NoPAC: No benefit from TXA in epistaxis

For the last two decades, TXA has been put on a pedestal in emergency medicine. It has been sold as the perfect drug: life saving with absolutely no side effects. The silver bullet. Unfortunately, the evidence for this ‘wonder drug’ has never been that great. I have a very large document summarizing all the of literature for TXA for basically every condition that I will publish once we record our Emergency Medicine Cases Journal Jam episode. (It has been in the works for almost 2 years. If anyone has the power to get Rory a few days off work, that might help.) Today, I am going to dip into a little bit of that evidence because of a new trial published on the use of TXA for epistaxis.

The NoPAC trial is the highest quality trial to date looking at TXA for epistaxis, but before diving into that trial, I thought I would share what I had previously written about this literature. My bottom line for the Journal Jam Episode was: The level of evidence is weak, and so I wouldn’t be surprised if it was overturned in the future, but the current evidence does support the use of TXA (either topical or oral) to reduce the risk of rebleeding. There is no evidence that it reduces more important outcomes like transfusions, need for interventions, or surgery.

When I wrote that review, there were six RCTs which included a total of 692 patients. They all had fairly different methods. Some used oral TXA and others used topical. The treatments in the control groups vary wildly. The Cochrane review rates the quality of these studies as “moderate to low”. (Joseph 2018)

One single-center, open-label RCT compared 500 mg of TXA on a cotton ball to usual packing in 216 patients with epistaxis. It worked quickly (bleeding was stopped at 10 min in 70% of the TXA group compared to only 30% of the packing group). Rebleeding at 24 hours was not statistically significant, but was lower in the TXA group (5% vs 10%). (Zahed 2013) There is another non-blind, single-center RCT from the same researchers randomizing 124 adult patients taking antiplatelet medications with ongoing epistaxis after 20 minutes of pressure to either 500 mg of TXA on a cotton pledget or nasal packing with epinephrine and lidocaine. The results were remarkably similar, with 73% of the TXA groups having their bleeding stopped at 10 minutes as compared to 29% of the packing group. There was no statistical difference in rebleeding at 24 hours (5% vs 10%), but this time it became statistically significant by 1 week (5% vs 21%). Patients also left the ED quicker in the TXA group. The big concerns with these studies are the lack of blinding and the fact that both these studies come from a single center. A third very similar study compared 1 gram of topical TXA to phenylephrine in 120 patients, and appears to have very similar results, but is not available in English so I can’t review it in detail. (Atabaki 2017)

Two inpatient studies looked at oral TXA (1 gram TID) compared to placebo. I don’t have access to Petruson (1974), and the trial isn’t listed on PubMed, but in admitted patients, all of whom had a Foley catheter and an anterior pack, oral TXA apparently resulted in a statistically significant decrease in rebleeding when the packs were removed. On the other hand, White (1988) looked at 89 admitted adult patients, and there was no statistical difference in the amount of rebleeding (57% with placebo, 47% with TXA). There was no difference in transfusion. They did find a statistical difference in the number of patients with minor rebleeds, but that means that there was absolutely no difference in the more important group of patients with major rebleeds. 

Overall, TXA seems to reduce the rate of re-bleeding (47% vs 67%; RR 0.71, 95% CI 0.56-0.9). It isn’t clear whether it affects other important outcomes. The only study that reported transfusion rates showed no difference, and none of the studies reported how many patients required further interventions like surgery or repacking. Furthermore, these studies likely don’t provide us with an adequate representation of harms. The Cochrane review states that “the body of evidence included in this review (six studies with a total of 692 participants) is insufficient to allow robust conclusions to be drawn.” (Joseph 2018)

There are a few ongoing trials. ISRCTN34153772 is a UK based RCT looking to enroll 450 patients who have failed initial ED management and randomize them to TXA or placebo. (This is the study that we are discussing today). NCT02930941 is an American single center RCT of atomized nasal TXA or placebo looking to enroll 70 ED patients. It is supposed to be done in December 2019, but the results are not available yet. NCT03360045 is a RCT comparing topical TXA with Merocel packing in 135 ED patients in Turkey. The trial was apparently finished in August 2018, but the results are not available yet.

That was my summary as of 2020. The studies were small and all had significant flaws. I have used TXA relatively routinely in patients with epistaxis, but it was clear that a single high quality study would over-rule all the data available to date. We now have that high quality study.

