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Wednesday, November 21, 2018

​P-Values Have No Value, but There is a Better (Bayesian) Way

BY PAUL YOUNG, MBChB, PhD

Conducting research and being science-based is what distinguishes medicine from crystal therapy and is fundamental to modern medical care. Despite many major advances in medicine, we are missing an opportunity to recognize the true potential of research to advance patient care. Some of our research concepts are problematic, and you need to understand the concepts to understand the problems.

Power is one such concept. Power is the probability of demonstrating an effect of a magnitude that you specify in your sample-size calculation if such an effect exists. Then there's the p-value. A p-value of less than 0.05 does not mean there is a one-in-20 chance that the result is a fluke. Instead, assuming that the null hypothesis is correct, the p-value is the probability of obtaining a result equal to or more extreme than what was actually observed.

These concepts underpin the frequentist statistical approach. You start with an experimental hypothesis, reframe it as a null hypothesis, gather some data, and then calculate the probability of the observed result under the assumption that the null hypothesis is correct. All this is abstract, and it is difficult to understand why this is such a problem, but you are basically accepting the null hypothesis when you apply a threshold p-value of greater than or equal to 0.05. If it's less, you reject the null hypothesis. The fundamental problem with this paradigm is illustrated by the picture of a young woman shown here. What are the chances this woman worships Satan? Look at the details and try to find the clues.

Whatever probability you came up with, did you consider that there are only 10,000 Satan worshippers in the world? What if I asked you what the chances are that she is Christian? How heavily do you weigh the fact that there are two billion Christians? This is the problem of base rate neglect. We tend to put too much weight on the specific and not enough on the general.

Another example: Let's say I have a test that detects 100 percent of drunk drivers, but it has a five percent false-positive rate. We have a driver with a positive test; what are the chances the driver is drunk? The answer that likely comes into your head is 95 percent. The problem with that answer is the same problem as the young woman: It neglects the base rate.

For the sake of argument, let's say one in every 1,000 drivers is drunk, so there can only possibly be one true-positive: the drunk driver. From the remaining 999 sober drivers, we can expect 49 false-positives with a five percent false-positive rate. Under this scenario, there is only a one-in-50 chance that the driver is drunk if the test is positive. We are all familiar with this kind of thinking in relation to the sensitivity and specificity of diagnostic tests. Think of a clinical trial as a diagnostic test of a trial hypothesis, and imagine that you're going to test 100 intensive care interventions and clinical trials, interventions that might reduce mortality. You have 100 things you want to test, and you want to demonstrate that you can save lives.

Testing Hypotheses
It obviously depends on what you're testing and the effect size you specify, but what percentage do you expect to be positive? The ICU literature is not exactly overrun with interventions that reduce mortality, but for the sake of argument, let's say 10 percent of the hypotheses are correct. With 90 percent power, we can expect to detect nine of 10 of the true hypotheses, with a p-value threshold of 0.05 where the null hypothesis is correct. We can expect the p-value to be less than 0.05 in five percent of the remaining 90 trials. These are the false-positives. If the prior probability that the hypothesis was correct is 10 percent and the p-value is less than 0.05, then it's a true-positive around two-thirds of the time, and it's a false-positive around one-third of the time. (See graph.)

Another scenario: If one percent of the hypotheses are correct, then a trial that's statistically significant is five times more likely to be false than it is to be true. From now on, the first thing you should do when you read a clinical trial is go to the sample size calculation part of the paper, where they say what their hypothesized fixed size was, and think about what you know about medicine, biology, and the world. What is the percentage chance, based on what you already know, that this hypothesis is correct?

Some effect sizes are manifestly implausible. If the prior probability that a treatment effect size is zero, then the posterior probability must also equal zero, no matter what the p-value is. If you believe, as I do, that most ICU trial hypotheses are long shots, then you must also accept that the two most likely results from a clinical trial are no different from a false-positive. This is a problem for all of medicine.

We are facing an epidemic of marginal p-values. There is a rapid upsurge in exciting findings in medical journals with marginal p-values. If you remember only one thing from this article, it should be this: P-values have no value. What we really should be thinking about is probability, particularly when it comes to treatments currently in clinical practice where there is practice variation. We want to have a higher probability of giving patients the right treatment for such comparative effectiveness situations. The p-value is not important. What is important is that we increase the probability of giving the patient the right treatment.

