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Friday, April 18, 2014

Tranexamic acid--why you may be less likely to bleed to death in Britain than the U.S.

The other day at an interdisciplinary rounds meeting at the hospital, one of our nurses who is also an emergency medical technician mentioned that in Britain injured patients receive tranexamic acid before arriving at the hospital because it reduces death from bleeding. “What’s that?” I said. I kind of barely remembered hearing this medication’s name associated with the treatment of a rare disease, but not treatment of trauma. So I was guessing that this was some drug that was invented long ago which had been found to be quite effective in other countries, but has not been really optimally used in the U.S. because it is generic and therefore unlikely to make drug companies money.

Bingo.

Here’s the story, as far as I can determine.

Tranexamic acid is a relatively simple cyclic molecule that blocks the fibrinolytic process, that is, the natural breakdown of blood clots in the body. In the setting of any injury, especially severe ones, fibrinolysis is intensified, leading to a condition of excess bleeding in trauma victims. This is hardly ideal, and tranexamic acid can help reverse this. It also appears to have an effect on reducing inflammation, which may be even more significant.

There have been a couple of major studies in the last 3 years showing significantly better outcomes in patients who have traumatic injury and who are treated with tranexamic acid intravenously soon after injury. The most recent study, published in the Archives of Surgery, looked at 896 patients injured in the military from registries in the UK and the U.S. and identified the subset treated with tranexamic acid. Although this group was generally more severely injured, the mortality rate was significantly lower, 6.5% lower, than the group that had not received the drug. In very seriously injured patients, those who received massive transfusion of blood products, the difference in survival was nearly 14%.

It is not often that we see an effect this powerful, especially in a group like this who are healthy and will likely have long and productive lives after being saved. An earlier study, published in 2011 in the Lancet titled CRASH-2, showed similar results in civilian trauma victims, with a double-blind, prospective design. The Cochrane Collaboration, a group of researchers who review randomized controlled trials, concluded that tranexamic acid was safe and effective in reducing mortality in trauma patients without increasing adverse events.

So maybe it’s actually very expensive, then. I called our hospital pharmacy to ask about that. Apparently a gram of it costs about $44. The usual protocol for trauma is 1 gram intravenously right away and then another gram over the next 8 hours. So $88 times 100 equals $8,800 to save 6.5 lives (using the data from the military study), or $1,353 per life saved. That’s pretty cheap. And since it probably reduces the severity of illness in the rest of the patients treated, it may end up reducing overall treatment costs.

Presently the only FDA (Food and Drug Administration) approved indication for this drug in the U.S. is an oral formulation to be used for women with heavy periods and intravenously for prevention of dental bleeding in hemophiliacs. It is also used off-label to reduce transfusion requirements in total joint surgeries (that’s why we have it in our pharmacy), also in some places for prostate surgery, general surgery, gastrointestinal hemorrhage, bleeding around pregnancy and delivery and bleeding within the eye. It reduces the frequency of attacks of swelling in a condition called hereditary angioedema, which is rare, and was why I had even heard of it in the past. It has been available over the counter for years in Europe, marketed for heavy menstrual bleeding. The injectable formulation is also on the World Health Organization’s list of 350 essential medicines which are considered safe and effective and necessary worldwide.

So what are its side effects? It may increase the risk of blood clots in the legs and lungs, but studies have shown this to be far less of an issue than one might guess, and it looks like the lives saved far outweigh this risk. The CRASH-2 study showed that there might be a slight risk of increasing mortality if it was given to trauma patients more than 3 hours after their injury.

Why is it not FDA approved for reduction of bleeding in trauma and other similar situations for which there is ample evidence of safety and efficacy? The FDA approves drugs and devices when approval is requested, and usually the drug or device manufacturers who stand to make money from an FDA approved indication are the ones to make the request. I suspect there has been no request for approval for these other indications. Just because it is not FDA approved to reduce bleeding in trauma and surgery doesn’t mean it can’t be used, but physicians have a certain hesitance to use unfamiliar drugs off-label.

