No drug is free of risks, or the potential for causing harm. Every decision to take a drug needs to consider expected benefits and known risks. One of the ways we can reduce harms is by studying drug use rigorously. Only by understanding the “real world” effects of drugs can we understand the true risks (and benefits) and design strategies to reduce the risk of iatrogenic harm — that is, harms caused by the intervention itself. Adverse events related to drug treatments are common. Some lead to hospitalization. Studies suggest 28% of events are avoidable in the community setting, and 42% are avoidable in long-term care settings. That’s a tremendous amount of possible harm from something prescribed to help. A new study published this week shows that adverse drug events (ADEs) continue to cause significant problems, sending over a million Americans to the emergency room every year.
Archive for Pharmaceuticals
Last week, in an unexpected upset, Donald Trump won the Presidential election in the Electoral College while losing the popular vote and is now President-Elect. Regular readers of my not-so-super-secret other blog know my opinion of this; so I won’t belabor it too much here. If you’re curious, I have written about Donald Trump’s antivaccine views here before in the context of last year’s Republican debates, and, amusingly, I’ve even been at the receiving end of criticism from an “integrative medicine” activist in which my snark was compared to that of Donald Trump and my criticism labeled “Trumpism.” As you might imagine, I was not pleased.
Leaving all that aside and leaving aside how we’ve now had two Presidential elections out of the last five in which the candidate with fewer popular votes became President (no, I’m not a fan of the Electoral College), Donald Trump won fair and square and will be our next President. As an advocate of science-based medicine, naturally I wondered: What can we expect in terms of medical science under President Trump next year? Jann Bellamy already began the discussion on this blog by undertaking a fairly comprehensive overview of the disturbing anti-science positions Donald Trump and many now coming into his new administration espouse. I’m going to do a bit of the same, but I’m going to drill down and focus solely on medical science. While I agree that Trump’s position on human-caused climate change and his stated intent to pull out of important climate treaties and, in essence, cease any attempt to mitigate the effects of human activity on climate change is a looming disaster that our grandchildren and great-grandchildren and beyond will likely curse our generation for, this blog is Science-Based Medicine.
Until a year ago very few people had ever heard of Martin Shkreli. In 2015 the then-32-year-old CEO of Turing Pharmaceuticals LLC became the poster boy for Big Pharma eXXXcesses when Turing acquired rights to Daraprim, an antiparasitic drug used widely to treat toxoplasmosis. The acquisition itself wasn’t particularly controversial. Raising the price of Daraprim from $13.50 per pill to $750 per pill was.
And so another round of hand-wringing and teeth-gnashing over health care costs began. There was a Congressional hearing where Shkreli preened and smirked and refused to answer questions, later asserting that he had been subpoenaed “unethically” and that it is, “hard to accept that these imbeciles represent the people in our government.” Benjamin Brafman, Shkreli’s attorney, clarified afterward that, “he meant no disrespect…” He wouldn’t want to leave the wrong impression. (more…)
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…)
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.
Is there a reproducibility “crisis” in biomedical science? No, but there is a reproducibility problem
Most 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.
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…)
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…)
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.
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:
Quacks citing problems in pharma make me laugh. FLAWS IN AIRCRAFT DESIGN DO NOT PROVE THE EXISTENCE OF MAGIC CARPETS.
— ben goldacre (@bengoldacre) January 31, 2013
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…)