We should see opportunity wherever there is uncertainty. If we randomize patients into a clinical trial, there is an opportunity to shift our understanding of probability. Therapy should be randomized where there is idiosyncratic practice variation. Randomized treatment is the best treatment when it's not plausible for a clinician to tell whether treatment A or B is better based on his clinical experience. Physicians are operating under uncertainty and have cognitive biases, and that means they are likely to make bad choices.

Consider attribution bias: The physician remembers a time he gave one drug to one person who did well, and then he uses that drug for the rest of his career. We are also subject to novelty bias: Doctors like the newest and most expensive treatment; it must be better because it is newer and more expensive. Perhaps most pervasive of all, doctors are biased toward doing something when doing nothing might actually be the best choice. When we don't know what to do, we should be randomizing to treatment A or treatment B and to treatment or control.

Randomized Treatment
There are likely collateral benefits from doing this. Clinical trials can put the best available standard care into a protocol and provide follow-up for patients who might not otherwise receive it. Randomized treatment is a good way of hedging one's bets and guarding against the cognitive biases that the doctor brings to the table. Not only that, but if we can also come up with a system where we learn rapidly from randomizing patients, then randomizing treatment is the best way to get the right treatment if you are ever sick again.

We need to change the paradigm completely. It should not be research but clinical care and a system to optimize treatment that reliably improves outcomes over time. We have to use an alternative method, the Bayesian approach. Here we have an experimental hypothesis and a null hypothesis, we collect some data, and we calculate two probabilities. The probability the hypothesis is correct divided by the probability the null hypothesis is correct is the Bayes factor. Take the prior probability that the hypothesis is true and multiply it by the Bayes factor to get the posterior probability that the hypothesis is true. We need big data sources that collect important outcomes for our patients, and then we need to randomize.

Using this Bayesian approach, we can then look at what has happened to patients and continually update the probability that particular treatments are better. Randomization can be unequivocally good for patients. We can start by randomizing patients in a 1:1 ratio and randomizing the aspects of treatment for ICU patients who are subject to idiosyncratic practice variation, like blood pressure, oxygen, and nutrition therapy targets. The information can go into a database, and as it looks like particular treatments are better over time, we can continue to randomize, but also weight the coin.

As soon as we have information that makes it look like one treatment might be better than another, even if we don't know for sure, we can increase the probability that patients get treatments that work. Doing this creates a new paradigm where there is a fusion of quality improvement and science so that every patient contributes information that improves the care of every subsequent patient. It no longer matters what the p-value is, but we can stop randomizing patients once we have decided a treatment works.

We can also declare that two treatments are equal, and we can systematically use the cheapest treatment from that time on, move on, and study something else. Instead of having indeterminate clinical trials where we wonder if the trial was too small and underpowered, we will have statistically robust results that are never indeterminate.

Optimizing care is a priority for global public health. Those with an acutely-reversible, life-threatening illness will be cared for in an intensive care unit, and there is about a one-in-two chance of needing intensive care over your lifetime if you live in a developed country, so you want the best intensive care therapy you can get. Using this system could save money by not using ineffective treatments, could save lives by immediately incorporating effective treatments into standard care, and could increase the probability that patients will get the treatments that work even before we know for sure that they work. This is the way that research should be.

Dr. Young is an intensive care specialist at Wellington Hospital, the medical director of the Wakefield Hospital Intensive Care Unit, and the head of the Intensive Care Research Unit at Wellington Hospital and the Medical Research Institute of New Zealand, both in Wellington, New Zealand. Follow him on Twitter at @DogICUma.

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Wednesday, November 14, 2018

Ruling Could Strip EPs of Right to Independent Practice

BY CARLO REYES, MD, JD

California's highest court recently issued a landmark decision that changed the legal standard to determine independent contractor status. This ruling makes it inordinately more difficult for EPs to practice medicine as independent contractors in California, and the physician groups and hospitals that hire independent contractors may need to offer employee benefits or run afoul of the decision.

 
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Aleutie/iStockphoto.com

Physician groups in California may now be required to pay for a physician's Social Security taxes, Medicare, worker's compensation, and health insurance even if they were hired as independent contractors. The court in Dynamex Operations West, Inc. v. Superior Court, adopted the so-called ABC test, which makes it much more difficult to demonstrate independent contractor status.