So the story of tranexamic acid is another excellent example of how simpler, cheaper and sometimes more effective treatments are not being widely used in the U.S., even though our patients may receive exorbitantly expensive medications and treatments of dubious or minimal benefit. This is because we allow powerful pharmaceutical companies to inform our practice. Sometimes this actually works, when companies produce groundbreaking innovations and encourage us to adopt them. It is unlikely, though, to help us find creative uses for inexpensive drugs that have been around a long time. This dynamic may mean that 6 or so people of the 100 who are probably just now being involved in accidents with bleeding will die when they would not have if use of this drug part of our routine practice.

Janice Boughton, MD, ACP Member, practiced in the Seattle area for four years and in rural Idaho for 17 years before deciding to take a few years off to see more places, learn more about medicine and increase her knowledge base and perspective by practicing hospital and primary care medicine as a locum tenens physician. She lives in Idaho when not traveling. Disturbed by various aspects of the practice of medicine that make no sense and concerned about the cost of providing health care to every American, she blogs at Why is American Health Care So Expensive?, where this post originally appeared.

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What the new dietary fat study results really mean

No, it is not suddenly good to eat more saturated fat, and the new study grabbing headlines showed no such thing.

The new study, a meta-analysis (meaning a pooling of previously published studies, not new research) in the Annals of Internal Medicine, shows the following 2 things in particular. You cannot get a good answer to a bad question, and there is more than 1 way to eat badly.

We’ll come back to those shortly, but first here’s an overview of the study objectives, methods and findings. The investigators, an international team, started out questionably by asserting that dietary guidelines emphasize “changes in fatty acid composition to promote cardiovascular health.” There is some truth to that, but there are some fundamental problems with the assertion as well. Dietary guidelines make recommendations about any given nutrient in the context of the overall diet. So, for instance, advice to eat less saturated fat also comes along with advice about eating less sugar. It is not in the form of “eat less saturated fat and do whatever else you want.” More importantly, good dietary guidance is increasingly about foods rather than isolated nutrients, although that is admittedly still a work in progress.

So, having framed the issue questionably, the researchers set off in the appropriately questionable direction to address it. They looked at variation in the intake of specific fatty acid categories (e.g., saturated, monounsaturated, polyunsaturated, trans), sub-categories (e.g., omega-3 and omega-6 polyunsaturates), and specific fatty acids within those sub-categories and corresponding variation in coronary heart disease.

The methods, as noted, were meta-analytic, the pooling of data from multiple prior studies to reach a summary conclusion. Some experts in meta-analysis have raised concerns about the methodologic details, with at least one expert at Harvard suggesting there may be a major mistake. But that debate can be left to play out. We will give the analytic methods the benefit of the doubt, and assume they correctly answer the questions asked.

Those questions were: What are the differences in rates of coronary heart disease (defined rather vaguely in the paper) in observational studies when the top third of intake is compared to the bottom third of intake for some particular class of fatty acid?; and what are the differences in coronary disease rates in intervention trials between groups when one group is given some kind of fatty acid supplement?

For the observational studies, representing more than 500,000 people, the investigators found more coronary heart disease in the highest intake of trans fat compared to the lowest; and less heart disease in the highest intake of omega-3 fat compared to the lowest. There was a hint of benefit for higher monounsaturated fat intake. And then the part spawning the predictably exaggerated headlines: there was no appreciable difference in coronary heart disease rates seen comparing the top to bottom third of saturated fat intake, although there was in fact a suggestion of more heart disease with more saturated fat consumption. There was no difference when comparing the top to bottom third of omega-6 fat intake either.

For the most part, the intervention studies, which included more than 100,000 people, administered some omega-3 supplement. A smaller batch of studies administered some other kind of polyunsaturated fat. You may recall we had already heard the news that omega-3 supplements, all other things being equal, did not appreciably reduce rates of coronary disease, so it should come as no surprise that this study found the same. In fact, while not statistically significant, there was a trend toward benefit seen with all of the polyunsaturated fat supplements, including omega-6 fat. For long-chain omega-3 fat, or so-called “fish oil,” the apparent benefit was very close to statistically significant.

