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Monthly Archives: May 2007

Recently (for anyone who hasn’t picked up a newspaper, watched TV, or checked their favorite online news sites), the safety of the diabetes drug Avandia has been questioned by Steven Nissen, M.D., President of the American College of Cardiology, in a meta-analysis to be published in the June 14, 2007 issue of the New England Journal of Medicine. The publication of this study has elicited a strong response from the popular media, the medical community of bloggers, and even a “calm-down” editorial from the Lancet. From what I’ve read, it seems that the bottomline messages are as follows:

1. Avandia (rosiglitazone) may have cardiovascular risks as suggested by Nissen’s analysis, but no conclusions can be made at this time. Further studies should follow – fast.

Despite the extensive ranting by various bloggers and editorialists, including those at the Wall Street Journal, Nissen and the accompanying NEJM editorial by Psaty and Furberg do clearly list and explain the weaknesses of Nissen’s study. Meta-analyses are not replacement for randomized clinical trials. Sometimes I wonder if people actually read the studies and articles they comment on.

What I find problematic (and what many have identified as being problematic) is the media response to a study such as Nissen’s study. Nissen, whether or not one considers him a “crusader” (carried over from his days as an anti-Vietnam war activist), has previously spearheaded the efforts to bring down Vioxx (rofecoxib) and Pargluva (muraglitazar). Is he on the right track this time? Either way, the popular media, intentionally or not, has generated hype over this story, perhaps ultimately leading to the interruption of a needed clinical trial to better assess the drug’s safety. Unfortunately, diabetes mellitus is a disease that develops slowly, and treatments that might stall the progression of the long-term complications of diabetes (peripheral neuropathy, diabetic retinopathy, microvascular damage, macrovascular damage, etc.) may not show an effect for as much as a year or two after treatments begins.

2. Sources matter.

I enjoy blogging, but at the same time, I understand that it is a very problematic medium. When anyone is given the chance to express their opinions and perspectives, how can you tell whether or not someone is writing with an even hand? How can you assess qualifications when someone is presenting themselves as an expert on a subject (when they might not have any qualifications or experience to speak of)? Since few bloggers cite sources for all of their claims (at best, because it would be tedious and blogs are not peer-reviewed journals), how can you tell which claims have valid evidence backing them?

There have been many attacks on Nissen in the past several days. There have been, moreover, high-profile attacks on the New England Journal of Medicine for allegedly not providing as rigorous an editorial process as one would desire from the most influential of medical journals.

While I do perhaps have bias in favor of NEJM (having worked with the Editors and the Editorial Staff for a few years), I look upon my friends as critically (if not more so) than others. After reading through Nissen’s study, the accompanying editorial, dozens of blog posts, and several popular media articles and editorials, I believe that the NEJM presented the paper and the editorial in the appropriate manner, and Nissen and the editorialists adequately presented the weaknesses of the study. There is always “more” that one can do, but at some point one is flogging a dead horse. The main problem was the hypersensitive reaction from the popular media. It seems to me that most medical bloggers are responding with a knee-jerk reaction to the popular media interpretation of Nissen’s study, and they are taking out their frustration at (almost) all levels: at the popular media, at Nissen, at NEJM, and most especially, at the lawyers preparing to launch lawsuits against GlaxoSmithKline, the maker of Avandia. I heard it mentioned on a blog somewhere that a doctor expressed frustration about the popular media’s health reporting, and that no one without “Doctor” in front of their name (physicians and researchers) should be allowed to publicly comment on drug safety issues. Despite my tendencies toward favoring free speech and the preservations of freedom, I don’t entirely disagree: improper (”hype”) portrayal of drug safety news may have severe, negative impacts on the process of assessing and handling drug safety, including reducing our supply of medications that are imperfect but may be useful for some patients (not all medications work for all patients, and many of our oldest, most useful medications may have severe side effects). In some ways, it feels like a fight between siblings: at some point, one will make a public outcry and bring in the parents to settle the dispute. In this case, it seems that physicians and researchers seeking to protect patients from bad drugs have to (intentionally or unintentionally) call upon the media to bring in the power of public opinion to bring the pharmaceutical industry to its news. This obviously isn’t an ideal situation; hopefully, new reforms at the FDA will strengthen and streamline the drug safety testing process and appease both the desire to make a profit from new drugs and the desire to keep patients safe from bad drugs or the improper use of good drugs with bad side effects.

