Dr. Zach Cost and Dr. Tem Bendapudi join the show to discuss the literature pertaining to tranexamic acid and thromboembolic risk.
Dr. Zach Cost is an anesthesia resident at the Massachusetts General Hospital. Dr. Pavan (“Tem”) Bendapudi holds a joint faculty appointment in the Division of Hematology and Blood Transfusion Service and is assistant professor of medicine at Harvard Medical School.
This podcast was recorded as part of the Depth of Anesthesia podcast elective.
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Music by Stephen Campbell, MD.
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References
CRASH-2 trial collaborators; Shakur H, Roberts I, Bautista R, Caballero J, Coats T, Dewan Y, El-Sayed H, Gogichaishvili T, Gupta S, Herrera J, Hunt B, Iribhogbe P, Izurieta M, Khamis H, Komolafe E, Marrero MA, Mejía-Mantilla J, Miranda J, Morales C, Olaomi O, Olldashi F, Perel P, Peto R, Ramana PV, Ravi RR, Yutthakasemsunt S. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet. 2010 Jul 3;376(9734):23-32. doi: 10.1016/S0140-6736(10)60835-5. Epub 2010 Jun 14. PMID: 20554319.
Henry DA, Carless PA, Moxey AJ, et al. Anti‐fibrinolytic use for minimising perioperative allogeneic blood transfusion. Cochrane Database of Systematic Reviews. 2011;(1). doi:10.1002/14651858.CD001886.pub3
Ker K, Edwards P, Perel P, Shakur H, Roberts I. Effect of tranexamic acid on surgical bleeding: systematic review and cumulative meta-analysis. BMJ. 2012;344:e3054. doi:10.1136/bmj.e3054
Myles PS, Smith JA, Forbes A, et al. Tranexamic Acid in Patients Undergoing Coronary-Artery Surgery. New England Journal of Medicine. 2017;376(2):136-148. doi:10.1056/NEJMoa1606424
Devereaux PJ, Marcucci M, Painter TW, et al. Tranexamic Acid in Patients Undergoing Noncardiac Surgery. New England Journal of Medicine. 2022;386(21):1986-1997. doi:10.1056/NEJMoa2201171 POISE 3 PeriOperative ISchemic Evaluation-3 (POISE-3) study
Shakur H, Roberts I, Fawole B, et al. Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum hemorrhage (WOMAN): an international, randomized, double-blind, placebo-controlled trial. The Lancet. 2017;389(10084):2105-2116. doi:10.1016/S0140-6736(17)30638-4
Roberts I, Shakur-Still H, Afolabi A, et al. Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-controlled trial. The Lancet. 2020;395(10241):1927-1936. doi:10.1016/S0140-6736(20)30848-5
Taeuber I, Weibel S, Herrmann E, et al. Association of Intravenous Tranexamic Acid With Thromboembolic Events and Mortality: A Systematic Review, Meta-analysis, and Meta-regression. JAMA Surgery. 2021;156(6):e210884. doi:10.1001/jamasurg.2021.0884
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AI-Generated Transcript
David Hao
Welcome back to Depth of Anesthesia. This is a podcast that critically explores our clinical practices. I’m David Hao, and I’m an anesthesiologist at the Massachusetts General Hospital. Our first guest today is Dr. Zach Cost. Dr. Cost is an anesthesia resident at Mass General. He’s a graduate of the Tufts University School of Medicine Main Track Program, and he recently completed the Depth of Anesthesia podcast elective. Zach, thanks for all your work on the elective, and welcome to the show.
Zach Cost
Oh, thank you, Dr. Hao. I’m excited to be here.
David Hao
And our second guest is Dr. Bendapudi. Dr. Bendapudi completed an internal medicine residency at Mass General where he developed an interest in bleeding and clotting disorders. This led him to pursue additional training in blood bank and transfusion medicine as well as adult hematology through the Harvard Combined Fellowship Programs. He currently holds a joint appointment in the division of hematology and blood transfusion service and is an assistant professor of medicine at Harvard Medical School. Dr. Bendapudi’s research focuses on the biology of the coagulation system and ways in which bleeding and clotting disorders impact human health. Dr. Bendapudi, welcome to the show.
Tem Bendapudi
Thanks so much for having me.
David Hao
So, our case for everyone today is that of a 65-year-old woman who has a history of hypertension, hyperlipidemia, and remote lower extremity deep venous thrombosis after surgery who’s undergoing a total hip arthroplasty. After inducing general anesthesia, the resident starts to draw up tranexamic acid. The attending anesthesiologist observes this and comments that TXA should probably be held in this case because of this patient’s prior DVT history. Zach, what are some of the claims in this case?
Zach Cost
Well, I think the first claim is that TXA increases the risk of thromboembolic events. And then the second claim would be that it’s contraindicated in patients at increased risk, for or with prior history of thromboembolic events.
David Hao
So here now are two questions for our listeners to consider. What is the level of your agreement with the claim that TXA increases the risk of thromboembolic events and that it is contraindicated in patients at increased risk for or with prior history of thromboembolic events. And what is the level of evidence for what you believe? Zach, how’d you get interested in exploring this subject and why did you end up picking this for the elective?
Zach Cost
Well, I’ve always found hemostasis really interesting. I appreciate how the biochemistry is directly applicable to our interventions, and it’s relevant to almost every field of medicine. TXA is a great example of this. I remember first learning about it during medical school, and I thought it was the perfect drug. It seemed simple and safe, had an elegant mechanism of action, and a growing list of indications. But as I’ve advanced in my training, I’ve heard more and more about the risk of thrombosis, and I’ve been wondering how warranted this is.
David Hao
Yeah. So, I’m glad we’re looking into that. And you mentioned this elegant mechanism. Tim, could you tell our listeners a little bit about how exactly TXA works?
Tem Bendapudi
Sure. TXA or tranexamic acid is a hemostatic agent that was, invented probably about 60 to 70 years ago. And so, it’s been around with us for a long time. What it does is it functions if you look at the structure, it looks a lot like the amino acid lysine, and it functions as an inhibitor of plasminogen, which as you all know is one of the major, fibrinolytic enzymes in the body. Plasminogen actually has to bind to a clot in order to lysate, and the mechanism by which plasminogen does that binding is through lysine residues on the surface of the fibrin clot. So, you can understand how having a lysine analog floating around in high concentration could compete with those lysines on the surface of the fibrin clot, for plasminogen binding. And that’s exactly how it functions.