Now, consider for a moment some of the leading arguments about diet and health swirling around us. Are they all about dietary fat? Not remotely. Much of our collective attention over recent years has been focused on sugar, starches, carbohydrates in general, meat in general, processed meats and grains.

I searched the new paper for the word “sugar,” and could find no mention of it. None.

People eating less saturated fat don’t simply stop eating a nutrient and leave a big hole in their diets. They eat less of A, and make up for it by eating more of B. The most obvious of questions, yet one to which this study was totally inattentive, is: what is B?

We know those trends at the level of the general population. When we started cutting back on saturated fat, we started eating more refined starch and added sugar. We also know that excess intake of sugar, starch, and calories is associated with obesity, diabetes, and coronary disease. So if eating less saturated fat means eating more sugar, it would at best be a lateral move in terms of health, and probably worse than that. The study simply ignored this consideration.

Does this show, as the titillating headlines suggest, that saturated fat is unrelated to coronary disease? No, however we might wish it to be so. It merely shows there is more than one way to eat badly, and from my perspective, our culture seems committed to exploring them all.

Basically, this study showed that if you vary your intake of saturated fat or omega-6 fat without altering the overall quality of your diet, you are not likely to alter your health much either. That’s not much of a revelation, and unlikely to make any headlines expressed as such. But the headlines we are getting, while much more exciting, are entirely misleading. There was no suggestion at all here of any health benefits of saturated fat, and some hint of harmful effects despite the important study limitations. There were suggestions of favorable effects of the usual suspects, omega-3 fat and monounsaturated fat.

But moving on from such one-nutrient-at-a-time preoccupations, there is a bigger fish to fry here than just fish oil, or olive oil or lard. Dietary guidance must be about the whole diet, and should be directed at foods rather than nutrients. If we get the foods right, the nutrients take care of themselves.

This study does nothing to refute what we already knew about diet and health, and frankly, that was quite a lot. We know what dietary patterns are associated with the longest, and most vital lives among peoples in the Blue Zones. We know what dietary patterns are associated with dramatic reductions in the lifetime risk of all chronic diseases. We know what dietary patterns are associated with reductions in the rate of heart attack in intervention studies.

Are such diets low in saturated fat? Yes, but as a byproduct of the foods that are eaten. A diet that is made up mostly of vegetables, fruits, beans, lentils, nuts, seeds, and whole grains, with or without fish, seafood, lean meats, eggs and dairy simply has less room for saturated fat, let alone trans fat. Such a diet is natively high in omega-3 and monounsaturated fat, and balanced in terms of polyunsaturates. Just as important, such a diet is relatively low in refined starch and added sugar, and natively rich in fiber, vitamins, minerals and antioxidants. Attend to the forest, in other words, and the trees thrive. Bark up any given tree, and you may fail to notice that the forest has burned to the ground.

Our one-nutrient-at-a-time approach to diet and health has been a decades long public health boondoggle. Our penchant to talk about nutrients rather than food is antiquated and substantially misguided. There is saturated fat in salmon and salami. There is carbohydrate in lentils and lollipops. Lumping foods together across such a spectrum is the garbage in that invites studies that will inevitably spit garbage out. Looking at variation in saturated fat while ignoring sugar is an exercise in futility.

Our inclination to play Ping-Pong with scientific findings comes at a cost in human potential. Our proclivity for hyperbolic headlines is a public health menace.

This new study shows we can vary our intake of any given fatty acid and not alter the quality of our diet or health. Well, duh. There is more than one way to eat badly.

And there are no good answers to misguided questions.

My advice is as it ever was. Chew carefully on headlines before choosing to swallow the hyperbole, and eat a diet of wholesome foods reliably associated with good health across a vast and stunningly consistent literature. Do that, and let the fatty acids and other nutrients sort it out for themselves.

