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Do pill organizers help or hurt?

"Blister packs" help people take their medication on the correct schedule.

“Blister packs” help people take their medication on the correct schedule.

In order for medication to work, getting a prescription filled isn’t enough. You have to actually take the medication. And that’s where you (the patient) come in. Estimates vary based on the population and the medication, but a reasonable assumption is that 50% of people given a prescription don’t take their medication as prescribed. In pharmacy terminology we usually call this medication compliance, but because that sounds a bit paternalistic, the term medication adherence is also used. People forget doses, deliberately skip doses, and sometimes even take more than directed. Often, the prescription isn’t finished completely. Perhaps not surprisingly, people are less likely to adhere to their prescribed medication schedule when the condition they are treating has no symptoms. All things being equal, you’re more likely to take your pain control medicine than your hypertensive medications: Pain medications have side effects, but should help you feel better right now. Hypertension medications can only make you feel worse. Statins (as a group of medications) are another good example. We treat high cholesterol to lower the risk of heart disease: heart attacks, strokes, and death. It has no obvious benefit now, nor will we ever be able to point to the benefit we received. We’re taking the medication to reduce the risk of something happening in the future. If the drug isn’t taken regularly (or at all) then you’re not going to get the expected benefits of statin therapy. The “value” that treatment delivers is reduced (or eliminated). And if you stop a medication periodically, then restart it, you might get more side effects than you would have if you just took it regularly. (more…)

Posted in: Medical devices, Pharmaceuticals, Quality Improvement, Science and Medicine

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Whither the randomized controlled clinical trial?

Whither the randomized controlled clinical trial?

One of the most frequent complaints about evidence-based medicine (EBM), in contrast to science-based medicine (SBM), is its elevation of the randomized clinical trial as the be-all and end-all for clinical evidence for an intervention for a particular disease or condition. Unknown but enormous quantities of “digital ink” have been spilled explaining this distinction right here on this blog, beginning with our founder’s very first post, continuing with Kimball Atwood’s series of posts explaining the shortcomings of EBM’s reliance on clinical trials über alles using homeopathy as his example, to my referring to this aspect of EBM as “methodolatry,” defined as profane worship of the randomized controlled clinical trial (RCT) as the only valid method of clinical investigation. The problem, of course, with methodolatry, is that it completely ignores prior plausibility, and when that prior plausibility is as close to zero as you can imagine (e.g., for clinical trials of homeopathy), then the only positive results that you see in such trials can reasonably be concluded to be due to noise, shortcomings in trial design, and bias. Unfortunately, a failure to realize this has led to many pointless clinical trials and contributed to the rise of a whole new “specialty” known as integrative medicine, dedicated to “integrating” quackery and pseudoscience into science-based medicine.

So we know that practitioners of “complementary and alternative medicine” (CAM), now referred to more frequently as integrative medicine, don’t like RCTs. They love pragmatic trials, because such trials are usually unblinded, often not randomized, and generally face a lower bar of evidence. That pragmatic trials are intended to test the “real world” use of medical and surgical interventions that have already been shown to be safe and effective in RCTs and that the vast majority of CAM nostrums have not met that standard appears not to concern them in the least. However, CAM practitioners are not the only ones critical of RCTs, as I learned when, via Steve Novella, I came across an article in The New England Journal of Medicine entitled “Assessing the Gold Standard — Lessons from the History of RCTs” by Bothwell et al. Given that the article is two weeks old, I wonder how I missed it. Be that as it may, although Bothwell et al make some good points, I tend to agree with Steve that the overall gist of the article is overly critical, to the point of, as Steve put it, portraying the RCT as broken rather than flawed and advocating revolution rather than reform.
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Posted in: Clinical Trials, Pharmaceuticals, Politics and Regulation

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Is there a reproducibility “crisis” in biomedical science? No, but there is a reproducibility problem

NOTE: Anyone who has seen several derogatory articles about me on the web and is curious about what the real story is, please read this and this.