It’s a competitive inhibitor of plasminogen binding to the fibrinogen clot to the fibrin clot.
David Hao
Perfect. And you mentioned that it was discovered or developed almost 6 years, 7 years ago. And, Zach, I know you have a little bit more about the history there.
Zach Cost
Yeah. So TXA was discovered in Japan in the 19 sixties by a husband and wife, physician scientists, Drs. Utako and Shosuke Okamoto. They were researching treatments for postpartum hemorrhage, which was a major cause of death of women in Japan at the time. And Dr. Itako Okamoto began her career actually researching the cerebellum, but in post-World War 2 Japan, resources were scarce, and she reckoned that research on blood could be done easily. She actually used blood drawn from her own veins as a lab sample. And in 1962, they reported the invention of a new chemical entity called Amino Caprylic acid. Later, they developed a much more potent form of the drug, tranexamic acid.
Unfortunately, she faced a lot of sexism in her career, and they had difficulty convincing obstetricians to use TXA. So, the full potential of the drug would not be recognized for decades.
David Hao
So, the focus of our episode will be on the risk of thromboembolic events. But before we dive in, are there any other adverse events that our listeners should know about or consider when using this agent?
Zach Cost
Yeah. So, some of the other notable adverse events include hypersensitivity reactions and seizures. Interestingly, tranexamic acid is also structurally similar to the amino acid and inhibitory neurotransmitter, glycine, and acts as a competitive antagonist at glycine and GABA a receptor, which might explain why it’s been associated with an increased risk of seizures.
David Hao
Perfect. And the risk profile as it pertains to seizures is something that we’ll talk about as we get into the primary literature very soon. Zach, do we have any idea of where some of these concerns for thromboembolic events actually originate from?
Zach Cost
Well, I think it’s, fair to start with the FDA label, which has a warning for a risk of thromboembolic events and advises against the concomitant use of prothrombotic agents including hormonal contraceptives. There have also been numerous case reports and observational studies that have reported an increased risk of thromboembolic events. There’s actually another antifibrinolytic agent with a different mechanism of action, aprotinin, which is a serine protease inhibitor that was pulled from the market due to increased rates of cardiovascular events and death. And then I also think part of it is the concern it’s more of a theoretical risk that as an antifibrinolytic drug, TXA may allow clots to propagate. Dr. Bendapudi, could you shed any light on this and perhaps explain the difference between prohemostatic agents and prothrombotic agents?
Tem Bendapudi
Sure. I think this is largely just a matter of the words that we choose to apply to specific agents that we use when patients are bleeding. A number of drugs have been attempted to affect the medical management of hemorrhage. So obviously that means management of bleeding that doesn’t involve surgical intervention. And some agents like recombinant factor 7 a, which kinda had its heyday in the early 2000 as a potential hemostatic agent, actually turned out to be quite thrombogenic and, had minimal, if any, detectable pro hemostatic effect. So, when it was used off label, I should add, in a non-hemophiliac population. So, I think in that kind of situation, you’re really talking about a prothrombotic agent rather than a prohemostatic agent.
When you are referring to TXA or Amicar, you’re talking about drugs with a much, much wider therapeutic window. In fact, arguably with respect to thrombosis, almost no signal for that, which of course we will discuss in a little bit more detail. And there you would really kind of talk about this more as a pro hemostatic agent. I just also wanted to quickly touch on something Zac just mentioned about TXA and Amicar versus aprotinin. Aprotinin was a hemostatic agent that was also a plasmid inhibitor that, was associated with a thrombotic signal and was removed from the market many years ago. I believe it is now available for select indications, but I don’t believe we actually carry it at our institution. And I did wanna note that these are very, very different drugs.
TXA and Amicar are, as we discussed lysine analogs that passively block the binding of plasminogen to the fibrin clot so that it can’t work on the fibrin clot and lice it. However, aprotinin is actually a serine protease inhibitor. It actively blocks the proteolytic or enzymatic activity of not just a plasmin, but of numerous other serine proteases. So, it’s actually not totally understood that the, prothrombotic effects of a protein, which were detected several years ago are really due to its effect on, plasmin and could be due to its inhibition of other serine proteases that are really important to preventing thrombosis in in our kind of coagulation system.
David Hao
I think that’s awesome background, and it’s definitely super to hear about some of the mechanisms and differences between the various agents. There have been trials in the perioperative space since at least 1972 that look at the effects of TXAM on bleeding. But we know that most of these trials were small, probably not well designed, and many of them did not report mortality or thromboembolic data. So, I think it’s appropriate that the first trial we talk about is the landmark CRASH 2 trial. So clinical randomization of an antifibrinolytic insignificant hemorrhage. This was the largest TXA trial at the time and was part of, what led to the inclusion of TXA ultimately in the World Health Organization’s list of essential medicines. Zach, what can you tell us about the study?
Zach Cost
Yeah. So, this was a randomized double-blind placebo-controlled trial undertaken in 274 hospitals in 40 countries, including over 20,000 adult trauma patients with or at risk of significant bleeding. Approximately half of these patients ultimately underwent surgery. Patients were randomly assigned within 8 hours of injury to either a TXA, a loading dose of 1 gram over 10 minutes, and an infusion of 1 gram over 8 hours, or a matching placebo. At 28 days, all-cause mortality was significantly reduced with TXA, 14.5% versus 16% in the placebo group. This was a relative risk of 0.91 with an absolute risk reduction of 1.5%. There were 33 deaths in the tranexamic acid group versus 48 in the placebo group from vascular occlusion.
Breaking this further down, there is 7 versus 22 deaths from myocardial infarction, 8 versus 5 from stroke, and 18 versus 21 from pulmonary embolism, respectively. Including nonfatal events, vascular occlusive events did not differ significantly. There was 1.7% of patients with 1 or more vascular occlusive events in the TXA arm and 2% in those allocated to placebo. And this came down to a p value of 0.084. So almost statistically significant. Definitely a trend there. And there was a statistically significant decrease in non-fatal MIs among the TXA group with a p value of 0.035.