One potential upside for EPs is that independent contractors hired by physician groups may be able to obtain employee benefits covered by their "employer." The downside? Physician groups and hospitals that contract with physicians as independent contractors must assume the responsibilities of an employer. Physicians no longer have the opportunity to incorporate as a business entity distinct from the hiring entity or be free of control imposed by hiring entity. Dynamex will increase the overhead of physician practices to maintain their physician workforce because providing employee benefits is the cost of doing business. Suddenly, physician groups must pay for Social Security taxes, Medicare, workers compensation, health insurance, and other employee benefits, even if the physicians were originally hired as independent contractors.

The ABC Test
Dynamex, a courier and delivery service, changed its workforce of drivers from employee to independent contractor status in 2004 to save money. The plaintiff, Charles Lee, filed a certified class action in 2005 asserting that Dynamex improperly classified him and others as independent contractors.

Before the Dynamex suit, the Borello test identified the "right to control" as the most important factor in determining independent contractor status. (S.G. Borello & Sons, Inc. v. Department of Industrial Relations; http://bit.ly/2OvReMq.) Another ruling, Martinez v. Combs, held that a determination of the employer-employee relationship can be made based on satisfying one of three definitions: exercising control over hours, wages, or working conditions; permitting to work; or engaging and creating a common law employment relationship. (https://stanford.io/2OtrQGV.)

The Dynamex court refuted that the "right to control" test is controlling and instead opted for the ABC test, which presumes employment status unless all three requirements are met: The worker is free from control and direction of the hiring entity in performance of the work in fact and under contract; the worker performs work outside the usual course of the hiring entity's business; and the worker is customarily engaged in an independently established trade, occupation, or business of the same nature as the work performed.

Most problematic for EPs is the second requirement. Any EP hired to provide professional medical services in the ED could not possibly be considered to be performing work outside the usual course of an emergency physician group's business. An EP group is hired for the express purpose of providing medical care to emergency department patients.

The first requirement is also troublesome—professional services agreements between the hospital and an ED group require that the EPs perform under certain acceptable metrics, sufficiently staff the ED, and follow certain protocols. It is a compelling argument that an EP group is not free from the control and direction of the hiring company.

The Upshot
Dynamex allows the twisted conclusion that every physician group in California must now employ its provider workforce. This is impractical because most EPs are accustomed to dictating the number of shifts for a particular group and the number of groups to work for, especially for young EPs coming out of residency.

Legislation should carve out physicians from the implications of Dynamex to prevent the nonsensical conclusion that all physicians must be employed by their physician groups. A call to action is in order to prevent this in California, or other state courts may follow suit and adopt the ABC test to prevent EPs from practicing medicine as independent contractors.

Dr. Reyes is the vice chief of staff and the assistant medical director of emergency medicine at Los Robles Hospital in Thousand Oaks, CA. He is also a clinical professor in emergency medicine and pediatrics at Olive View/UCLA Medical Center, a health law attorney with Boyce Schaeffer Mainieri, LLP, in Oxnard, CA, and the founder and CEO of Health-e-MedRecord, a patient-centered and emergency physician-designed EHR solution. (www.health-e-medrecord.com.) Follow him on Twitter @carloreyesmdjd, and read his past articles at http://bit.ly/EMN-Defense.

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Wednesday, November 7, 2018

First Responders Worried about Fentanyl OD? 
Minimize Fear by Quashing that Myth

BY DAN RUNDE, MD

It's not difficult to see how we got here. Every week it seems like there's a terrifying headline about how a drug bust seized enough fentanyl to kill the citizens of a city, state, or even a small country. (The Washington Post May 25, 2018; https://wapo.st/2IZV4rb.) Enough narcotics to kill 26,000,000 people?! That sounds bad.

The article noted that the Drug Enforcement Administration "has even warned law enforcement officers not to touch the white powdery substance or inhale it while on the job." It stands to reason that our colleagues would be worried about the dangers of lapsing into a coma while on the job.

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Fentanyl pills and crystals. (Courtesy of DEA.gov.)

The idea of being forced into an accidental nap might sound lovely if you're a parent of young children, but this is an understandably undesirable outcome to the rest of the working world. The end result: Fentanyl is being banned from courtrooms, officers are wearing hazmat suits during drug busts, police departments are spending hundreds of thousands of dollars on portable fentanyl detection devices (at $46,000 a piece, you could supply every first responder in America with latex gloves), and seemingly endless reports of unwitting professionals nearly overdosing, only to be saved by a timely naloxone administration.