Journal of Irreproducible ResultsMost scientists I know get a chuckle out of the Journal of Irreproducible Results (JIR), a humor journal that often parodies scientific papers. Back in the day, we used to chuckle at articles like “Any Eye for an Eye for an Arm and a Leg: Applied Dysfunctional Measurement” and “A Double Blind Efficacy Trial of Placebos, Extra Strength Placebos and Generic Placebos.” Unfortunately, these days, reporting on science is giving the impression that the JIR is a little too close to the truth, at least when it comes to reproduciblity, so much so that the issue even has its own name and Wikipedia entry: Replication (or reproducibility) crisis. It’s a topic I had been meaning to write about again for a while. Fortunately, A recent survey published in Nature under the somewhat clickbaity title “1,500 scientists lift the lid on reproducibility” finally prodded me to look into this question again. Before I get to the survey itself, though, I can’t help but do my usual pontificating to provide a bit of background.
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Posted in: Basic Science, Pharmaceuticals, Politics and Regulation, Science and Medicine

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Hormone Replacement Therapy for Menopausal Symptoms: Setting the Record Straight

HRT
Whether you call them hot flashes or “power surges,” the symptoms of menopause can be very distressing. They were routinely treated with hormone replacement therapy (HRT) until the Women’s Health Initiative study in 2002 persuaded many patients and doctors to abandon that treatment. The results of that study were misunderstood by some and questioned by others, and there continues to be confusion about what the evidence shows and how menopausal symptoms should be treated. We have learned much more about this subject since 2002. HRT is still the most effective treatment and can be used safely under the new treatment guidelines.

The history of hormone replacement therapy

In the second half of the 20th century, there was much enthusiasm about estrogen. Mimicking the estrogen levels of a young woman was seen as a way to remain young and healthy. Doctors recognized that there were risks, but they seemed minor. There were studies showing that HRT protected women from the increased risk of heart disease after menopause. Few if any doctors prescribed it solely to prevent heart disease, but cardiovascular protection and osteoporosis prevention were seen as added benefits that served to tip the balance towards a decision to prescribe it for menopausal symptoms.

Then the Women’s Health Initiative study (WHI) dropped a bomb. It found that HRT didn’t protect women from cardiovascular disease after all. It showed that HRT did more harm than good. The number of prescriptions dropped by as much as 80%. Many women turned to alternative treatments that had not been studied anywhere near as extensively as HRT. (more…)

Posted in: Obstetrics & gynecology, Pharmaceuticals

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More drugs, more supplements, and potentially more problems

drugs and supplements

Early in my career I was fortunate to be offered a role as a hospital pharmacist, working on an inpatient ward along with physicians, nurses, and a number of other health professionals. My responsibilities included conducting a detailed medication review with each newly admitted patient. We would sit together, often with family members, going through what was sometimes a literal garbage bag full of medications, and documenting the drug, the dose, and the reason for use. I can’t remember the most medications I ever counted, but a dozen or more was normal. Some were taking medications four or five times per day, every day. Were all these drugs necessary? In many cases, no. They’d been started at different times, often by different physicians. Some drugs treated the side effects of other medications. Few had ever had a health professional document them all in a single list. There had rarely been an overall review for safety and appropriateness. Few patients knew the treatment goals of their medications. Often, they’d never been asked about their treatment preferences.

In addition to auditing every prescribed medication, I asked about vitamins, supplements and over-the-counter drugs. I usually encountered the same scenario – multiple products, often without any clear medical need. There were vitamins for “eyes”, tonics for “the blood”, and supplements believed to treat or prevent illness. There was regular (and sometimes dangerous) over-the-counter painkiller consumption. Sometimes all of these combinations were clearly antagonistic: concurrent laxatives and treatments for diarrhea, or sleeping pills taken along with stimulants. Worryingly, few had disclosed the use of many of these products to their physician beforehand.

Medication reviews were a tremendous amount of work – but enormously rewarding. It was not difficult to find one or more cases of drugs potentially causing harm, or situations with clear drug-drug or drug-supplement interaction. In some cases, it was the medications that had put them in the hospital in the first place. Working with the residents and medical staff we could usually find ways to simplify their regimen, often discontinuing one or more drugs, reducing the doses of others, and suggesting ways to cut their supplement and over-the-counter drug use – or at a minimum, reduce the risk that these products could cause problems. Not only did patients end up with simpler medication schedules, we were helping them feel better, too. Before every patient was discharged, they’d get a follow-up visit from me. I’d provide a detailed list of current medications with a simplified schedule designed to make medication use easier. We’d provide copies for them to take to the pharmacy and to any specialist. In many cases, patients were still on a long list of drugs. But we’d cleaved away the most harmful and unnecessary, trying to leave only the medications that were appropriate. (more…)