David Hao
Okay. So, a reduction in all-cause mortality and when including nonfatal and fatal vascular occlusive events, there was no difference between groups except for less nonfatal MIs with TXA. I imagine these numbers can change depending on how these events are classified and measured. Do you have any insights into that?
Zach Cost
Well, they did not specifically define how these events were assessed, but they did, provide a little commentary, and I’ll quote the authors here. We sought high specificity in the diagnosis of nonfatal vascular occlusive events and stipulated that occlusive events should be recorded only when there is clear clinical evidence. As a result, we might have underreported the frequency of these events.
David Hao
Got it. So, there’s some acknowledgment from the authors about that as a potential concern. Tim, any other thoughts about this this, pivotal trial?
Tem Bendapudi
Oh, yeah. I think this was, just really a seminal, study, and it’s become such a part of, trauma management, both military trauma management and also trauma management outside the military at this point that it’s often easy to forget how really groundbreaking it was to find a medicine, a medical therapy that actually reduced mortality in trauma patients. And so, I think, you know, this is a this is a major, you know, was just, as you said, a landmark study and really something that I think anyone who helps to take care of trauma patients, should know about. David, there’s actually one other thing I wanted to mention about the CRASH 2 trial, which I think is of interest. As Zach kind of alluded to, there is a trend towards, if anything, decreased thromboembolic risk in patients with, patients who receive TXA in that trial.
So, p value is like 0.08. So, it’s something that we really, I think, need to be thinking about. Why is it that patients who are getting TXA in a trauma setting might actually be doing better from a VTE standpoint, fewer clots. And one thing that people have theorized is that folks who are receiving TXA in this setting or randomized to receive TXA in this setting have less bleeding, less need for reoperation, and are actually able to get out of bed, work with PT, and get out of the hospital sooner, which are all, as we all know, factors that contribute to suppressing the risk of, developing a VTE. So, I think that’s a really fascinating thing to kind of speculate about. Again, not proven in any way in the study, but certainly a hypothesis that should be explored as to why we may have a paradoxical improvement in thromboembolic outcomes in at least some populations receiving antifibrinolytic therapy.
David Hao
So, with this trial and the subsequent enthusiasm, you know, in terms of using tranexamic acid, there were a number of studies that were subsequently done looking at antifibrinolytic drugs. Ultimately, this culminated in a Cochrane systematic review that was published in 2011 that I do think is worth going over. Zach, what are your thoughts about this?
Zach Cost
Yeah. So, this Cochrane review investigated, antifibrinolytic use, for minimizing perioperative allogeneic blood transfusion. And I actually looked at 3 different drugs, all the drugs we’ve spoken about today, TXA, Aprotinin, and Amicar, and it included 252 randomized control trials with over 25,000 participants. And we’ll focus on TXA for the sake of this podcast. There are 65 trials that compare TXA with control. 34 of these were in cardiac surgery, 27 involved orthopedic surgery, 2 involved liver surgery, and 1 with vascular surgery, and 1 involved gynecologic surgery. The doses of TXA varied significantly between the trials.
The use of TXA significantly reduced the need for allergenic blood transfusion by a relative 39%, and this was statistically significant and represents an absolute risk reduction of 18%. 21 of the trials, looked at data for myocardial infarction, and they did not find that is associated with an increased risk of MI. There’s a trend towards a decreased risk, but it was not statistically significant. 18 trials looked at stroke. There this was not statistically significant association. 23 of the trials, looked at DVT, and there did not appear to be an association between TXA and the risk of developing a DVT. And 14 of the trials reported data for pulmonary embolism.
And again, there did not appear to be an increased risk of pulmonary embolism. There’s actually a trend towards a decreased risk.
David Hao
I’m glad the authors take time to acknowledge that, underreporting of uncommon events like thromboembolic conditions is a potential problem. These events were not the primary outcomes and many of these trials were small. But with what we have, this review suggests that based on the included trials of TXA, there does not seem to be a signal for increased risk of myocardial infarction, stroke, deep vein thrombosis, or pulmonary embolism. Before we get any further, Zach, I remember you mentioned that there’s a close relationship between aminocaproic acid and tranexamic acid. And, Tim, I’m wondering if you could provide some insight into how to think about these two medicines.
Tem Bendapudi
That’s a great question, David. You know, we often use TXA and Amicar kind of interchangeably. They’re both lysine analogs that, as we mentioned earlier, function by passively blocking or competitively inhibiting the binding of plasminogen to cross link fibrin clot. However, they’re not exactly the same drug. An important thing to keep in mind is that TXA is somewhere between 10 to 20 times more potent than Amicar. Gram for gram or milligram for milligram. So, it’s one of the reasons you’ll see the dosing really different.
The dosing of the 2 drugs is really quite different. A second thing that, we think a lot about on the hematology side, maybe a little bit less important to anesthesiologist, is that the PO bioavailability is different.
So, Amicar is about a 100% PO bioavailable. So, if you just give it orally, patient will get extension whatever dose you’re giving them. Whereas TXA is more like about a third bioavailable. So, this has implications for people we like to treat kind of as an outpatient or, using PO medications because even though it’s less, orally bioavailable, TXA still is so much more potent that you could give a lot more orally than you can for Amicar, and that’s another, important distinction that we have. So, I will just say, you know, kinda to close out this comment to say that the fact that TXA is so much more potent than Amicar has also led to many more studies being done of TXA than Amicar. And so, I think, in general, you will see the literature, focus on TXA, but we often extrapolate those results to Amicar.
David Hao
Zach, it looks like this Cochrane review was followed, just about a year later by a systematic review and meta-analysis published in the BMJ that included almost double the number of trials and specifically compared tranexamic acid with no tranexamic acid or placebo in surgical patients. Could you tell us a bit more about this review?
Zach Cost
Yeah, David. Like you said, this systematic review included almost double the number of trials. There were 129 trials totaling over 10,000 patients carried out between 1972 and 2011. Tranexamic acid reduced the probability of receiving a blood transfusion by a third. The risk ratio is 0.62, which was almost identical to the Cochrane review we just discussed that had a 0.61. And the effect of TXA on myocardial infarction, stroke, and DVT and pulmonary embolism, the authors describe as uncertain,
David Hao
Yeah.