Thankfully, no law enforcement or first responder lives have been lost as a result of this growing crisis, but the fear is real and all too pervasive. The only problem? Accidental fentanyl overdose is not a thing. All those reports you've seen in the news? Not a single one has been verified by an actual toxicologist or physician.

Several cases described toxidromes that more closely resemble panic attacks or, to be more generous, potential methamphetamine exposure. In several others, the accidental overdose victim reported self-administering naloxone. As EPs, we can confidently say that if you can self-administer an opioid overdose reversal agent, then you weren't overdosing on opioids in the first place.

 

Fear of Accidental Harm
I happen to be lucky enough to be friends and colleagues with a brilliant clinical toxicologist, Joshua Radke, MD, whose pharmacokinetic knowledge is rivaled only by his spectacular red beard. I asked him if it was possible to overdose on fentanyl by touching it with intact skin. Dr. Radke said, "Nope, fentanyl isn't absorbed that way. That's why pharmaceutical companies had to spend years and millions of dollars developing a special patch to get fentanyl into the body through skin."


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Joshua Radke, MD


What about these super-fentanyls we keep hearing about like carfentanil? Can that be absorbed through skin? That got another "nope" from Dr. Radke, who added, "It's more potent, but it's not magically more dangerous."

Then what about breathing in fentanyl dust that's kicked up into the air? "Again, very unlikely for two reasons," Dr. Radke said. "First, fentanyl has a low vapor pressure, which means it would be hard to have very much of it floating around in the air. Second, even if it were, you'd have to breathe it in for a really long time, like hours, to get a meaningful amount into your bloodstream."

Last question: Is your amber mane really natural? It's almost impossible to believe it's not chemically enhanced. Said Dr. Radke: "It is 100 percent natural, and 1,000 percent magnificent."

On the off chance that the words of my red-headed colleague don't have you completely convinced, here's a position statement from the American College of Medical Toxicology and the American Academy of Clinical Toxicology echoing exactly what Dr. Radke said but in more highfalutin language: "Fentanyl and its analogs are potent opioid receptor agonists, but the risk of clinically significant exposure to emergency responders is extremely low. To date, we have not seen reports of emergency responders developing signs or symptoms consistent with opioid toxicity from incidental contact with opioids." (Clin Toxicol [Phila] 2018;56[4]:297; http://bit.ly/2J1uSw7.)

          As EPs, we have important partnerships with first responders and law enforcement, and a key part of our interaction should be education, especially when we're talking about a situation that is increasingly common and is subject to so much well-intentioned but incorrect information. Perhaps more importantly, we know the people who use and inject drugs are subject to tremendous stigma, inside and outside the hospital.

If first responders are afraid of touching patients who have actually overdosed and are in need of emergent reversal out of a misplaced fear of overdosing themselves, it puts this vulnerable population at further risk. The same is true for law enforcement—introducing fear of accidental bodily harm into what can already be a potentially fraught interaction is bad for everyone. Our colleagues in these fields have tough and sometimes scary jobs. If we can use our expertise and close ties to help minimize fear and misinformation, we'll be doing a service to our fellow professionals and to our future patients.

Dr. Runde is the assistant residency director and an assistant professor of emergency medicine at the University of Iowa Hospitals and Clinics, where he serves as co-director for the associate fellowship in medical education. He creates content for and is a member of the editorial board for www.TheNNT.com, and is a content contributor for www.MDCalc.com. Follow him on Twitter @Runde_MC, and read his past articles at http://bit.ly/EMN-MythsinEM.

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Wednesday, October 31, 2018

A Career Spent Looking for a Sense of Belonging

BY L.E. GOMEZ, MD, MBA

The analogy of a fish swimming in water with no idea what water is describes an experience I have frequently had with colleagues in emergency medicine. Twenty years ago, I beat my head against a wall sharing with fellow residents and faculty that implicit bias and prejudice were adversely affecting the health outcomes of our patients. In the words of my mostly white male colleagues, they just didn't see it. To them, I simply had a chip on my shoulder.

