Tuesday, April 29, 2008

Blood Substitutes Doomed by Natanson's Meta-Analysis in JAMA

When the ARMY gives up on something, you should be on the lookout for red flags. (Pentagon types beholden to powerful contractors and highly susceptible to sunk cost bias still haven't given up on that whirligig of death called the Osprey, have they?) But the ARMY's abandonment of a blood substitute that it found was killing animals in tests was apparently no deterrent to Northfield Laboratories, Inc., makers of "Polyheme", as well as Wall Street investors in this an other companies working on products with a similar goal - to cook up an extracellular hemoglobin-based molecule that can be used in lieu of red blood cell transfusions in trauma patients and others.

Charles Natanson, an intramural researcher at the NIH and co-workers performed a meta-analysis of trials of blood substitutes which was published on-line today at the JAMA website: http://jama.ama-assn.org/cgi/content/full/299.19.jrv80007 . They found that these trials, which were powered for outcomes such as number of transfusions provided or other "surrogate-sounding" endpoints, when combined demonstrate that these products were killing subjects in these studies. The relative risk of death for study subjects receiving one of these products was 1.3 and the risk of myocardial infarction increased more than threefold. The robustness of these findings is enhanced by the biological plausibility of the result - cell-free hemoglobin is known to eat up nitric oxide from the endothelium of the vasculature leading to substantial vasoconstriction and other untoward downstream outcomes.

In addition to my penchant for cautionary tales, my interest in this study has to do with study design. We are beholden to "conventional" study design expectations where a p-value is a p-value, they're all 0.05, and an outcome is an outcome, whether it be bleeding, or pain or death, we don't differentially value them. But if you're studying a novel agent, looking for some crumby surrogate endpoint like number of transfusions, and your alpha threshold for that is 0.05, then the alpha threshold for death should be higher (say 0.25 or so), especially if you're underpowered to detect excess deaths. That kind of arrangement would imply that we value death at least 5 times higher than transfusion (I for one would rather have 500 or more transfusions that be dead, but that's a topic for another discussion).

Fortunately for any patients that may have been recruited to participate in such studies, Natanson et al undertook this perspicacious meta-analysis, and the editiorialists extended their recommendations for more transparency in data dissemination to argue, almost, that future trials of blood substitutes should be banned or boycotted. Even if the medical community does not have the gumption to go that far, prospective participants in such studies and their surrogates can at least perform a simple google search, and from now on the Natanson article is liable to be on the first page.

Thursday, April 3, 2008

A [now open] letter to Congress re: Proposed Medicare Reimbursement Cuts

I'm not sure that this is entirely in keeping with the theme of this blog, but I will justify it by saying that the health of the healthcare system is of vital interest to all stakeholders including researchers with an interest in clinical trials. The following letter was sent via the ACCP to my senators and congressmen in regards to the Medicare reimbursement cuts that are to be instituted in July of this year. We were solicited via the medical professional society to be a voice in opposition to the cuts....

Dear Sir or Madam-

Physicians' income, especially that of primary care providers, upon whom patients rely most heavily for basic care, has been falling in real dollars (not keeping pace with inflation) for years, and the newest cuts will markedly exacerbate the disconcerting trend that already exists.

Most physicians do not begin earning income in earnest until they are over 30 years old, a significant lost opportunity due to prolonged schooling and training. This compounds the problem of substantial debt burden that recent graduates must bear. Economically speaking, medicine, especially in the essential primary care fields, is no longer an attractive option for many talented students and graduates. From a job satisfaction standpoint, medicine has also become far less attractive due to regulatory burdens, paperwork, lack of adequate time to spend with patients, and fragmentation of care.

This fragmentation of care is in fact at least partially driven by Medicare cuts. When reimbursement to an individual physician is cut, s/he simply "farms out" parcels of the overall care of the patient to other physicians and specialists. This "multi-consultism" militates against any cost savings that might be achieved by cuts in reimbursement to individual physicians. Perhaps more alarming is the fact that care delivery is less comprehensive, more fragmented, and less satisfying to patients and physicians alike, the latter which may feel a "diffusion of responsibilty" regarding patients' care when multiconsultism is employed. Reduced reimbursements also likely drive the excess ordering of laboratory tests and radiographic scans, both in situations where the physician stands to profit from the testing and when s/he does not, in the latter case because the care is being "farmed out" not to another physician, but to the laboratory or radiology suite. The result is that Medicare "cuts" may paradoxically increase overall net healthcare expenditures. Physicians are already squeezed as much as they can tolerate being squeezed. Further cuts are certain to backfire in this and myriad other ways.

A perhaps more insidious, invidious, and pernicious result of reimbursement cuts is that it is driving the talent out of medicine, especially primary care medicine. Were it not for the veritable reimbursement shelter that I experience as a practitioner at an academic medical center, I would surely not be practicing medicine in any traditional way - it is simply not worth it. Hence we have the genesis and proliferation of "concierge practices" where the wealthy pay an annual fee for entry into the practice, only cash payments are accepted, and more traditional service from your physician (e.g., time to talk to him/her in an unhurried fashion) can be expected by patients. Hence we have, as pointed out in a recent New York Times article (http://query.nytimes.com/gst/fullpage.html?res=9C05E6D81E38F93AA25750C0A96E9C8B63&scp=2&sq=dermatology&st=nyt ), the siphoning of medical student talent into specialties such as dermatology and plastic surgery because the lifestyle is more attractive and reimbursement is not a problem since the "clientele" (aka patients) are affluent and pay out-of-pocket. Hence we have the brightest physicians, such as my colleague and close friend Michael C., MD, leaving medicine altogether to work on Wall Street in the financial sector. All of these disturbing trends threaten to undermine what was heretofore (and hopefully still is) one of the best healthcare systems on the planet. I, for one, will not recommend a career in primary care to any medical student who seeks my advice, and to undergraduates contemplating a career in medicine I say "enter medicine only if it is the only field you can invision yourself ever being happy in."

The system is broken, and we as a country cannot endure and thrive if our healthcare expenditures continue to eat up 15+% of our GDP. But cutting the payments to physicians, the very workforce upon which delivery of any care depends, is no longer a viable solution to the problem. Other excesses in the system, such as use of branded pharmaceuticals (e.g., Vytorin or Zetia) when generic alternatives are as good or better, use of expensive scans of unproven benefit (screening CT scans for lung cancer) when cheaper alternatives exist (stoping smoking), excessive and wasteful laboratory testing of unproven benefit (daily laboratory testing on hospital inpatients, wanton ordering of chest x-rays, head CTs, EKGs, and echocardiograms), use of therapeutic modalities of very high cost and modest benefit (AICDs, lung transplantation, back surgery, knee arthroscopy, coated stents, etc.), and provision of futile care at the end of life are better targets for cost savings, limitations on which are far less likely to compromise delivery of generally effective and affordable care for the average citizen.

I urge congress to consider the far-reaching but difficult to measure consequences of further reimbursement cuts before an entire generation of the most talented physicians and potential physicians determines that the financial, lifestyle, and opportunity costs of practicing medicine, especially primary care medicine, are just too much to bear.


Scott K Aberegg, MD, MPH, FCCP
Assistant Professor of Medicine
The Ohio State University College of Medicine