Zach Cost
Yeah. I think the biggest weakness is the quality of the data. The number of studies included in this review is almost double that of the Cochrane review we just discussed, but it seems to be that they may have increased their sample size at the cost of lower quality trials. Mortality data was only reported in 1 third of the included trials, and less than half reported data on myocardial infarction, stroke, DVT, or pulmonary embolism. They ultimately reached out to the trial authors and were able to obtain some missing data to include, mortality data for 3 quarters of the trials and data on, thromboembolic events for half of the trials.
David Hao
Got it. So, it sounds like this systematic review and meta-analysis of a 129 RCTs show that TXA reduced the probability of receiving a blood transfusion by about a 3rd. And while there was no statistically significant effect on thromboembolic events, the effect ultimately does remain uncertain. Tem, anything else you wanna add here?
Tem Bendapudi
No. I mean, I think this is a good point. These are all good points. And, I would only add just to what you were already saying, which is that, you know, this is a drug that’s been around for 60 years. There are a lot of trials that have been done. One of the later meta-analysis that we’ll probably discuss cover almost 200 different trials of tranexamic acid. And so, you’ll expect that a lot of the trials if you’re familiar with, for example, clinical literature from the 19 sixties seventies and even eighties, it’s very common to have clinical trials being published in big journals that are, you know, in the dozens of people, maybe a 100 or 2.
And so, I think it’s a very well taken point that some of the studies that were included in in some of these meta-analyses could be of lower quality and shouldn’t necessarily trump, the results of 1 or 2 extremely large, well designed, well conducted trials. And I think the authors of most meta-analyses attempt to wait for that, so it normally comes out okay. But it’s just something to keep in mind.
David Hao
Alright. So, we’ve discussed some systematic reviews that have now taken us through the kind of the state of the literature up to around 2,012. Zach, I know we’re going to head into some studies that have actually looked at specific subpopulations to explore the potential link a little bit further here. So, after these systematic reviews were published in 2012, have there been any high impact RCTs in the perioperative population subsequently?
Zach Cost
Yeah. There are 2 large RCTs published the last 5 or 6 years. One in the cardiac surgical population, the results of the Atticus trial, which stands for aspirin and TXA in coronary artery surgery, and the other in the non-cardiac surgical population, the POISE 3 trial, which is the perioperative ischemic evaluation trial. We can talk about the first one, which was published by Biles et al in New England Journal of Medicine in 2017, and this is the results of the TXA arm of the Atticus trial. And there’s a multicenter, double-blind trial with a 2 by 2 factorial design in which patients were randomly assigned to receive TXA or placebo and aspirin or placebo. Eligible patients included adults who were at increased risk for major complications related either to age or coexisting conditions, and who are about to go undergo on pump or off pump coronary artery surgery with or without cardiac valve replacement or other procedures. Over 4,600 patients were enrolled at 31 sites and in 7 countries.
Notably, patients with previous thromboembolic disease, as well as patients who are pregnant were excluded. The TXA dose was a 100 milligrams per kilogram, and it was administered intravenously more than 30 minutes after induction. However, there were increased reports of seizures that were thought to be dose dependent. So, the dose of TXA was reduced to 15 milligrams per kilogram after the first 1500 patients were enrolled. Notably, they encourage blinding of the trial drug preparation but allowed the attending anesthesiologist to prepare the drug if research personnel were not available.
David Hao
So random assignments to TXA or placebo and aspirin or placebo for patients at increased risk for complications going for on pump or off pump coronary artery surgery. It sounds like the TXA was given 30 minutes after induction, but then this dose was changed after the first 1500 or so patients out of more than 4,000 total, because of concerns about seizures that was thought to be dose dependent. What was the primary outcome here?
Zach Cost
The primary outcome was death or thrombotic complications within the first 30 days after surgery. This occurred in 16.7% of patients in the TXA arm and in 18.1% in the placebo group. This was a relative risk of 0.92 and was not statistically significant. Rates of death, stroke, pulmonary embolism, MI, and bowel infarction were similar in the two groups or individually not statistically significant either. The tranexamic acid group had a statistically significant lower rates of the following bleeding related outcomes. The number of units of red cells and other blood products that were transfused, the number of patients who required transfusions, and the number of patients who required reoperation for hemorrhage or tamponade. Notably, seizures occurred in 0.7% of the patients in the TXA arm compared to only 0.1% in the placebo arm.
David Hao
So, a couple of things I want to point out here. It it’s important to keep in mind that there were key exclusions here. So, patients with a history of postoperative or spontaneous pulmonary embolism, spontaneous arterial thrombosis, or familial hypercoagulability would have been excluded but interestingly, our patient that we discussed at the top of the show with the post op DVT would actually have been eligible. Also, the composite outcome of death and thrombotic events does help us answer the question of fatal thromboembolic events, but it does make it difficult to assess if TXA increases the risk of non-fatal thromboembolic events, if it also decreases the risk of death kind of through an independent mechanism here. So, it sounds like what we have is a large, multicenter, mostly double blind, placebo-controlled trial that showed there’s no evidence that TXA increases the risk of death or thrombotic complications after coronary artery surgery, trending towards actually a decreased risk. TXA was ultimately associated with a lower risk of bleeding complications, including need for transfusion and reoperation compared to placebo, but here, we are starting to see signal of a higher risk of postoperative seizures, which, Zach had discussed was a potential complication of TXA administration.
Tem Bendapudi
So, I did wanna comment briefly on the issue of seizures, especially in the Miles trial, the one that you’re referring to cardiac surgery trial with TXA, there was a small but statistically significant increase in, seizures that were clinically detected. And I wanna bear to keep this in mind is that these are seizures that were not really confirmed by EEG but were just viewed to have occurred clinically. And I think the authors are very circumspect in how they discuss this. They do point out that seizure and stroke is very common in post cardio cardiopulmonary bypass pay, patients in general. And I would also, just point out as well that there was no impact on long term outcomes from, these post op seizures, which seem to be isolated self-limiting events. Not trying to downplay the importance of the potential importance of these events, but I think the potential importance itself is not truly understood, particularly from this trial. The reduction in dose that occurred during this trial, so about halfway through the trial, they were noticing these events.