The paper

Reuben A, Appelboam A, et al. The use of tranexamic acid to reduce the need for Nasal Packing in Epistaxis (NoPac): randomised controlled trial. Annals of Emergency Medicine. 2021. 10.1016/j.annemergmed.2020.12.013

The Methods

This is a multicenter, pragmatic, block-randomized, double-blind, placebo controlled trial at 26 emergency departments in the United Kingdom.

Patients

They enrolled adult patients with epistaxis persisting despite first aid (a minimum of 10 minutes of pressure, ice, or both). All patients received a topical vasoconstrictor on emergency department arrival, and if the bleeding stopped those patients were excluded. Also excluded were patients with hemodynamic instability, trauma, out-of-hospital packing, allergy to TXA, nasopharyngeal malignancy, pregnancy, and hemophilia. 

Intervention

Tranexamic acid (TXA) 100mg/ml. 2 mL (200 mg) was placed on a dental roll and left in the nare for 10 minutes with pressure. If there was ongoing bleeding, the same dose was repeated a second time. 

Comparison

Placebo (sterile water), with the same procedure.

Outcome

The primary outcome was the use of anterior nasal packing at any time during the index emergency department visit.

The Results

They enrolled 496 patients. They had screened 2622 patients, and a large number were excluded for reasons such as “other” or “department too busy” so selection bias is a significant concern. The mean age was about 70, and about half of patients were female. 69% of the placebo group and 61% of the treatment group were on anticoagulants. 

Overall, 45% of patients received an anterior nasal pack. There was no difference between the groups. 43.7% of the TXA group were packed as compared to 41.3% of the placebo group (odds ratio 1.11, 95% CI 0.77-1.59).

There was one thrombotic event in the placebo group and none in the TXA group. More patients in the TXA group reported adverse reactions, although the difference was not statistically significant (3.5% vs 1.2%). Serious adverse events occurred in 4.3% of the TXA group and 2.1% of the placebo group.

There were no differences in the secondary outcomes, including other treatments for epistaxis, hospital admission (which was amazingly high at 45%), blood transfusion, or recurrent epistaxis.

My thoughts

This was an important and generally well done trial. It is much higher quality of evidence than anything we had to date. It should probably, therefore, change practice, but I imagine a lot of people will find that difficult.

TXA for epistaxis might be the best example of the limitations of anecdote that I have encountered in my career. Based on my experience using topical TXA over the years, I would have sworn that it works. It really seems to work. I can think of many examples where bleeding stopped only after I applied TXA, but there is a reason that we developed the scientific process. Anecdote and experience are incredibly flawed. Bias is built into the human brain. I will naturally remember my successes and forget my failures. I will naturally assume that my actions stopped the bleeding, even if it would have stopped on its own. Anecdote can easily lead us astray, but unfortunately anecdote and experience are much more compelling than evidence. I think that explains a lot of the problems we see in the world today. 

Of course, no trial is perfect. One might quibble with the dose and timing. The dose of TXA that they used is smaller than I usually use. I typically dump 500-1000 mg of TXA on cotton balls and get as much in the nose as I can. However, these authors looked at this before the study, and a fully saturated dental roll only absorbed 200 mg of TXA, so it is likely that I have been wasting medication. Timing might be a bigger concern. We are often impatient with bleeding, but patience, pressure, and time are incredibly effective. When I place topical TXA for epistaxis, I give it a minimum of 20 minutes before I check again. I am not aware of any science looking at clotting times in the context of TXA, but I worry that disrupting the developing clot too early could counteract any benefit of the therapy.

Some people might quibble about the universal use of a vasoconstrictor before patients were randomized. Personally, I tend to use all the medications I am going to use at the same time. I get the patient to blow their nose, remove as many clots as possible, and then apply a mixture of local anesthetic, epinephrine, and TXA on a cotton ball, and then have the patient apply pressure for 15-20 minutes. Therefore, the protocol in this trial doesn’t exactly translate to my practice. However, if all the patient needed was a vasoconstrictor and pressure (or maybe just pressure alone), why add all this other stuff? Personally, I don’t think this is a major weakness of the paper.

