidis) examined the proportion of medical trials showing a very large treatment effect (eg. 5X or more). They looked at over 228,000 trials and found only 9% did so. Topics with large effects were less likely to be about mortality and more likely to be about a laboratory value. They then looked at other studies addressing the same questions as those demonstrating the very large treatment effect - 90% of the time, the large treatment effects got smaller when one looked at other studies, thus strongly suggesting the largest magnitude of effect ae more likely statistical flukes. Across all the studies, only one had a large effect on mortality - a method for oxygenating blood of newborns who cannot adequately breathe on their own.RCTs have intrinsic error rates, added to by early termination of RCTs, publication bias,Industry-sponsored studies are 4X as likely to reach a positive conclusion; they are also less likely to be published/presented, or published after a delay. When companies hold back evidence (device-makers, drug formulators), the medical literature becomes selectively drawn from a much larger pool. Tamiflu was thought to prevent transmission of the flue, decrease hospitalizations, and save lives - an RCT found it decreased flu symptoms by less than a day - while causing nausea and vomiting, did nothing to prevent transmission of the virus, reduce hospitalization or deaths. Previously, Roche (Tamiflu manufacturer) had published its own meta-analysis, and found large benefits. Their study included only those proven to have influenza (rather than those with influenza-like illness) and focused on those receiving the drug early - different than typical use.The FDA cannot consider cost as part of its deliberations, nor relative efficacy. Then, in the early 1990s, the FDA pioneered an accelerated-approval program - allowing drugs for serious diseases with few treatment options to gain approval by showing benefit on a surrogate end point reasonably likely to predict clinical benefit. The drug is then given a period of time to prove it benefits a more important end point. However, after a drug is approved, it is much harder to get participants to enroll in a study (no one will pay for a trial if there is no prospect for large returns) and after 20 years one-third of these post-approval confirmatory studies had not been completed.What is also not acceptable is for a drug company to develop a drug for one indication and then market it for something else - gabapentin is an egregious, but not the most recent, example. In 1993, under the trade name Neurontin, it was approved to be used for the treatment of seizures when combined with other drugs. Its maker, Parke-Davis, then marketed it for eg. bipolar disorder, pain disorders, etc. AND as a single agent for seizures - despite having previously being rejected for the latter by the FDA. A $430 million settlement followed, but over 20 years later gabapentin is still not approved for most of the off-label uses for which it was initially promoted. (Another reversal-prone situation.)A bias to 'act now, data later' also contributes to reversal, rapid reporting on new technology is another, along with direct-to-consumer advertising (we're one of only two nations {New Zealand} that permit such). An evaluation of DTC advertising found 10% of those with 'adjustment disorder' symptoms and did not request a medication received one, vs. 39% of those making a general request and 55% making a brand-specific request. Between 1999 and 2005, DTC advertising increased from just under $1 billion to over $4 billion. Another - a medical school emphasis on 'reductionism' (understanding the mechanism by which a drug purportedly works), instead of empiricism (does the drug work).