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  RaStudio & SonofPromise/Thinkstock.com

When it came time for senior grand rounds presentations, I proposed the topic of racial dissonance and miscommunication leading to poor clinical decision-making and health inequity. My program director said no one on the faculty had any expertise in that area, and our department chair said, "I don't think anyone here knows what you're talking about." Several residents shared a conviction that affirmative action was no longer needed because we were serving a largely poor African-American community on the south side of Chicago and "doing these people a favor." One white peer said I should feel fortunate as an African-American to be there. After all, there were now two of us in the program.

My mentors pejoratively suggested I look into a master's in public health, but my black peer and I leaned toward pursuing a master's in business administration, believing we might have more impact as business leaders than as health justice policy advocates.

Twenty years later, the situation in that residency has improved as a result of diversity and inclusion efforts; there is presently a senior black mentor in leadership, and half of the residents in the program are women. Unfortunately, the vast majority of training programs are still swimming in the water of white hegemony; even when managing to achieve diversity, they still struggle with inclusion. Diversity is not inclusion.

My first job as a newly boarded EP was as the associate medical director for a contract management group (CMG) at a Catholic hospital serving a largely Latino community on Chicago's west side. It was gratifying to be the one bilingual physician on staff. The community welcomed me, inviting me to advocate for their interests. The hospital public relations coordinator asked me to record public service announcements on health and safety for our local Telemundo/Univision affiliate.

 

Racist Comments
Meanwhile, I tried to balance meeting benchmarks (already the sole index for increasing revenue) against support for patients struggling against the real determinants of health: social and economic constraints. Cultural competence was not a company priority, even though inclusion was clearly on the hospital's agenda. Any emphasis on community advocacy seemed superfluous to my medical director, who I considered an ally until he made clear he was not interested in how health disparities affected the revenue cycle.

Eventually, the hospital's identity transformed its mission and its market. It became a designated stroke center and tertiary care referral center, shifting its mission to healing ministry rather than serving the local community. The contract group is now long gone, but they still have no blacks or Latinos in senior leadership roles, though they do have an Asian-American vice president. Inclusion seems a threat to some and possibly irrelevant to those not serving minority communities.

With this lesson learned, I moved to a Latino community, in part because I reasoned it would not be made a marginalized market. Here lies one of the greatest hypocrisies and formidable challenges to understanding diversity and inclusion: Latin American society in southern Florida is more vested in white hegemony than Anglo culture is in America. I thought my childhood experience with racist Cuban Americans-in-exile would be different, tempered by my professional credentials, but Cubans on those hospital staffs routinely expressed the racist view that blacks, particularly American ones, are inherently inferior to whites.

I commonly interrupted conversations in the physician lounge peppered with loud references to a black presidential candidate they called "the monkey." This toxic and deplorable behavior is entrenched in the culture. (Recently, a black student movement at the University of Miami was set off by the increased frequency of white students using the n-word and monkey emojis and calling for the enslavement of blacks, all despite the university establishing a diversity task force the year before to combat bigotry.)

Connecting
It was around this time that I moved to a North Miami Beach hospital serving a black community. There I met David Farcy, MD, the president of the American Academy of Emergency Medicine and the chairman of emergency medicine at Mount Sinai Medical Center in Miami Beach, and several other forward-thinking physicians who were becoming increasingly active in the Florida Chapter of the American Academy of Emergency Medicine (FLAAEM) and the National Medical Association in part to call attention to health equity, professionalism, and ethics in emergency medicine practice. A culturally diverse group of professional friends and I put together a TV show called Connections to speak about unity in the minority melting pot of our community, but it was nowhere near enough to put a dent in the inertia of divisiveness.

Minority presence does not equal diversity or impede hostility in the workplace. I set out to acquire the language of the C-suite with a health care MBA and a goal to promote a new model prioritizing health creation and curbing wasteful expenditure on catastrophic care. Everyone knew health disparities lead to a lack of care for chronic disease and the unequal allocation of power and resources. A significant part of the $4 trillion misspent in this country every year could be addressed by funding relatively simple preventive measures. My classmates and I came up with proposals for strategic corporate philanthropic efforts for community-based health care academies and clinics, education for local labor pools, and career paths into training. We researched how clinical documentation systems could be used to help patients save money and limit health expenditures. Of course, this doesn't fit current business models or strategies focused on the next quarter.