David L. Katz, MD, FACP, MPH, FACPM, is an internationally renowned authority on nutrition, weight management, and the prevention of chronic disease, and an internationally recognized leader in integrative medicine and patient-centered care. He is a board certified specialist in both Internal Medicine, and Preventive Medicine/Public Health, and Associate Professor (adjunct) in Public Health Practice at the Yale University School of Medicine. He is the Director and founder (1998) of Yale University's Prevention Research Center; Director and founder of the Integrative Medicine Center at Griffin Hospital (2000) in Derby, Conn.; founder and president of the non-profit Turn the Tide Foundation; and formerly the Director of Medical Studies in Public Health at the Yale School of Medicine for eight years. This post originally appeared on his blog at The Huffington Post.

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Antimicrobial overuse: A tragedy of the commons?

The CDC released a report on antimicrobial use practices in U.S. hospitals that confirms what many already suspect: antibiotics are overused and/or used incorrectly a large percentage of the time. The details are summarized in the MMWR report and accompanying Vital Signs.

Eli Perencevich, MD, ACP Member, just posted on our post-antibiotic era, and we will undoubtedly have more to say about this later. For now, though, I’ll outsource to this excellent commentary by Scott Flanders and Sanjay Saint in JAMA Internal Medicine. I have a minor quibble with any construction of this problem as a kind of “tragedy of the commons,” where rational decisions to improve individual health run counter to the interests of society. Inappropriate or unnecessary antibiotic use hurts both the treated individual and society. Moreover, the most persuasive arguments for improving antibiotic use are those that appeal to improving individual patient outcomes (rather than to saving money or reducing resistance rates in aggregate).

Finally, the clinical microbiologist in me can’t help but emphasize one of the greatest obstacles to optimizing antimicrobial therapy: the absence of rapid and accurate diagnostics. On that note, here is some bedtime reading.

Daniel J. Diekema, MD, FACP, practices infectious diseases, clinical microbiology, and hospital epidemiology in Iowa City, Iowa, splitting time between seeing patients with infectious diseases, diagnosing infections in the microbiology laboratory, and trying to prevent infections in the hospital. This post originally appeared at the blog Controversies in Hospital Infection Prevention.

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QD: News Every Day--Pharmacists may be effective in reducing inappropriate benzodiazepine use

Direct-to-consumer education by pharmacists led to a reduction in the amount of inappropriate benzodiazepine use in patients older than 65, a study found.

To compare the effect of a direct-to-consumer educational intervention against usual care on benzodiazepine therapy discontinuation in community-dwelling older adults, 30 community pharmacies in Quebec, Canada were randomized 1:1 to the educational intervention (148 patients) or to the control group (155 patients).

The intervention arm received an 8-page booklet outlining the risks of benzodiazepine use, presentation of the evidence for benzodiazepine-induced harms, education about drug interactions, peer champion stories, suggestions insomnia and/or anxiety substitutes, and stepwise tapering recommendations. The control arm received usual care. Results appeared online April 14 at JAMA Internal Medicine.

A total of 261 participants (86%) completed the 6-month follow-up. Of the recipients in the intervention group, 62% talked to a physician and/or pharmacist about stopping benzodiazepine. At 6 months, 27% of the intervention group had stopped benzodiazepine compared with 5% of the control group (risk difference, 23%; 95% CI, 14% to32%; number needed to treat, 4) or had reduced their dose (risk difference, 11%; 95% CI, 6% to 16%).

Researchers noted that patients reported that their physicians discouraged discontinuation of benzodiazepines in several cases, that benzodiazepines were sometimes substituted with equally harmful sedatives, and that pharmacists were solicited less often than physicians to discuss stopping benzodiazepine therapy.

“With the expanding scope of pharmacists’ practice and an increasing emphasis on interprofessional models of care, community pharmacists may be underutilized players to participate in efforts to reduce costly and unnecessary medical treatments,” the authors wrote.

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Blog log

Members of the American College of Physicians contribute posts from their own sites to ACP Internistand ACP Hospitalist. Contributors include:

Albert Fuchs, MD
Albert Fuchs, MD, FACP, graduated from the University of California, Los Angeles School of Medicine, where he also did his internal medicine training. Certified by the American Board of Internal Medicine, Dr. Fuchs spent three years as a full-time faculty member at UCLA School of Medicine before opening his private practice in Beverly Hills in 2000.