Posted in: Herbs & Supplements, Pharmaceuticals, Science and Medicine

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Testing Testosterone Treatments

hey

Whatever is in this water, it isn’t testosterone

Ponce de Leon is said to have been looking for the Fountain of Youth when he explored Florida. That’s only a myth. Now there’s a new myth, that testosterone supplements are a Fountain of Youth for aging men. Men are urged to get their testosterone levels checked if they have any of a long laundry list of vague symptoms. Anti-aging clinics promote testosterone supplementation in many forms: prescription, bioidenticals from compounding pharmacies, natural remedies, testosterone boosters, and precursors. There are highly inflated estimates of the number of men who need supplementation, often relying on broadened criteria for diagnosis or non-standard lab tests. Testimonials abound: “My depression symptoms disappeared in 20 minutes when I started using Androgel.” (That one’s particularly hard to believe. Suggestion can be powerful.)

Until recently, evidence for the benefits of testosterone supplements was scanty, and there was concern about increased cardiovascular and prostate risks and other side effects. A 2013 study found that while testosterone was clearly indicated for younger men with classic hypogonadism caused by known diseases, a general policy of testosterone replacement in all older men with age-related decline in testosterone levels was not justified. In 2003 an Institute of Medicine panel called for a set of coordinated clinical trials to determine whether testosterone would benefit older men who had low testosterone levels for no known reason other than age and who had clinical conditions to which low testosterone might contribute. The results of those trials are starting to come in. The findings to date were covered in an article in the New England Journal of Medicine in February 2016. The full text is available online.
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Posted in: Pharmaceuticals

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The hijacking of evidence-based medicine

One of our heroes at SBM: John Ioannidis.

One of our heroes at SBM: John Ioannidis.

It’s no secret that I’m a fan of John Ioannidis. So, I daresay, are pretty much all of the editors and regular contributors to this blog. (If you don’t believe me, just type Ioannidis’ name into the blog search box and see how many posts you find.) Over the last couple of decades, Ioannidis has arguably done more to reveal the shortcomings of the medical research enterprise that undergirds our treatments, revealing the weaknesses in the evidence base and how easily clinical trials can mislead, than any other researcher. Indeed, after reading what is Ioannidis’ most famous article, “Why Most Published Research Findings Are False“, back in 2005, I was hooked. I even used it for our surgical oncology journal club at the cancer center where I was faculty back then. This was long before I appreciated the difference between science-based medicine (SBM) and evidence-based medicine (EBM). So it was with much interest that I read an article by him published last week and framed as an open letter to David Sackett, the father of evidence-based medicine, entitled “Evidence-based medicine has been hijacked: a report to David Sackett.” Ioannidis is also quoted in a follow-up interview with Retraction Watch.

Before I get to Ioannidis’ latest, I can’t help but point out that, not surprisingly, quacks and proponents of pseudoscientific and unscientific medicine often latch on to Ioannidis’ work to support their quackery and pseudoscience. They’ve been doing it for years. Certainly, they’re already latching on to this article as vindication of their beliefs. After all, their reasoning—if you can call it that—seems to boil down to: If “conventional” medicine is built on such shaky science, then their pseudoscience isn’t wrong after all, given that the same scientific enterprise upon which conventional medicine is based produces the findings that reject their dubious claims and treatments. Of course, whenever I hear this line of argument, I’m reminded of Ben Goldacre’s famous adage, seen in one form on Twitter here:

The adage can be generalized to all EBM and SBM as well. Just because big pharma misbehaves, EBM has flaws, and conventional medicine practitioners don’t always use the most rigorous evidence does not mean that, for example, homeopathy, acupuncture, or energy medicine works.

Still, when Ioannidis publishes an article with a title provocatively declaring that EBM has been “hijacked,” we at SBM take notice. (more…)

Posted in: Basic Science, Clinical Trials, Medical Academia, Pharmaceuticals, Politics and Regulation

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Why Antibiotic Use Scares Me

Editor’s note: Today we present a guest post from fourth-year medical student Joshua Horton, about the looming problem of antibiotic resistance. Welcome!

Antibiotic sensitive (left) and resistant (right) bacterial colonies. They probably shouldn't be that close together.

Antibiotic sensitive (left) and resistant (right) bacterial colonies. They probably shouldn’t be that close together.