They dropped the dose to up from a 100 milligrams per kilo to 50 milligrams per kilo. And in the post hoc analysis, they did not notice any difference in the seizure rate before and after the dose change, which is kind of interesting. This was a very high dose of TXA that was used in this trial. For a 70-kilogram person, it comes out to be about 7 grams. That said I mean, at the higher dose, at the at the 100 milligrams per kilo dose. That said, I will say that other trials have, reproduced similar findings of clinical seizure in patients getting TXA, particularly higher dose TXA. So, it’s something to be aware of, particularly in the anesthesia world, because these are, generally happening, in the post in the PACU setting.
And it is something to be aware of, but the clinical importance is, still to be determined.
David Hao
Well, put. I’m glad you mentioned the dose aspect of this study because it’s an important consideration as we continue through many of these manuscripts. To put this into clinical context for joint arthroplasty, we’ll use 1000 milligrams IV at the start of the case and 1,000 milligrams IV at the conclusion. So that comes out to something like 30 milligrams per kilogram for a 70-kilogram patient. And that’s certainly something we have to keep in mind here.
Tem Bendapudi
Exactly. The dosing is very different. And if it isn’t dose dependent, that would or just it’s just an idiosyncratic, event that occurs in some people who see the drug, you know, of course, that’s very different than something that is that’s, you know, just dose dependent with the drug.
David Hao
Absolutely. So, Zach, that was the Atticus trial, and I know the second one you have is the POISE 3 trial. Right?
Zach Cost
Yes. The POISE 3 trial looks at TXA in patients undergoing non cardiac surgery. And this was published by Devereux et al in the New England Journal of Medicine in just 2022. So, this is another multicenter randomized, placebo-controlled trial with partial factorial design, like the Atticus trial we just discussed. But this was a non-inferiority trial. They included almost 10,000 patients aged 45 or older and at 114 hospitals in 22 countries. Patients were undergoing inpatient non cardiac surgery and were at risk for bleeding and cardiovascular complications according to criteria previously associated with perioperative bleeding and cardiovascular complications.
For example, atherosclerotic disease, undergoing major surgery, age greater than 70, etcetera. Patients were excluded if they were undergoing cardiac surgery, obviously, but also if they’re undergoing intracranial neurosurgery. Additionally, exclusion criteria included a history of seizure or thromboembolic events in the last 3 months. This was a 2 by 2 factorial design in patients who are receiving at least one long term antihypertensive medication to evaluate a hypotension avoidance strategy as compared with a hypertension avoidance strategy. And these patients were assigned in a one to 1 ratio to receive tranexamic acid, 1 gram IV bolus, or placebo at the start and end of the surgery.
David Hao
I’m just gonna take a moment to summarize here. So, they wanted to look at the effects of TXA compared to placebo in non-cardiac surgery. The partial factorial design allowed them to answer multiple questions in the same study and look at potential interactions, in this case, hypotension avoidance or hypertension avoidance strategies. They chose to look specifically at patients at risk for bleeding and cardiovascular complications. And I’ll point out that on top of the exclusion criteria Zach discussed, the study also excluded patients if a physician planned to administer systemic TXA during surgery or if the patient had a creatinine clearance of less than 30 ml’s per minute or was receiving long term dialysis. Alright, Zach.
What was the primary outcome?
Zach Cost
Primary efficacy outcome was a composite of life-threatening bleeding, major bleeding, and bleeding into a critical organ, which we’ll call the composite bleeding outcome at 30 days after randomization. The primary safety outcome was myocardial injury, non-hemorrhagic stroke, peripheral artery thrombosis, or symptomatic proximal vein thromboembolism, which they call the composite cardiovascular outcome at 30 days. The non-inferiority hypothesis was evaluated in the per protocol population, but all other analyses data were analyzed in the intention to treat population. The composite bleeding outcome occurred in 9.1% in the tranexamic acid group and an 11.7% in the placebo group. This corresponded to a hazard ratio of 0.76, which was statistically significant and an absolute difference of negative 2.6 percentage points. The composite cardiovascular outcome occurred in 14.2% of the patients in the TXA group and 13.9% in the placebo group. This resulted in a hazard ratio of 1.02 with a confidence interval of 0.92 to 1.14.
To satisfy the non-inferiority hypothesis, the upper boundary of the one-sided 97.5% confidence interval, which corresponds to an upper boundary of the 2 sided 95% confidence interval, had to be below 1.125. This would correspond to a relative increased risk of 12.5%, which was actually kind of a somewhat subjective number. And we could spend some time discussing it, but non inferiority was not shown, so I don’t think we need to discuss it further.
David Hao
And, Zach, just to quickly clarify, they the composite cardiovascular outcome was their primary safety outcomes. That included all things like myocardial injury, stroke, thrombosis, peripheral artery thrombosis, and symptomatic proximal venous thromboembolism. So, they looped that all into the composite cardiovascular outcomes. Is that correct?
Zach Cost
Yep. That’s correct. And it seems pretty similar to the composite thromboembolic outcomes we’ve seen in other studies.
David Hao
Okay. Perfect. I wanna take a pause here to go over some of the non inferiority concepts that you’ve discussed. I know that you, Tim, and I spent some time talking about what this all means, so I think it’s worthwhile for our listeners if you could potentially go over it again. Yeah.
Zach Cost
I found this concept tricky the first time I read it as well in the paper. But basically, the authors wanted to show, non-inferiority of TXA to placebo with regards to this composite cardiovascular outcome, really, thromboembolic events. And to do that, they wanted their confidence interval to be less than a one point 125, meaning that they’d be willing to accept an increased risk of 12.5% as being non inferior. But their confidence interval went all the way up to 1.14 saying that basically with 95% confidence that there is up to a 14% increased risk of this composite cardiovascular outcome. So, they weren’t able to prove their non inferiority.
David Hao
Okay. So based on all these, they were not able to establish non inferiority of tranexamic acid compared to placebo with respect to the composite cardiovascular outcome, which includes myocardial infarction, non-hemorrhagic stroke, peripheral arterial thrombosis, or symptomatic proximal venous thromboembolism. If a study fails to establish noninferiority, it means that the new treatment did not demonstrate effectiveness comparable to the standard treatment within the predefined margin of noninferiority. In other words, there is evidence that the new treatment may be inferior to the standard treatment by an amount that’s considered clinically relevant.