And Thus, It Begins
Amanda Xi, ACP Medical Student Member, is a first-year medical student at the OUWB School of Medicine, charter class of 2015, in Rochester, Mich., from which she which chronicles her journey through medical training from day 1 of medical school.

Auscultation
Ira S. Nash, MD, FACP, is the senior vice president and executive director of the North Shore-LIJ Medical Group, and a professor of Cardiology and Population Health at Hofstra North Shore-LIJ School of Medicine. He is Board Certified in Internal Medicine and Cardiovascular Diseases and was in the private practice of cardiology before joining the full-time faculty of Massachusetts General Hospital.

Zackary Berger
Zackary Berger, MD, ACP Member, is a primary care doctor and general internist in the Division of General Internal Medicine at Johns Hopkins. His research interests include doctor-patient communication, bioethics, and systematic reviews.

Controversies in Hospital Infection Prevention
Run by three ACP Fellows, this blog ponders vexing issues in infection prevention and control, inside and outside the hospital. Daniel J Diekema, MD, FACP, practices infectious diseases, clinical microbiology, and hospital epidemiology in Iowa City, Iowa, splitting time between seeing patients with infectious diseases, diagnosing infections in the microbiology laboratory, and trying to prevent infections in the hospital. Michael B. Edmond, MD, FACP, is a hospital epidemiologist in Richmond, Va., with a focus on understanding why infections occur in the hospital and ways to prevent these infections, and sees patients in the inpatient and outpatient settings. Eli N. Perencevich, MD, ACP Member, is an infectious disease physician and epidemiologist in Iowa City, Iowa, who studies methods to halt the spread of resistant bacteria in our hospitals (including novel ways to get everyone to wash their hands).

db's Medical Rants
Robert M. Centor, MD, FACP, contributes short essays contemplating medicine and the health care system.

Suneel Dhand, MD, ACP Member
Suneel Dhand, MD, ACP Member, is a practicing physician in Massachusetts. He has published numerous articles in clinical medicine, covering a wide range of specialty areas including; pulmonology, cardiology, endocrinology, hematology, and infectious disease. He has also authored chapters in the prestigious "5-Minute Clinical Consult" medical textbook. His other clinical interests include quality improvement, hospital safety, hospital utilization, and the use of technology in health care.

DrDialogue
Juliet K. Mavromatis, MD, FACP, provides a conversation about health topics for patients and health professionals.

Dr. Mintz' Blog
Matthew Mintz, MD, FACP, has practiced internal medicine for more than a decade and is an Associate Professor of Medicine at an academic medical center on the East Coast. His time is split between teaching medical students and residents, and caring for patients.

Everything Health
Toni Brayer, MD, FACP, blogs about the rapid changes in science, medicine, health and healing in the 21st century.

FutureDocs
Vineet Arora, MD, FACP, is Associate Program Director for the Internal Medicine Residency and Assistant Dean of Scholarship & Discovery at the Pritzker School of Medicine for the University of Chicago. Her education and research focus is on resident duty hours, patient handoffs, medical professionalism, and quality of hospital care. She is also an academic hospitalist.

Glass Hospital
John H. Schumann, MD, FACP, provides transparency on the workings of medical practice and the complexities of hospital care, illuminates the emotional and cognitive aspects of caregiving and decision-making from the perspective of an active primary care physician, and offers behind-the-scenes portraits of hospital sanctums and the people who inhabit them.

Gut Check
Ryan Madanick, MD, ACP Member, is a gastroenterologist at the University of North Carolina School of Medicine, and the Program Director for the GI & Hepatology Fellowship Program. He specializes in diseases of the esophagus, with a strong interest in the diagnosis and treatment of patients who have difficult-to-manage esophageal problems such as refractory GERD, heartburn, and chest pain.

I'm dok
Mike Aref, MD, PhD, FACP, is an academic hospitalist with an interest in basic and clinical science and education, with interests in noninvasive monitoring and diagnostic testing using novel bedside imaging modalities, diagnostic reasoning, medical informatics, new medical education modalities, pre-code/code management, palliative care, patient-physician communication, quality improvement, and quantitative biomedical imaging.

