Tranexamic Acid & The WOMAN Trial

Tranexamic acid is popular for the treatment of freckles and nosebleeds – oh, and major bleeding in the setting of trauma. But, originally, the drug was developed for use in controlling hemorrhage in obstetrics and gynecology. Finally, then, we have a trial examining its use for its intended purpose.

Comprising 20,060 patients with clinically significant post-partum hemorrhage across 193 hospitals in 21 countries, the WOMAN trial is – inconveniently – negative as originally designed. The initial study design called for 15,000 patients and a composite endpoint of hysterectomy or death within six weeks of childbirth. However, as the study progressed, it was clear the standard practice in the settings involved indicated the intervention was going to have no effect on hysterectomy rates, and the trial was then expanded to examine the effect on mortality.

So, then, with their expanded sample size, does TXA save lives, as reported profusely throughout the lay media?

Nope.

Mortality within 6 weeks was 2.3% in the TXA cohort and 2.6% with placebo a relative risk of 0.88 (0.74-1.05).

There is, however, some layered complexity in these outcomes. Broken down by cause of death, deaths due to bleeding were 1.5% in the TXA cohort compared with 1.9% with placebo, reaching “statistical significance” with a p-value of 0.045. Then, if you further unpack these results, it seems even within the TXA cohort there is probably a time-to-treatment effect similar to CRASH-2.  Mortality was 1.2% in those receiving their TXA within 3 hours compared with 1.7% treated with placebo. In those treated beyond 3 hours, there was no difference in outcomes – and much higher mortality, regardless (2.6% vs. 2.5%).

So, what should we take away from these data? Is TXA more than just a treatment for freckles, or are these authors and the lay media exaggerating secondary outcomes in the setting of an overall negative trial? As usual, the answer is a little bit of both. The magnitude of the treatment effect, considering the size of this trial, is very, very small. That said, death is a quite meaningful clinical outcome, TXA is fairly inexpensive, and no specific harms were detected in this trial. Therefore, in the settings in which this trial was conducted – Nigeria, Pakistan, Sudan, Albania, etc. – this is likely an important treatment for post-partum hemorrhage.

In more robust clinical settings where additional resources are typically available to support the resuscitation of women suffering bleeding complications from childbirth, the effect size on mortality is likely even much smaller. There may be clinically important effects regarding hysterectomy, hemostasis, and reduction in transfusion utilization, but I again suspect they will be very small and difficult to quantify without a similarly large trial. Then, as the NNT increases for clinically important outcomes, even the very rare harms of a treatment become relevant – and failure of this trial to detect harms may simply be a limit of its statistical power.

Ultimately, as the mortality benefit decreases, the range of acceptable practice variation for protocols incorporating TXA increases.  This is an important trial – but, as typically, not quite as breathlessly so.

“Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial”
http://thelancet.com/journals/lancet/article/PIIS0140-6736(17)30638-4/abstract

Tylenol & Case of the Flawed Fetus

If you’re like most folks advising pregnant patients on pain and fever control, you’ve advised against ibuprofen and recommended acetaminophen. It is, after all, considered to be generally safe throughout pregnancy, in contrast to the alternatives.

I’m afraid I do not know precisely what to make of this study, but it is the latest in a context of several other studies linking maternal acetaminophen use during pregnancy with behavioral issues in young children. These authors link surveys of pregnant women performed over a decade ago with follow-up surveys of their children, with specific emphasis on identifying potential cofounders for their observed association.

The ultimate conclusion is fairly clear from just the title, with the subtitle of “Evidence Against Confounding”. An association is clearly observed between those they identify with likely or confirmed usage of acetaminophen and increased behavioral and attention difficulties in childhood. However, the evidence against confounding is rather incomplete. There are small differences in maternal psychiatric illness, maternal smoking, and maternal alcohol use favoring normally behaved children – and, while these authors attempt to control for these factors, this still introduces some element of statistical tomfoolery. There are also several non-genetic and non-prenatal risk factors for ADHD, and these authors are able only to collect a handful of these – absent completely any observations of the home environment of the children evaluated. Finally, no dose-response relationship is ultimately measured, as well.

I would, of course, ultimately advise minimal medication exposure in pregnancy, regardless. If pain control is necessary, it is not clear this risk – if true – is specifically of greater magnitude than those associated with alternative analgesia. For, this does not yet change practice.

“Association of Acetaminophen Use During Pregnancy With Behavioral Problems in Childhood”

http://archpedi.jamanetwork.com/article.aspx?articleid=2543281

Gestational Age and D-Dimer Levels

In general, the utility of D-dimer for the evaluation of venous thromboembolism declines with gestational age.  The typical cut-offs for the 95th percentile, depending on your assay, become less and less relevant as pregnancy progresses.  Wouldn’t it be nice, perhaps, if we had reliable data?

So, well, here’s something:

One glaring hole in this data is the broad inclusion criteria of “healthy” women.  No testing was specifically performed to exclude asymptomatic venous thromboembolism, so the possibility exists of inclusion of small, subsegmental pulmonary emboli, or of non-occlusive lower extremity deep venous thrombosis.  The effect on this data would be to increase the 95% percentile, and to widen the 95th percentile confidence interval.

Jeff Kline has proposed gradually increasing cut-offs of 750, 1000, and 1250 ng/mL for the first, second, and third trimester, respectively (based on a standard cut-off of 500 ng/mL).  This sample is much larger than the one cited by Kline in his “PE in pregnancy” algorithm, but his appear to be reasonable, sensitive cut-offs.  By far, the most important aspect of evaluating pulmonary embolism in pregnancy is simply to communicate the uncertainty, and to inform and share decision-making with the patient along the way.