Zach Cost
Yes. That that’s correct. And I’ll actually read a quote from the authors that I think kinda makes it a little more clear. They write that health care providers and patients will have to weigh a clear beneficial reduction in the incidence of a composite bleeding outcome with an absolute difference of negative 2.6 percentage points against the low probability of a small increase in the incidence of the composite cardiovascular outcome, which only showed an absolute difference of 0.3 percentage points.
David Hao
Awesome. So, to summarize, it sounds like we have an international double blind randomized placebo-controlled trial among patients undergoing non cardiac surgery who are at risk for bleeding and cardiovascular events, And the incidence of the composite bleeding outcome was significantly lower with TXA than with placebo. And although the between group differences in the composite cardiovascular outcome was small, the non-inferiority of tranexamic acid was not established. So that takes us through the cardiac surgical population, the non-cardiac surgical population. And I know the next trial that you’re gonna talk about is actually specifically in women. Is that right?
Zach Cost
Yeah. It’s in, the obstetric population. It’s the WOMAN trial, which, stands for the World Maternal Antifibrinolytic Trial. It was published by Shaker et al in Lancet in 2017. Included 20,000 women actually, over 20,000 women aged 16 years or older with a clinical diagnosis of postpartum hemorrhage after vaginal birth or cesarean section from 193 hospitals in 21 countries. These women were randomly assigned to receive either 1 gram of IV TXA or matching placebo in addition to usual care. And if bleeding continued after 30 minutes or restarted, a second dose of 1 gram of TXA or placebo could be given.
Notably, they originally planned to enroll 15,000 women with a composite primary endpoint of death from all causes or hysterectomy within 42 days of giving birth. But I’ll quote the authors here, but they did have to increase their enrollment. And during the trial, it became apparent that the decision to conduct a hysterectomy was often made at the same time as randomization. Although TXA could influence the risk of death in these cases, it could not affect the risk of hysterectomy. We therefore increased the sample size from 15,000 to 20,000 women in order to estimate the effect of tranexamic acid on the risk of death from postpartum hemorrhage. So that primary outcome, the original primary outcome, the risk of death from all cause or hysterectomy, was not reduced in the TXA group with 5.3% of versus 5.6% in the placebo group. However, death due to bleeding was significantly reduced in women given TXA with 1.5% in the TXA group versus 1.9% in the placebo group with a risk ratio of 0.81, which was statistically significant.
The incidence of thromboembolic events, including pulmonary embolism, DVT, myocardial infarction, and stroke did not significantly differ in the TXA versus placebo group. There were 30 thromboembolic events, 0.3 percent in the TXA group compared to 34 in the control arm, also 0.3%, which was not statistically significant.
David Hao
So, the incidence of thromboembolic events was not significantly different in the TXA versus placebo group. But like prior studies, there’s not much in the paper describing how these events were identified or measured. We do know that these outcomes were examined up to hospital discharge or day 42. Zach, any other concerns about the study?
Zach Cost
Well, I always find it a little concerning when trial has changed their primary outcome, and they did explain their reasoning. But the other thing that, I guess, concerns me is that they were able to show a reduction in death due to bleeding, but not from all-cause mortality. And I guess thinking through that, if you can reduce death from bleeding, but not reduce death from all cause, it makes me wonder if there is an increase in death, you know, or a harm from TXA.
David Hao
And, Tim, any other thoughts about this particular study?
Tem Bendapudi
No. I mean, I think those are great points. I would only add that death from bleeding is, by definition, a subjective outcome. And I can’t recall what you just said, Zach. Was this a double blinded trial, the woman trial? Yes. Yeah. So that does help.
But in any in any event, it’s a sub subjective outcome. And it is very hard to show in any of these sorts of trials an overall survival benefit because, especially in and as you all both know very well, young people, mothers, can be very resilient. And actually, there are so many other things that can be done to intervene to prevent death from happening even if the patient is hemorrhaging that it is very hard to show an overall survival benefit, which I think is why they went after this more subjective outcome of death from bleeding. I personally don’t put a ton of stock in that outcome. You know, I think it’s nice, but I’ve seen other studies where it’s kind of used as a way to get around a more objective outcome measure. Of course, all that being said, I completely understand the difficulty of showing overall survival benefit in some of these studies.
David Hao
Excellent. So, we’ve now looked at 4 RCTs and 2 meta-analyses including trauma, surgical, and obstetric patients. And I think it’s fair to say they’ve been reasonably unimpressive with respect to suggesting an increased risk of thromboembolic events. This is, of course, within the context of the various limitations that we’ve discussed and some key exclusions like patients with a history of thromboembolism. Zach, to your knowledge, are there any trials that have suggested an increased risk?
Zach Cost
Yes. There’s actually only one trial that I found, and that’s the HALT IT trial, which stands for hemorrhage alleviation with TXA intestinal system. It’s a little awkward to say. This was published by Roberts et al in The Lancet in 2020, and it was an international, multicenter, randomized, double blind, placebo-controlled trial in 164 hospitals in 15 countries that enrolled over 12,000 patients with significant, upper or lower GI bleeding. Eligible patients were randomly assigned to a loading dose of 1 gram of TXA or placebo, followed by an infusion or a maintenance dose of 3 grams of TXI or placebo over the course of 24 hours. Death due to bleeding occurred in 4% of both arms of the study and was not statistically significant.
Risk ratio is actually 0.99. And there was no statistically significant difference, in any other bleeding related outcomes, including endoscopy, IR procedures, surgical interventions, transfusions, or the number of units transfused. Arterial thromboembolic events occurred in 0.7% of patients in the TXA arm versus 0.8% in the placebo arm. However, venous thromboembolic events were higher in the TXA arm occurring in 0.8% versus 0.4%. And this was a relative risk of 1.85 and was statistically significant. In an exploratory subgroup analysis, the risk of VTE was higher in patients with variceal bleeding or liver disease. And I guess, only one other thing to point out here, because we’ve been talking about it a little bit throughout the podcast, Seizures occurred in 38 patients on the TXA arm and 22 patients in the placebo arm, which was statistically significant difference.
David Hao
Zach, any thoughts about the dosing and duration of TXA used in this trial?
Zach Cost
Yes. So, the dose used in this trial, 4 grams, and the duration over 24 hours was a higher dose and longer duration than in any of the other RCTs we just spoke about. So that that may contribute to some of these findings of increased, VTE.