Some speculations of mine: (but I’m not a physician yet, so this isn’t medical advice – not that I would give medical advice on a blog anyways)

1. It’s trendy to be skeptical. You’re even more trendy if you can find some clever way of picking apart someone else’s published claim.

Skepticism is an important part of science. However, a lot of people don’t know what it means to be skeptical and analytical in a meaningful way. Everyone wants to be Gregory House, but few bloggers (at least, that I know of) can consistently make a sound argument. Most go for sensationalism, catharsis through complaint, and self-indulgence. Many people complain about the popular media, but many bloggers are just as bad, if not worse.

2. Simply stating that diabetes is a risk factor for cardiovascular disease is not a meaningful criticism for Nissen’s study.

Cardiovascular disease (CVD) is a primary outcome for diabetics: diabetics have the same risk of having a myocardial infarction (ischemic heart attack) as someone who has previously already had a heart attack (high risk!). Notably, the controls in Nissen’s analysis were also diabetics. Since Nissen’s analysis suggests a greater CVD/MI risk for patients taking Avandia than patients “receiving any drug regimen other than rosiglitazone”, the study is only comparing diabetics. Again, some people simply don’t do their reading.

3. Given that Avandia (rosiglitazone) increases LDL (low-density lipoproteins) by almost 20%, it seems that physicians should generally be careful about prescribing Avandia even without Nissen’s meta-analysis.

A 20% increase in LDL is a lot. Considering that CVD is one of the greatest risks for diabetics (more so than non-diabetics), it would seem that any diabetes drug that increases CVD risk factors would be of questionable value.

On this line of thought, I think the NEJM editorialists have the right idea:

Physicians who chose to prescribe rosiglitazone perhaps focused on the single dimension of glycemic control. The underlying assumption represents a kind of linear “physiological” argument: high levels of glycated hemoglobin increase risk, so a reduction in glycated hemoglobin will automatically translate into improved health outcomes for patients. This perspective ignores the many actions of the genes activated by PPAR-gamma agonists, only some of which are currently known. Many physicians did not require proof of health benefits as a criterion for selecting rosiglitazone as a therapy for type 2 diabetes.

Had practicing physicians required this higher standard, they would have been at a loss for evidence from large, long-term trials. Rosiglitazone was approved on the basis of short-term studies of the surrogate end point of glycemic control. The use of surrogate end points in the drug-approval process has been problematic… Indeed, at the time of approval of rosiglitazone, the evidence from 26-week studies of expected health benefits was at best mixed. For a lifelong condition such as diabetes, how do the risks of weight gain, edema, and adverse changes in lipids play out against the benefits of improved glycemic control? For a drug that activates a large set of genes, what is the overall balance of risks and benefits?

In other words, Avandia may help reduce blood glucose, but it might not improve a patient’s overall diabetic condition. One step forwards, one step backwards (or perhaps even two). If I’m not mistaken, the general consensus is that exercise and weight loss are still the best means by which to control diabetes and halt the progression of its long-term complications (the unpleasant and sometimes lethal parts of the disease). Even though it is often hard for patients to adhere to these regimens, should we allow the use of a drug such as Avandia in light of virtually-no-risk alternatives? It seems that diabetes drugs should have a higher safety standard than many others, especially since diabetes is a slow-moving disease that can sometimes be managed without medications.

On a side note related to the issue of sources, it’s interesting to note that the WSJ editorial accusing NEJM of “journalistic malpractice” was written by Scott Gottlieb, M.D., former Deputy Commissioner for Medical and Scientific Affairs. I really wish medical bloggers would pay more attention to who writers are when they express criticism. While some have questioned Nissen’s ties to the pharmaceutical industry, no one has (recently) bothered to take a closer look at Gottlieb, formerly a Wall Street pharmaceutical industry golden boy (who would point out pharmaceutical company stocks to invest in) and a Bush administration recruit to the FDA. It’s surprising that a non-career FDA scientist or expert in a particular field would get the second highest position at the FDA. The words of a former FDA commissioner: “The appointment comes out of nowhere. I’ve never seen anything like that.” During his time at the FDA, Gottlieb did everything in his power to break down barriers to quicken approval of drugs, possibly at the expense of properly determining the safety of drugs before they go to the market (arguing instead that drug safety cannot be determined meaningfully until they are on the market and in use by many patients for some time). Is it at all possible to take this guy seriously? I wish I could have faith in all people with M.D.’s after their names, but sadly that isn’t the case.