"Ending Medical Reversal" is an essential book for medical students, physicians, and anyone even peripherally involved in medicine; for everybody else, it's merely highly recommended. The core of the book, paraphrasing, is that sometimes physicians decide to do things to patients without great evidence. These practices are, later on, 'reversed' by well-done trials, often to the great surprise of thought leaders and experts in a specialty. This is "Medical Reversal", which doesn't sound all too exciting, but is actually super important. To understand why, the underpinnings of the evidence-based medicine community need to be examined, and the books lay them out in understandable and lucid prose, with lots of examples for people unfamiliar with medical practice. The most important of them is the following: medical theory, in the sense of scientific models that allow for accurate prediction of real-world outcomes, is very poor. Another way of saying this: biology is very complex, and predicting real-world outcomes in biological systems with any precision is mostly impossible.The second most important assumption is that the vast majority of modern medical interventions, even when they do work, have modest effect sizes. A new cancer drug, if you're lucky, might increase survival by an average of a month, a new weight loss drug might let you lose another 5-10 lbs, and a surgery might save 79% of patients instead of 77%. These are made-up numbers, but the point stands: on average, when new drugs works, which is itself rare, they tend to be incremental improvements over the old standard of care.There are exceptions, but they're rare in the modern era: for instance, you didn't need RCT's to see that antiseptic techniques improves surgery, because the effect sizes were enormous-- for instance, operating on the peritoneum, previously a death sentence, became possible. Amputation mortality rates fell by more than 50%. The effects were so powerful they could be seen with practically any study design.The third tenet of EBM is that most interventions, even the best funded and most plausible candidates, fail when tested in the real world. As the authors put in their book, this means that the prior probability of any given intervention working is very low, even in the late phases of drug development. This has implications for the types of evidence that physicians should require to shift their guess on whether a given drug works. Importantly, developing medical interventions is incredibly hard and expensive, and seems to be getting harder over time, giving rise to the reverse Moore's Law that has been termed "Eroom's Law" .As a result of these 3 factors, to really know if a medical intervention is effective, you need randomized controlled trials where the effects of a single intervention are tested on roughly similar groups of patients and outcomes are tracked in a rigorous manner. RCT's are onerous, slow, and require immense coordination-- but they've overturned many pet theories and biologically plausible interventions. The fact that these theories and interventions turn out to not work is not the problem-- after all, false starts and experimentation are how science progresses-- the problem is that they're often implemented prematurely, before rigorous testing, and only later, as doubt builds, are they truly tested.This is "Medical Reversal". There are other important arguments in the book, but they're mostly subsidiary to these 3 key arguments. Among them is a critique of surrogate endpoints, criticism of sloppily and hastily implemented 'systemic' interventions in hospital systems, the profusion of observational studies purporting to show harmful or beneficial effects of lifestyle factors, and the supplement industry. All of these other criticisms could be short books on their own, but they're woven in to this book in a seamless way. If I could pin the critique of systemic interventions with only preliminary evidence on the wall of every major hospital chain, I would!There's a more radical part of the book, which I think is underappreciated: the call to action in the later half of the book. The authors argue for a new era in medicine, wherein a large fraction of patients will be enrolled in RCT's, constantly testing medical dogma, even for simple questions that are currently poorly understood. They want an easier and more seamless way to recruit patients in clinical trials, which would be done at lower cost than current methods, and think this can be done partly by viewing RCT's as the default. Any practice in medicine that is currently understudied would be subject to this "RCT by default, opt out if you want" framework. Since RCT's would be testing treatments that are, theoretically, in equipoise, this is far more ethical than our current era, in which many medical interventions are only tested rigorously AFTER being used on patients in uncontrolled settings. As they correctly point out, the "safest way to receive a new drug is in a trial with a control arm. The randomized-controlled-trial design provides a built-in safeguard—trials are stopped if the treatment turns out to be harmful".As they acknowledge, this radical change is a big ask, but "evidence-based medicine...is the only rational way to provide care" and in my view, is the only ethical way to practice medicine. They make this radical change seem like the self-evidently obvious thing to do...Later in the book they critique medical education for it's elevation of purported drug mechanisms and biological minutiae over a better understanding of medical evidence, landmark clinical trials, and more contact with patients in clinical settings. They call for an overhaul of medical education. A nice quote on this: "The primacy of the basic sciences is the reason that cardiologists could not accept the finding that niacin did not save lives. It is why radiologists could not accept that vertebroplasty did not help back pain. It is the reason orthopedists could not accept that repairing torn menisci did not help knee pain."The book isn't perfect. There are some relatively minor factual stumbles which don't affect the core arguments.For example, it uncritically cites "Nudge" by Sunstein and Thaler, which is based in large part on Behavioral Economics-- but at least some of that work has not fared well in the replication crisis, as Kahneman himself has pointed out in a blog post. So that's pretty ironic. Very little of their argument rests on these points, merely a few throwaway paragraphs, so it's a very minor misstep.I also think its slightly deceptive to say that supplements don't have to admit to a lack of evidence, as they claim. They do. Every supplement I've ever purchased has had, in clear writing, "This product is not approved....to treat or prevent any disease". Of course, these same supplement bottles claim benefits, so its a mixed message, but supplements certainly have labeling to indicate they're not approved. I would certainly agree with them, that, as a whole, the supplement industry is mostly a waste of consumer money for little purpose.The authors also repeatedly criticize pharma-funded trials and influence, but my understanding is that pharma-funded trials generally comply with reporting regulations better than academia funded trials, and may, in fact, be more trustworthy than the average academic study. I'm not sure about this, but I vaguely recall a high-profile article showing this. Not sure.Then there are the ideological disagreements one can have with the book. I wonder what the authors would think of cosmetic surgery when they write "The list of medical practices that improve outcomes among healthy individuals is a very short one." They're right about medical outcomes, but individuals have goals besides health, and cosmetic surgery can occasionally help achieve those goals. They do mention quality of life as an outcome of importance, and I would certainly agree with them that cosmetic surgery should be rigorously tested, but it would be an interesting debate to have... In regards to supplements, individuals often have goals besides health as well: performance in the gym, aesthetics, etc. There are a small handful of supplements with RCT evidence of efficacy: creatine is probably the best example. It works pretty reliably, though with a modest effect, on increasing muscular endurance and likely muscle growth. Caffeine is another example. Both are used by millions, with very good safety profiles. Would the authors propose that all non-medical usage of supplements be banned? I would love to hear their thoughts on that.More controversially, plenty of people would make trade-offs between quality of life and lifespan. How would a clinical trial be run on these questions? They could theoretically be done, but as it stands I think any trial that, for instance, allowed healthy middle-aged men access to exogenous testosterone in supraphysiological doses, would struggle to get run. Since most of medicine doesn't fall into these cracks, their argument is still a very solid one-- these are more just wrinkles of disagreement I'd be interested in hearing about. Cosmetic surgery and supplement use for non-medical purposes both push on an interesting corner of their argument: freedom. For the clinical trial infrastructure to work, participating in a trial has to be the main way that drugs get approved and patients get access to experimental medications. If alternative pathways to drugs are available in large numbers, and enrollment in trials is threatened, this whole RCT structure falls apart. Medical freedom is not exactly compatible with "RCT's for all".To their credit, the authors sort of touch on this: they focus on the pull side of RCT incentives-- if clinical trials are much easier to run, if inclusion criteria for new drugs were not so strict, if many more patients were enrolled, etc. then patients would have much fewer incentives to try to get drugs outside of approved protocols. And yet, with urine and blood testing of drugs, medical tourism, and patients sharing information about side effects with each other over social media, it is becoming increasingly possible for patients to figure out who is in a control/experimental arm and get drugs outside of approved channels. These are real threats to RCT's, and I'm very curious what the authors think of these developments.My final disagreement is with optimism in medicine. I'm not even sure the authors would disagree with this, since they're not really aiming their critique at drug researchers per se, but just in case: while drugs with large effect sizes are rare in medicine, they're not unknown. In the modern era, perhaps only HIV and Hep-C drugs, along with immunotherapy in some cancers and Gleevec meet this benchmark of large effect sizes. While most medicines will be incremental advances of the state of the art, I hope we continue looking for moonshots. We should be properly skeptical of anybody who claims to have found one, but rejoice if a good RCT shows them to be right. Expect failure or incremental advance, rejoice when we're wrong!Overall, I can't recommend this book enough!