“Gestation-specific D-dimer reference ranges: a cross-sectional study”
http://www.ncbi.nlm.nih.gov/pubmed/24828148

Ondansetron vs. Metoclopramide in Hyperemesis

I hate to say it, but this is one of the first randomized trials I’ve stumbled across from Obstetrics and Gynecology – so, even though it’s not terribly profound, I felt compelled to cover it.

This is a double-blind, randomized trial of women admitted to observation with hyperemesis gravidarum.  They received either 4mg of ondansetron or 10mg of metoclopramide every 8 hours for 24 hours, and patient were tracked for vomiting episodes and self-reported nausea.  With regard to these co-primary outcomes, there was no difference between study drugs – most had full resolution, and most in each group had 2 episodes of vomiting or fewer.  However, secondary outcomes and adverse effects – drowsiness, xerostomia, and persistent ketonuria – favored ondansetron.

The authors therefore conclude ondansetron ought probably be favored – all else being equal.  But, for these authors, all else is not equal – ondansetron is markedly more expensive.  Therefore, the ultimate conclusion of these authors is rather in favor of metoclopramide, considering their similar efficacy.

Of other interesting note, one patient, despite admission and supportive care, had 23 episodes of vomiting during the study period.  Oy.

“Ondansetron Compared With Metoclopramide for Hyperemesis Gravidarum
A Randomized Controlled Trial”
http://www.ncbi.nlm.nih.gov/pubmed/24807340

The Curious Story of Diclegis

For no particular reason, I’ve recently become familiarized with the story of Diclegis (Diclectin in this study, and in Canada).  For use in pregnancy-induced nausea and vomiting, Diclegis is a delayed-release combination formulation of 10mg each of doxylamine and pyridoxine.  It was approved by the FDA in April of 2013, and has rapidly become first-line therapy.

The surprising bit – this is precisely the same drug our mothers took in pregnancy.  It was introduced in the 1950s as Bendectin, and it was estimated as many as 30% of pregnant women took this combination pill in the 1970s.  However, in the early 1980s, the manufacturer was the target of innumerable lawsuits alleging fetal malformation – and in 1983, voluntarily withdrew the drug from the market.  This choice was made solely due to the costs of defending against litigation, and not a reflection of the safety of the drug.  The physicians who had published data suggesting fetal risk were eventually discredited, and even the FDA noted in 1999 that Bendectin was not withdrawn for reasons of safety or effectiveness.

So – now it’s back, and, unsurprisingly, it works better than placebo.  This manufacturer-sponsored, double-blind, placebo-controlled trial demonstrated improvement with Diclectin in almost every measure.  And, 48% of Diclegis users asked for compassionate use of the study drug following conclusion of the study (although, so did 32% of placebo).  I’ve also discovered my new favorite disease-severity scoring system: the PUQE Score.

The downside: it costs ~$160 for 30 pills.

A brief perusal of the internet shows doxylamine, a sedating, first-generation antihistamine costs as low as 3 cents per tablet.  Pyridoxine, vitamin B6, costs as little as 6 cents per tablet.  Diclectin costs ~$5 per tablet.  You could pay for Diclegis – after all, it is a special “delayed-release” formulation where doxlyamine reaches peak concentration 6 hours after ingestion.  Or, you could do what obstetricians have been telling their patients to do for the last several decades: make your own equivalent dosing from the component medications at a fraction of the cost.

It certainly seems prudent to try the cheaper option, first.

“Effectiveness of delayed-release doxylamine and pyridoxine for nausea and vomiting of pregnancy: a randomized placebo controlled trial”
http://www.ncbi.nlm.nih.gov/pubmed/20843504

Whole Blood Works For POC Pregnancy Tests

If there is such thing as a “cult favorite” article amongst Emergency Physicians, right now, this probably qualifies as the one receiving its 15 minutes of fame on Twitter.

If there is any singular agony known to all Emergency Physicians it is the inability to obtain urine samples in a timely manner.  Sometimes, this is for the urinalysis.  Other times, this is for the qualitative pregnancy test result.  If only there were a better way….

And, perhaps, there is.  This is a two year study of sensitivity/specificity of the POC pregnancy test using the Beckman Coulter ICON 25 – comparing the performance of using urine vs. whole blood, with laboratory quantitative bHCG >5 as the gold standard.  95.3% sensitivity for the urine test, 95.8% sensitivity for whole blood, with 100% specificity.  Most of the false negatives were due to beta hCG < 100.

Interesting alternative!

“Substituting whole blood for urine in a bedside pregnancy test”
http://www.ncbi.nlm.nih.gov/pubmed/21875776

Sometimes, The Pregnancy Test Lies

A couple years ago, my hospital pulled the POC urine pregnancy tests from the ED because of false negatives – leading to incredulous discussions of how it was possible for a nursing assistant to screw up something so simple as a dichotomous colormetric test.

Well, at Washington University, when they had multiple issues with their POC pregnancy test, they investigated the issue in more depth, and this nice little article is an overview of the limitations of the the test.  There are two ways the POC test fails:
 – Not pregnant enough.
 – Too pregnant.

We all know about sensitivity in early pregnancy really only being 97% or so at one week, and no one will fault the test for that.  However, their case series of five patients, all of whose serum hCG was >130,000, are hypothesized to have saturated the reagent to the point of a false-negative test.

In any event, interesting article about something I hadn’t put much thought into.

“‘Hook-Like Effect’ Causes False-Negative Point-Of-Care Urine Pregnancy Testing in Emergency Patients”
http://www.ncbi.nlm.nih.gov/pubmed/21835572