Informatics Professor
William Hersh, MD, FACP, Professor and Chair, Department of Medical Informatics & Clinical Epidemiology, Oregon Health & Science University, posts his thoughts on various topics related to biomedical and health informatics.

David Katz, MD
David L. Katz, MD, MPH, FACP, is an internationally renowned authority on nutrition, weight management, and the prevention of chronic disease, and an internationally recognized leader in integrative medicine and patient-centered care.

Just Oncology
Richard Just, MD, ACP Member, has 36 years in clinical practice of hematology and medical oncology. His blog is a joint publication with Gregg Masters, MPH.

KevinMD
Kevin Pho, MD, ACP Member, offers one of the Web's definitive sites for influential health commentary.

MD Whistleblower
Michael Kirsch, MD, FACP, addresses the joys and challenges of medical practice, including controversies in the doctor-patient relationship, medical ethics and measuring medical quality. When he's not writing, he's performing colonoscopies.

Medical Lessons
Elaine Schattner, MD, FACP, shares her ideas on education, ethics in medicine, health care news and culture. Her views on medicine are informed by her past experiences in caring for patients, as a researcher in cancer immunology, and as a patient who's had breast cancer.

Mired in MedEd
Alexander M. Djuricich, MD, FACP, is the Associate Dean for Continuing Medical Education (CME), and a Program Director in Medicine-Pediatrics at the Indiana University School of Medicine in Indianapolis, where he blogs about medical education.

More Musings
Rob Lamberts, MD, ACP Member, a med-peds and general practice internist, returns with "volume 2" of his personal musings about medicine, life, armadillos and Sasquatch at More Musings (of a Distractible Kind).

Prescriptions
David M. Sack, MD, FACP, practices general gastroenterology at a small community hospital in Connecticut. His blog is a series of musings on medicine, medical care, the health care system and medical ethics, in no particular order.

Reflections of a Grady Doctor
Kimberly Manning, MD, FACP, reflects on the personal side of being a doctor in a community hospital in Atlanta.

The Blog of Paul Sufka
Paul Sufka, MD, ACP Member, is a board certified rheumatologist in St. Paul, Minn. He was a chief resident in internal medicine with the University of Minnesota and then completed his fellowship training in rheumatology in June 2011 at the University of Minnesota Department of Rheumatology. His interests include the use of technology in medicine.

Technology in (Medical) Education
Neil Mehta, MBBS, MS, FACP, is interested in use of technology in education, social media and networking, practice management and evidence-based medicine tools, personal information and knowledge management.

Peter A. Lipson, MD
Peter A. Lipson, MD, ACP Member, is a practicing internist and teaching physician in Southeast Michigan. The blog, which has been around in various forms since 2007, offers musings on the intersection of science, medicine, and culture.

Why is American Health Care So Expensive?
Janice Boughton, MD, FACP, practiced internal medicine for 20 years before adopting a career in hospital and primary care medicine as a locum tenens physician. She lives in Idaho when not traveling.

World's Best Site
Daniel Ginsberg, MD, FACP, is an internal medicine physician who has avidly applied computers to medicine since 1986, when he first wrote medically oriented computer programs. He is in practice in Tacoma, Washington.

Other blogs of note:

American Journal of Medicine
Also known as the Green Journal, the American Journal of Medicine publishes original clinical articles of interest to physicians in internal medicine and its subspecialities, both in academia and community-based practice.

Clinical Correlations
A collaborative medical blog started by Neil Shapiro, MD, ACP Member, associate program director at New York University Medical Center's internal medicine residency program. Faculty, residents and students contribute case studies, mystery quizzes, news, commentary and more.

Interact MD
Michael Benjamin, MD, ACP member, doesn't accept industry money so he can create an independent, clinician-reviewed space on the Internet for physicians to report and comment on the medical news of the day.

PLoS Blog
The Public Library of Science's open access materials include a blog.

White Coat Rants
One of the most popular anonymous blogs written by an emergency room physician.

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