David Hao
So, to summarize, we have an international randomized placebo-controlled trial that showed that TXA did not reduce the death from gastrointestinal bleeding but was associated with an almost twofold increased risk of venous thromboembolic events and seizures. And so, Tim, I’m wondering what thoughts you might have about this signal that we’re seeing here.
Tem Bendapudi
Yeah, David. I think that’s a great question. And it’s something that is worth focusing a little bit of attention on because the halted trial is really the only major study that’s been done, certainly in the modern era of TXA, that’s shown any signal for, thromboembolic events. You know, when we get into these kinds of situations, we often end up a little bit overinterpreting the data because this is one study. So, I just wanna take a step back and say, as we talked about earlier, there’s something on the order of 200 randomized controlled trials that have been done, of TXA. And so, to have 1 or 2 that show some signal for thrombosis might be just statistical noise or happening by chance. So, the statistical argument here is that if you adjust for multiple comparisons, which, you know, they’re they would have to do as a second because this is a secondary analysis, the p value for this would not be significant, for this finding would not be significant.
They look at, I think, 14 or 16 different secondary outcomes and found one that that did show a p value of a nominal p value of less than 0.05, which is this VTE outcome. But, again, that wasn’t adjusted for, multiple comparisons. Now that said, I don’t think we can just dismiss the idea that there may be something in this population that we need to know about that places them at higher risk for VTE when they receive an antifibrinolytic treatment. I think there’s a lot of speculation around what the clotting physiology of liver patients might look like, but I don’t think we have anything for sure that would tell us that, or a mechanism that would give us real clarity on why these patients had may have had a signal for increased VTE. So, I would interpret this finding with extreme caution. I think that it’s something that needs to be further worked up. In my own personal view, I think the paper, authors of the paper did not do a very thorough job of working up what the potential contributors and covariates that might be relevant to clotting in this population are.
I would have been very interested to have seen regression results looking at age, sex, ancestry, BMI, other known risk factors for thrombosis, as well as hospital length of stay to better understand who it was within the patients who received TXA, who are actually having these, thrombotic events. Because only with that kind of information can we gauge how seriously, to take this one finding out of, as I said, almost 200 randomized controlled trials.
David Hao
Perfect. I think those are very, helpful insights into how to place this trial in the greater context. I do think it’s worth commenting also that most of these studies have looked at thromboembolic events as secondary endpoints, and as we have seen several times already, these studies have been conducted in specific patient populations and sometimes they do exclude patients with a history of prior thromboembolism. So, Zach, I know you do have a study that actually looks at thromboembolic events as the primary outcome, and for me, this was the study that actually got me interested in this topic in the first place. So, I’m glad that we’re gonna finish on this.
Zach Cost
Well, this is a systematic review and meta-analysis, published in JAMA Surgery in 2021, and they included a total of 216 eligible trials with 125,000 patients, and this was across all medical disciplines. They systematically searched the Cochrane Central Register of Control Trials as well as MEDLINE, for RCTs published between 1976 and 2020. And as you’d imagine in a meta-analysis, the dose of TXA varied widely from 0.5 to 5 grams or from 10 to a 100 milligrams per kilogram. But their total thromboembolic events found, there was 2.1% in the group receiving TXA compared to 2% in the control group, and this was not a statistically significant difference. And also, when they broke it down for individual thromboembolic events such as venous thrombosis, pulmonary embolism, myocardial infarction or ischemia, and cerebral infarction or ischemia, none of these, even as individual outcomes, had a statistically significant difference. As a giant meta-analysis, they to assess for possible effect of study size or risk of bias, they conducted sensitivity analyses for the primary endpoint of thromboembolic events, and the results remained robust. Interestingly, they did a meta, regression for 143 interventional groups and I showed no association between the TXA dosing and the risk for venous thromboembolic events.
And most importantly to your point, when looking in patients with a history of thromboembolism who would be at high risk of future thromboembolism, they did not see an increased risk of any vascular occlusive event. And this was in 56 studies. Well, actually, only 49 assessed the thromboembolic events, but they did have a history of prior thromboembolism. And lastly, administration of TXA was associated with a significant reduction in overall mortality as well as bleeding mortality.
David Hao
A couple things again to point out here. So, some of these RCTs did exclude patients with increased risk of thromboembolism. Aside from the dose ranges, there’s also follow-up variation, which ranged sometimes from 24 hours to several months. So, it sounds like what we have here is a systematic review and meta-analysis of 216 studies suggesting that intravenous TXA, irrespective of dosing, does not seem to be associated with an increased risk of any thromboembolism. And in addition, when they look specifically at studies including patients with a history of thromboembolism, there was again no signal for increased risk for vascular occlusive events. Tim, anything you wanna add here?
Tem Bendapudi
Yeah. You know, I think this is a really nice meta-analysis that was done, and it is actually the study that I broadly use to guide my clinical practice with respect to TXA. And the reason for that is exactly what Zach just mentioned, which is, you know, when you have a huge body of science and of data out there on a topic, it’s really easy to get, as we discussed, to get a single trial that has maybe a signal in one direction or another and over interpret it kinda out of context. I feel like this the TABA meta-analysis is a very rigorously done project that really brought in pretty much all of the relevant trials they could find, covering over a 100000 people in many decades. And you would expect that they would have been able to identify if there was a significant risk of increased thrombosis, they would have been able to identify it. Of course, keeping in mind the caveats, David, you mentioned that a lot of these studies did exclude people who might have been perceived to be at higher risk for thromboembolism. And they actually did detect, differences in, improvements in, as you said, mortality and bleeding as well as, I believe, if I remember correctly, transfusion requirement as well in patients who receive TXA, which suggests that the analysis is robust.
They did it wasn’t like they didn’t see anything anywhere. They actually did see signals for things that we think TXA is actually doing. I would also like to address briefly this idea that, you know, what the inclusions and exclusion criteria for these studies are. I agree that many studies did exclude patients perceived to be at higher risk for, thrombosis. But as a hematologist, I can’t get around the fact that these studies are inherently many of them are inherently evaluating patients at extraordinary risk for VTE. Trauma patients, peripartum patients, patients undergoing surgery. And the fact that even with these extraordinarily high-risk populations, especially if you think about it, you know, cardiac surgeries, they’re not just go undergoing surgery.