The book is very informative and should be read by healthcare professionals, those who plan on working in healthcare, and anyone who is interested in the improvement of the healthcare system. The book's information motivates healthcare professionals to take care of patients more thoughtfully. The book also empowers people to be better healthcare advocates for themselves and their family members by explaining how to decrease their chances of being victims of medical reversals.It can be intimidating reading a book about medical research without a medical background. Fortunately, the authors explain everything so well throughout the book that the content is easy to read and understand.As a hospital nurse, I did see some of the medical reversals which were mentioned in the book. That is why the book was even more interesting for me to read. I highly recommend that nurses and nursing students read the book.

I recommend this book to everyone who is in the medical field and to anyone who has the difficult task of dealing with medical issues in their own life.It certainly gave me good insight for how similar the medical profession deals with methodological inertia; just like every other professional field - with resistance and wariness toward change.

Anche se certe posizioni sono un po' talebane, fa veramente riflettere su quelli che sono i claim di efficacia di molti trattamenti. Per non parlare delle presunte mirabilie di intrugli che non sono neppure farmaci e quindi non hanno alcuna validazione scientifica a supporto. Il suggerimento che "potrebbero" avere un qualche effetto diventa una certezza indiscutibile per accalappiare i gonzi e spennarli.

Required reading for all medical providers in this time of pharmaceutical and device maker propaganda. Providers need to critically evaluate everything we do to avoid unintended consequences. This includes many things we do which are accepted as proper or guideline directed practice.

Esta obra arroja luz sobre aspectos de la medicina donde se dan por definitivas y probadas prácticas médicas cotidianas de las que cada vez hay más evidencias de su inutilidad y hasta su capacidad de dañar. Es un libro imprescindible para todos, pero muy especialmente para médicos de cualquier especialidad.

Excelente livro do Dr. Prasad sobre a realidade das tecnologias médicas que são lançadas no mercado, sobre a falta de controle da qualidade das mesmas e sua utilização no mundo real e como são excluídas do mercado depois de tanto anos de uso, causando danos aos pacientes além de custo elevado. Toda obra com referências científicas. Excelente leitura!