She means business. As soon as the young man in the white coat calls her name (”Stacy R.?”), she jumps out of her seat and instinctively leads the way back to the clinic. She suddenly realizes that she’s walking ahead and turns back to make sure she’s walking in the right direction. “This way, right?” “Yes, Ma’am!”

The young man introduces himself and a young woman in a white coat as medical students: he explains their roles, and assures her that the attending physician will be arriving soon. As soon as the first student pulls out his pen, Stacy launches into a rapid-fire recall of her chief complaints and history: she’s a young, recovering heroin addict with an annoyingly itchy (fungal) infection on both feet, among a laundry list other complaints. She’s a mother of one but divorced. She’s also a war veteran: honorably discharged for medical reasons. As the first student is frantically jotting down the details, she continues on with the real kicker: an accident during the war left her unconscious, and when she woke up, she was amnesiac and couldn’t recognize her own family. Her husband promptly divorced her and took their five-year-old daughter with him, and when she finally regained her memory some time later, she plunged from her straight-shooter life into despair and drugs. Now, a year later, she’s trying to get back on her feet again, with a promise from the courts that if she cleans up her act, she can have her daughter back.

Having told her story and seemingly inspired some empathy and eagerness to help, she’s happy enough to put up with the students’ double-examination. “Do her radial pulses feel weak to you?” the male student asks. “Heh, they’re fine,” his more experienced partner replies. “The four heart sounds sound good, but what’s the one that sounds like ‘Kentucky’ again? S3, right? I thought I heard one.” “Nope, her heart sounds good to me,” she says.

Eventually, the students finish their examination and present the case to the attending physician. “Do you believe this story? What sort of husband leaves his wife like that? Don’t get me wrong, she might be telling the truth. Maybe I’ve just been in this business too long,” she says. The first student replies, “Eh. I haven’t been in this business long enough.” They go in to see Stacy again, and the attending interviews her: her story checks out exactly as the students described it. The physician counsels her to address the issues one at a time: she’s still early in the detoxification and rehabilitation process, and there will be plenty of time to address the less immediate issues during subsequent appointments. Stacy is eager to have everything sorted out at once: she doesn’t want to waste time getting her life back on track. Nonetheless, she defers to the doctor’s recommendations and goes home with topical cream for the fungal infection. On the bus ride, she repeatedly thinks to herself to keep her eyes on her goal: I want my baby back.

While I was trudging through exam number sixteen of approximately eighteen (first year exams) a couple of days ago, thousands of individuals (premedical students, post-bacs, graduates, and those leaving their previous careers and pursuits) passed the point of no return as they committed themselves to a single medical school. Sometimes these decisions are quite complicated and stressful, sometimes there is no decision to make at all. It was definitely complicated and angst-ridden for me, though I am very happy how it turned out. As many former premeds are excitedly or apprehensively starting to look into housing and transportation options, others are anxiously beginning the long wait until classes begin to see if they will receive a Golden Ticket off the wait list. I’m not sure that many are as eagerly self-reflective as me, but I wonder how many are thinking to themselves: was all this work worth it? Will all the work and hardship to come be worth it?

I recently read a couple of insightful and thoughtful posts by Panda Bear, M.D. and Hybrid Vigor exploring these questions and the long and arduous medical school application process. In the fall, my successor at the Next Generation, Serene Chen, interviewed me and asked me to reflect on my early medical school experiences. Here, at the end of my first of what Panda Bear calls the “cool years,” I have found much in my experiences thus far that reinforce my motivations and make me happy to be on the road to becoming a physician. Here’s why:

My Thoughts

1. Medical school is actually kinda fun.

I’m not crazy. I swear. Granted, medical school is hard, and I’m spending the majority of my time in class or studying. However, some of the material I’ve learned is pretty interesting, and some of my physician- and researcher-instructors have very effectively illustrated the value of their lessons by incorporating engaging clinical correlations and the recounting of relevant, meaningful personal experiences. I’m very lucky in this respect: many of my instructors are quite serious and passionate about teaching, usually resulting in high quality instruction. On the other hand, some of my instructors have failed to engage the attention of my class and express the excitement and applicability of their fields to the practice of medicine.