They’re actually elderly folks for the most part undergoing surgery who should have very high risk for VTE. The fact they’re not seeing clearly elevated risks of VTE with TXA, to me, is very reassuring.
David Hao
Well said. I think as you mentioned, we have to contextualize the findings of individual trials in the greater body of literature. We have to consider key strengths and limitations, and I appreciate your insights into how to think about all this data and how to put it all together.
Tem Bendapudi
So, on the point of how I how I think about thrombosis risk in in patients receiving antifibrinolytic therapy, another, point I would raise is there is a condition of severe congenital plasminogen deficiency that has been described. It’s quite rare, but it’s out there. And it’s been pretty well characterized. These are folks who are essentially are born they’re born without plasminogen, so they’re essentially on lifelong high dose TXA. And what’s very remarkable is that they do not develop, VTE. These folks do not appear to have a higher risk of venous thromboembolism. They develop, ligneous conjunctivitis, which is this condition where people get accumulations of fibrin depositions in their eyes, in their conjunctiva.
They can get gum disease. They have other manifestations, but they do not actually get a significantly increased risk of VTE. So, I do think there is some value to considering the kind of biologic correlate and the implications of that phenotype as well.
David Hao
That’s fascinating and certainly an interesting correlate to consider.
Zach Cost
So, David, another thing I wanted to add about the WOMEN trial is we talked earlier about how the FDA listed hormonal contraceptives as a contraindication to concomitant use of TXA. And I think it’s interesting the women trial included women who were peripartum or postpartum who I from my understanding, I think are at an increased risk of VTE compared to even being on a hormonal contraceptive. And if they didn’t see any, you know, evidence of harm there, then I can’t imagine there’d be evidence of harm in women on oral contraceptives. Tem, do you have any thoughts on this?
Tem Bendapudi
No. I think that was very well put, and I think something that often gets lost in the discussion is just how high risk the patients being evaluated in these trials really are. I would expect to see or if there was any biologic effect to, by on, from TXA on increasing the risk of VTE, I would expect to expect to see it in these exact populations. And, David,
Zach Cost
the other thing I wanted to mention about the halted trial, this was the only trial that did not show a reduction in at least, bleeding related mortality or bleeding outcomes. And kind of in thinking about that, one thing that came to mind is that in both the trauma population, the surgical population, the postpartum population, we know when these patients, they presented early, and we know roughly when they started bleeding. Whereas patients with a GI bleed, it can be more occult. It can be more chronic. And I think that’s just an important distinction to make when, thinking about why maybe we didn’t see any efficacy there.
Tem Bendapudi
I think that’s a terrific point, Zach. And I also just wanted to add, another issue with the HALT with the patients included in the HALT IT trial is that they, are overwhelmingly upper GI bleeders who have a varices or liver disease. And what we know about that kind of bleeding is that it is fundamentally an anatomic bleed. These patients require intervention. They require a conservative transfusions restrictive transfusion strategy.
That’s the [ ] trial from the New England Journal 2013. They require, you know, careful medical management of their coagulopathy, but they’re probably not gonna benefit from only treatment or treatment directed primarily at the coagulopathy because that’s not their fundamental problem.
David Hao
All very insightful things to consider as we interpret these papers. Zach, I think it’s time to wrap it up. Do you wanna take a crack at summarizing some of the things we discussed today?
Zach Cost
Sure. So, we’ve covered a lot of literature today. We discussed 2 large systematic reviews and meta-analyses in, the surgical population that showed meaningful reductions in bleeding related outcomes, but no statistically significant effect on mortality and no effect, at least statistically significant on thromboembolic events. We then discussed 5 very large, well done RCTs in different populations, including trauma, cardiac surgery, non-cardiac surgery, obstetrics, and in patients with GI bleeds. All of these trials demonstrated a reduction in bleeding related outcomes except the halted trial, which was in patients in GI bleeds. This was also the only population found to have a statistically significant increased risk of thromboembolism. Notably, only the crash 2 trial in trial in patients demonstrated a reduction in overall mortality.
Finally, we concluded our review of the literature with a systematic review and meta-analysis in patients from all medical disciplines that showed no increased risk of thromboembolic events, including in patients with a history of thromboembolism. And this was irrespective of dose and, most importantly, did include at least a subgroup that had patients with a history of prior thromboembolism.
David Hao
Perfect, Zach. And, Tim, any closing thoughts for our listeners?
Tem Bendapudi
Yeah, David. You know, I just to provide kind of my opinion on how these drugs should be used, just I think in summary, you know, I would say that I think the efficacy of, antifibrinolytic therapy with respect to reduction in bleeding, reduction in transfusion requirement is not disputed. I think it’s very clear from the literature that in practically every tested population that those two things are true. I think where you run into questions is whether TXA or Amicar are really able to improve your long-term outcomes in overall survival. While they may do a good job of reducing mortality in situations like trauma, it’s much less clear whether that’s true in other situations such as cardiac surgery or peripartum hemorrhage.
David Hao
So here now again are 2 questions for our listeners to think about. What’s the level of your agreement with the claim that TXA increases the risk of thromboembolic events and that it is contraindicated in patients at increased risk for or with prior history of thromboembolic events? And what is the level of evidence for what you believe? Zach, thank you so much for joining the show. I thought you did a wonderful job with the literature review and putting everything together for this podcast recording today.
Zach Cost
Well, thank you, David. It was really fun doing this elective with you, and it’s an honor to be on this show.
David Hao
And, Tam, thank you so much for all your valuable insights. So, it’s always nice to get somebody, who’s not an anesthesiologist to give their perspectives on things like tranexamic acid, which we use often but sometimes don’t always have the greatest understanding of.
Tem Bendapudi
Thank you so much for having me on. This was wonderful.
David Hao
Thanks to all our listeners for tuning in this week. We have a couple of episodes that are lined up that I’m gonna try to get recorded within the next few months. Many of these episodes are based on the work of our residents in the Depth of Anesthesia podcast elective. And I’m very grateful to the department here for supporting this initiative and helping me create educational content. And thanks to all the listeners who spent the time to write emails with comments, feedback, and suggestions. I try to do my best to get back to each and every one of you. That’s all for this show today.
Stay hungry and keep asking questions.
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