There is something incredibly different about this population than the patients I see with epistaxis. 45% of these patients were admitted to hospital! That is an insanely high number. (Remember that patients with hemodynamic instability, cancer, and hemophilia were excluded.)  I have only admitted a handful of epistaxis patients in my entire career, and we see epistaxis almost every shift. The patients here don’t seem to be any sicker than my patients, with only 2% requiring transfusions. I honestly don’t understand why so many of these patients are being admitted, and that makes it very hard to extrapolate this data to my own patients. It is incredibly rare not to be able to stop the bleeding with one of the many available anterior packing devices. It is also very rare for patients to bleed enough to become symptomatic or require transfusions. If the bleeding is stopped and the patient is fine, what is the admission for? Hopefully some of our UK colleagues can explain this in the comment section. (Edit: It sounds like the admission rate is the result of a combination of traditional practice and the 4 hour rule in the UK. Essentially, an anterior pack leads to admission there, whereas in Canada you get discharged home after the pack stops your bleeding. This is discussed in the twitter exchange below.)

Any thoughts on the 45% admission rate?
That is more than an order of magnitude higher than I see in my practice. I honestly don't understand it.

— Justin Morgenstern (@First10EM) February 20, 2021

The study was technically under-powered, as they based their power calculation on the assumption that 95% of patients would need an anterior pack, but only 45% received one. However, considering that the results were worse in the TXA group, it is unlikely that a lack of power is causing a type 2 error. Furthermore, there were more patients in the placebo group on anticoagulants, so TXA might actually be worse than we are seeing here. 

Although we think of TXA as a very safe medication (and it generally is), and there were no statistical differences here, adverse events were higher in the TXA group. Considering the lack of benefit, potential harms should drive our decision making, even if they are rare and mild. 

This evidence might be difficult to operationalize. I think we should follow the evidence. When treatments have no benefit, there can only be harm. But what are you going to do if there is ongoing bleeding? The ENT surgeon you call will almost certainly ask if you have used TXA, and if you haven’t they will tell you to try it a shot before they come in. I care a lot about evidence based medicine, and spend a lot of time advocating for my patients in the face of specialist suggestions that run counter to the best science, but I am certainly not going to get into a fight about TXA. 

I think the biggest lesson comes from the placebo group. Sterile water prevented 55% of these patients from requiring an anterior pack. As a patient, I would want to do everything possible to avoid nasal packing. We can recreate placebo in real life with patience and ongoing pressure, and that might be a real value to our patients.  

Bottom line

In the highest quality trial to date, there was absolutely no value in using topical TXA in the management of epistaxis. 

Other FOAMed

REBEL EM: Topical TXA in Epistaxis

The NNT: In summary, for patients who received TXA to reduce the risk of rebleeding

Other TXA evidence

The CRASH-2 trial (a review)

CRASH 3: TXA is no wonder drug

3 misunderstandings about WOMAN (TXA in postpartum hemorrhage)

TXA in ICH (TICH-2)

TXA for GI bleeds: No benefit (The HALT-IT trial)

TXA in traumatic brain injury – a quick update

References

Atabaki P, Samarei R, Aribi MS, Soheili A, Mehryar HR. A comparative study on the effect of topical phenylephrine with topical tranexamic acid in management of epistaxis. Journal of the Urmia Nursing and Midwifery Faculty 2017; 15(7):488–96.

Joseph J, Martinez-Devesa P, Bellorini J, Burton MJ. Tranexamic acid for patients with nasal haemorrhage (epistaxis). The Cochrane database of systematic reviews. 2018; 12:CD004328. [pubmed]

Petruson B. A double blind study to evaluate the effect on epistaxis with oral administration of the antifibrinolytic drug tranexamic acid (Cyklokapron®). Acta Otolaryngologica 1974;77(Suppl 317):57‐61.

Reuben A, Appelboam A, Barton A, Vickery PJ, Body R, Hilton M, Coppell J, Ewings P. Novel use of tranexamic acid to reduce the need for Nasal Packing in Epistaxis (NoPac) randomised controlled trial: research protocol. BMJ Open. 2019 Feb 15;9(2):e026882. doi: 10.1136/bmjopen-2018-026882. PMID: 30772866

White A, O’Reilly BF. Oral tranexamic acid in the management of epistaxis. Clinical otolaryngology and allied sciences. 1988; 13(1):11-6. [pubmed]

Zahed R et al. 2013. A new and rapid method for epistaxis treatment using injectable form of tranexamic acid topically: a randomized controlled trial. Am J Emerg Med. 31(9):1389-92. PMID: 23911102