But medical school isn’t just about classes. One thing I have enjoyed most about medical school so far is getting to know more about my classmates. There are a lot of cool, sincere people, and it’s refreshing to know that not all medical students were once cut-throat, backstabbing, eye-gouging, two-faced, résumé-padding premeds. Not that I have ever actively condoned such a characterization of premedical students, but one of my motivations for founding the Next Generation was my worry that a considerable amount of good people with good motivations would have their views of the medical profession jaded and discolored by the conduct and behavior of their cutthroat classmates. Nonetheless, there’s a certain camaraderie in medical school that one doesn’t find in college: we’re part of the same group, we have the same allegiances and the same general goals.

Another thing I’ve enjoyed: early clinical experiences. Some have been awkward, some have been incredible. I never would have expected to intubate a patient as a first year medical student, or get so much practice taking histories, performing physical exams, and presenting cases to attendings. I’ve noticed that my classmates who have actively sought extracurricular clinical experiences (e.g. free clinics, working in the various hospital services, etc.) seem to be the happiest and most content with their education, while those who haven’t seem to be the most discontent and the most likely to think of medical school as a depressing and tiring experience. My impression is that this is a reflection of the power of early clinical experiences in reinforcing initial motivations for entering medical school, but I’m sure there are other reasonable, alternate theories.

Lastly, one thing I find encouraging is that my upperclassmen have all individually expressed that their experiences have improved with time: they all thought second year was better than first year, third year was better than second year, and fourth was better than third. If that’s the case, I’m off to a pretty good start.

2. Though we shouldn’t give ground to forces that would erode our ability to effectively, eagerly, comfortably, and happily provide excellent medical care to patients, doctors will undoubtedly adapt and deal with changes.

Current doctors have a lot to complain about, as evidenced by the plethora of angry rants to be found on the medical blogosphere. There is much imperfection in the health care system, and a lot of unhelpful pressure and many impeding factors that make the practice of medicine so miserable and unsatisfying as to encourage many doctors to jump ship or scale down their clinical practice.

However, while doctors should resist these forces and strive for positive reform, there also remains the default option taken by most younger, incoming physicians: deal with it. While older, more experienced physicians may complain about the growing amount of paperwork, the difficulty of navigating electronic health records, and the shift from more personal, longitudinal care to shift-oriented, hospital-based care, many new physicians dive right in and take the status quo in stride. This is both encouraging for younger physicians and potentially discouraging for those who seek to improve health care: younger physicians are usually able to adapt to what seems to be an increasingly more challenging health care system, but at the same time, they might not have the historical context and institutional memory to recognize long-term trends that may severely paralyze or damage the practice of medicine.

One thing I wonder about is the value of advice and insight from former medical students or graduates who have since abandoned medicine because they found that it wasn’t what they thought it was made out to be. A good friend of mine had one such individual as her premedical advisor, and it often seemed that this individual tended toward trying to justify his decision to leave medicine rather than help her find out whether or not medicine is the right profession for her.

3. Medical school is insanely expensive, but if you think on your feet and aren’t a big spender, you’ll do just fine.

I feel like I’m hemorrhaging money. But at the same time, I suspect that I will likely specialize or at least work in an academic hospital with a decent (but not phenomenal) salary. I don’t need a beautiful mansion or an expensive car (at least, not right away!), and although I would like to honor my (pirate) ancestors, I really don’t need to buy a boat.

Anyways, there are medical disciplines that are in a rut at this point in time with respect to salaries, reimbursement, and paying for malpractice insurance. I don’t want to discourage people from selecting these fields; instead, these are areas that can use strong advocacy to illustrate why these fields are essential and need help. If you aren’t interested in swimming against the stream, then don’t pick these fields. If you do have the strength, resilience, and foresight, I (and many others) have great respect for you and will try to support you along the way.

4. Find out what makes you happy.

Medical school takes up a lot of time, but if you learn how to manage your time well, there is plenty of time for enjoyment. Although I’m performing well in my classes, I hardly ever study at night: I spend my nights playing video games, watching TV shows, writing on this blog and reading others, videochatting with my girlfriend and instant-messaging my friends, playing my guitar, practicing martial arts, and so on. I have time to go out with my classmates for dinner or ice cream. I have time to hang out with my friends outside of the medical school. I feel like I have more spare time now than I did in college, and I’m using that time to have fun, improve myself, and make myself happy.

I also really enjoy learning: I’m happy to be a life-long student, and I like glancing through medical journals, reading the news (medical and other), and spending time in the clinics and hospitals. I hope that all medical students would like at least some of these things; otherwise, they might be in the wrong place, or they might not have exposure and access to good opportunities and resources. If that’s the case, be proactive and seek out what you’re paying for: the best medical education you can possibly get.

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