I read a study recently that alarmed me: acute bronchitis is a condition that rarely requires antibiotics, but three quarters of patients presenting with this condition receive a prescription for antibiotics. Even more worrisome, this statistic has not changed in 20 years. To those of us on the cusp of a career in medicine – I am a fourth year medical student – this is terrifying because we are going to have to deal with the consequences. Antibiotic overuse leads to:

  • Increased morbidity and mortality for patients infected with resistant bugs
  • Unnecessary and exorbitant healthcare expenditures
  • The potential to cultivate multi-resistant bacteria that could spread to pandemic proportions

We still take them for granted, but antibiotics are a finite resource. Each time we breed a bug that is resistant to a particular drug, we are forced to relinquish that gun from our armamentarium. With fiscal impetus for pharma to develop new antibiotics waning, we may have reached a point of no return. That’s why this study scared me. Hopefully, clever techniques based on behavioral theory designed to reduce antibiotic prescribing may pull us back from that edge – read on to learn more. (more…)

Posted in: Pharmaceuticals, Public Health, Science and Medicine

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Statin Side Effects

statins

A recent article in The New England Journal of Medicine by Andrew L. Mammen, MD, PhD, reviewed statin-associated myopathies. Reading his article prompted me to revisit the subject of statin side effects.

It can no longer be disputed that statins statistically benefit patients who have cardiovascular disease or who are at high risk of cardiovascular disease. But there are still disputable issues. Which patients should be treated? The recent treatment guidelines have been widely criticized. And the actual magnitude of the benefit is small, although we know the benefits are greater for patients at higher risk. It has been argued that as many as 99% of patients who take statins will take them unnecessarily, risking side effects for no benefit. The problem is that we can’t identify which patients those are. Until we learn more, we are stuck treating the many to help the few. As with any medication, there are risks to be balanced against the benefits. What do we really know about the side effects of statins?

Lots of anecdotes, conflicting evidence

It’s very hard to pin down the truth. The Internet is full of anecdotal reports of devastating side effects from statin drugs, including cancer, dizziness, depression, anemia, acidosis, pancreatitis, cataracts, heart failure, hunger, nausea, sleep problems, memory loss, ringing in the ears, “a sense of detachment,”… the list goes on. When symptoms such as these have been evaluated in controlled studies, they have not been shown to occur more often with the drug than with placebo.
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Posted in: Pharmaceuticals

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Patient Beware: Off-label drug promotion by pharmaceutical companies

In truth, physicians are rarely this happy to see a drug rep.

In truth, physicians are rarely this happy to see a drug rep.

Pharmaceutical companies and their sales reps can distribute information, such as medical journal articles, about unapproved (“off-label“) uses of their drugs as long as they adhere to FDA guidelines. However, the FDA takes the position that this information must be distributed separately from information that is “promotional in nature,” i.e., for marketing purposes, a position that is now open to question.

Off-label promotion of a drug for a use that has not been approved by the FDA is, in the FDA’s view, a violation of the federal Food, Drug & Cosmetic Act (FDC Act). It is subject to criminal prosecution, because promoting a drug for new, unapproved uses is evidence of an intent that the drug be used before it has gone through the extensive process of clinical trials and a review of the evidence of safety and efficacy by a panel of experts, as required by law before a drug can be marketed. Thus, off-label promotion is seen as an end-run around the approval process that perverts the purpose of the FDC Act, which is to protect the public from ineffective and unsafe drugs.

Studies show that personal sales visits to physicians by pharmaceutical reps (called “detailing”) drives prescriptions in favor of the drugs being promoted. This is true even though physicians’ view of detailing ranges from neutral to highly negative, a “necessary evil,” and physicians are aware of potential conflicts of interest these visits precipitate.

While there are restrictions on off-label promotion, off-label prescribing by a physician is not illegal. Physician practice is regulated by the states and not within the jurisdiction of the FDA. In fact, off-label prescribing is considered both ethical and within the standard of care in appropriate circumstances. (I am currently taking a drug for an off-label use, and was informed of this, plus the risks and benefits, by my physician prior to his prescribing it.) It is also common, according to an article by law professors Ryan Abbot and Ian Ayers in the Duke Law Journal, which is well worth reading:

for the 3 leading drugs in each of the 15 leading drug classes, off-label use accounts for approximately 21% of prescriptions. Moreover, off-label uses may be the norm in some areas of practice, such as oncology, pain management, and palliative care, and in some patient populations, such as children, the elderly, and the severely ill. For example, about 80 percent of all drug prescriptions for children are off-label, and between 80 and 90 percent of all drug prescriptions for rare diseases are off-label. [Footnotes omitted.]

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Posted in: Clinical Trials, Ethics, Legal, Pharmaceuticals, Politics and Regulation

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