It ultimately dawned on us that we could not reinvent the wheel if we wanted to be included in the current health care business structure. Even in meetings set up by a small consulting group I joined later, we never met black people in leadership to champion novel strategies. Being open to diversity does not guarantee it, and health equity requires powerful leaders. I headed north to pursue an interest in policy and advocacy, finally accepting that that might be a better path to health justice. What better area for that than Washington, DC?

I took part in AAEM's Policy and Advocacy Congressional elective while awaiting credentialing at a hospital where I accepted a position as a medical director at a small hospital in a rural farming community. The welcome can best be summed up this way for anyone familiar with the movie Blazing Saddles: I was the new Sheriff Bart. Shortly after I started, two scribes and a unit clerk told me they heard one EP repeatedly make racist remarks about me. I met with him, and he emphatically denied it. I notified our regional director about the issue, and the response was that nothing could be done.

I decided this company was not worth any more of my time and energy. I was active in the National Medical Association, and a colleague suggested I consider the Howard University College of Medicine. I have been practicing there as an associate professor for emergency medicine ever since. There was initially enthusiasm for collaborative work on social justice at Howard, but then the contract was taken over by a CMG.

Diversity and inclusion require integrity and commitment. Last summer while attending emergency medicine lectures at the National Medical Association Scientific Assembly, I ran into the AAEM's president-elect, Lisa Moreno-Walton, MD, who invited me to join the AAEM's Diversity and Inclusion Committee and to speak at the Scientific Assembly. The enthusiasm around diversity and inclusion in most organizations is fueled by avoiding lawsuits and meeting compliance and workplace safety measures. Many diversity and inclusion initiatives and officers are not taken as seriously as other leaders, but I can tell you that even my limited involvement has already been immensely rewarding.

At my first AAEM Scientific Assembly about 20 years ago, I felt isolated and alone as one of a handful of black EPs wandering aimlessly from one lecture to the next. Last year I wandered about expecting that same experience, but the response was more often a positive greeting or suggestion to connect and collaborate. I even came across a young black physician who said he had been wandering around the conference not knowing where to go. "You just made my week," he said. "Thank you for helping me feel part of this."

Dr. Gomez is a clinical instructor in emergency medicine at Howard University College of Medicine and a health care consultant focusing on the economic advantage of diversity and inclusion. He is the chair of AAEM's Diversity & Inclusion Committee. This articles previously appeared in the July/August issue of Common Sense, AAEM's magazine, where his articles frequently appear. (http://bit.ly/2xoLEQH.) Visit his blog at https://liberalartsmd.com, and follow him on Twitter @LiberalArtsMD.

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Wednesday, October 24, 2018

​No Reason Not to Use TXA for Critical GI Bleeds

 BY RICHARD PESCATORE, DO

The application of evidence-based medicine is at its easiest after large trials and rigorous analyses have been popularized and widely disseminated. The evidence-based clinician must juggle online resources, academic manuscripts, and trade journals, but ultimately can remain current through the cornucopia of open-access educational resources available to the modern emergency medicine physician.

A true test of bedside Bayesianism, however, comes when we are presented with clinical conundrums not yet thoroughly vetted and extensively analyzed by contemporary emergency medicine educators. It is when no clear answer exists that we are forced to faithfully apply the best available knowledge to answer critical questions in real time. As methodical skepticism in emergency medicine continues to permeate and propel our evidence-based culture, it is crucial that we not abdicate our underlying responsibility to do what we think is best for the patient in front of us.

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Often, it seems, we treat the absence of compelling evidence as an indication of an intervention's futility or ineffectiveness, which may be a disservice to the patient in need. In reality, a synthesis of the available literature with our clinical experience, individual patient factors, and the medical degrees and extensive body of knowledge we all have fought so hard to obtain is more than sufficient where top-level evidence may be lacking.

Consider the patient dying of a gastrointestinal bleed. It's no rarity—tens of thousands of these patients pass through our doors annually. Emergency medicine residents cut their procedural teeth in resuscitation bays full of GI bleeders and almost every EP has a story about that time he put a Blakemore in. We often lament how little we have to offer these patients while awaiting reticent gastroenterologists.

Octreotide and ceftriaxone are quickly delivered. Proton pump inhibitors are lambasted for their lack of efficacy yet dutifully ordered despite compelling evidence of no benefit and even a signal of harm. We evidence-based clinicians know the literature, and we cling to transfusion trial talismans as we seek to stem the tide of dark blood that seems to flow as quickly as we can replace it. (N Engl J Med 2013;368[14]:1362; http://bit.ly/2NaBTA8; JAMA 2015;313[5]:471; http://bit.ly/2CRG535.)

Curiously, one medication has remained inexplicably absent from our routine resuscitation of the critically ill GI bleeder. Tranexamic acid, or TXA, recently championed in trauma and publicized for every bleeding source from epistaxis (EMN 2018;40[4]:1; http://bit.ly/2Qq5Iux) to abnormal uterine bleeding (EMN 2018;40[3]:5; http://bit.ly/2N7MAmW), often sits unused in the pharmacy as the blood bank is emptied and our patients deteriorate. Despite strong physiologic justification for its use and a level of clinical evidence that should sate even the strictest of EBM evangelists, TXA has yet to find permanent purchase in the GI bleed armamentarium.

We have suspected since 1979 that TXA might benefit critically ill patients with GI bleeds when a small trial of 149 patients demonstrated decreased transfusion requirements and hinted at a mortality benefit. (Scand J Gastroenterol 1979;14[7]:839.) Since then, multiple randomized controlled trials have consistently demonstrated not only improvement in hemodynamic markers and transfusion requirements but also sustained evidence of mortality benefit.

Clot Breakdown
A meta-analysis of seven randomized controlled trials of 1,385 patients in 2008 showed a relative mortality improvement of 39 percent. (Aliment Pharmacol Ther 2008;27[9]:752; http://bit.ly/2xgvIAL.) This was confirmed with a 2014 Cochrane Review, where eight RCTs and more than 1,700 patients found a relative risk for mortality of 0.60, with no difference in venous thromboembolic events. (Cochrane Database Syst Rev 2014 Nov 21[11]; http://bit.ly/2NbRxvc.)

Tranexamic acid reduces clot breakdown by inhibiting the action of plasmin, an active agent in fibrinolysis. The CRASH-2 and MATTERS trials convinced the trauma and emergency medicine communities of TXA's value in reducing death due to bleeding and all-cause mortality in major trauma, and multiple systematic reviews and meta-analyses since then have consistently demonstrated statistically significant reductions in death when TXA is applied in patients with GI bleeds. As is the case in modern evidentiary science, though, medical societies and guideline organizations have (appropriately) called for additional data before making a recommendation to routinely include TXA in the resuscitation of the GI bleeder.

A 2014 trial sequential analysis—a statistical technique that combines information already available from meta-analyses with weighted interim analyses and helps to quantify how much more information is needed before a treatment effect can be confidently confirmed—indicated that 5,500 more patients would need to be included in clinical trials (more than double the number already analyzed) before the mortality benefit of TXA in GI bleed could be confirmed. (BMJ 2014;348:g1421.)

Fortunately, an ongoing RCT, the HALT-IT trial, has recruited nearly 10,000 patients on the way to their goal of 12,000, and should provide definitive confirmation of the benefit of TXA as a life-saving medication. The frustrating part, however, is that the trial isn't set to conclude until next year, and the timeline of publication and knowledge dissemination likely stretches far beyond that.

The question, then, is what we should do in the interim.

Tranexamic acid has shown itself to be safe and effective in a constellation of emergency conditions, and not one but eight randomized trials have reliably established that it saves lives in patients with gastrointestinal bleeding. Overblown fears of precipitating increased rates of venous thromboembolic events have not panned out in large studies across a variety of applications, and the biochemical basis of the drug and its expected action correspond with demonstrated success in clinical trials.

The much-anticipated HALT-IT trial will settle the debate, but in the meantime we are left with consistent and compelling evidence that tranexamic acid should be routinely incorporated into the resuscitation of the critically ill GI bleeder. Our patients deserve nuance and rational integration of the literature where definitive studies are lacking. Our patients deserve TXA.

 Dr. Pescatore is the director of emergency medicine research for the Crozer-Keystone Health System in Chester, PA. He is also the host with Ali Raja, MD, of the podcast EMN Live, which focuses on hot topics in emergency medicine: http://bit.ly/EMNLive. Follow him on Twitter @Rick_Pescatore, and read his past columns at http://bit.ly/EMN-Pescatore.

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