I wonder if the after 3 hr group was a marker of poor protocolization and poorly delivered care and that early treatment was associated with better systems and overall better care, hence lower mortality. The similar situation is if D2B >90 minutes being associated with greater mortality is also associated with more poorly delivered care vs <90 minutes in a hospital with better overall care i.e. marker of institutional excellence rather than cause and effect?
Hey Mel, I'm an emerg doc who also does some work in palliative care. I've used Tranexamic acid in patients who are bleeding from their airway tumor's (lung, throat etc) I nebulize 500mg and repeat if needed. We've had some good results using Tranexamic acid in this way.. I was able to find one case report in the literature. It's also great in dental bleeds and epistaxis. Just soak 500mg on 2x2 or 4x4 and get patient to bite down if it's a dental bleed and soak on gauze for nasal packing and leave the packing in the nare until you reasses. Another application I've used is to soak a gauze with transxemic acid and place it on bleeding tumors of the neck ,breast etc. Often these patients are not surgical candidates and starting IV's are not an option.
I presented this paper in residency and if I remember correctly the crash-2 study did NOT take all comers, the patients randomized were those in which the treating physician was UNSURE if TXA should be utilized, but the study never gave criteria for when they thought that's its use would be obvious, nor were those patients included. That makes the study much more difficult to interpret.
Interestingly, my program recently did a journal club on TXA. The CRASH-2 and subsequent data re-analysis are not the only papers on TXA in trauma. I know that it's a completely different cohort, but the MATTERs study is another good one to look at when reviewing the data. My take - the MATTERs study used it on the really sick, with benefit, showing that it works. The CRASH-2 trial excluded the really sick (unsure if the patient would need TXA), and showed no increase in adverse (VTE) events, showing that it is safe. Both ends of the spectrum seem to be covered.
It's important to note that the CRASH-2 trial criteria were:
"Adult trauma patients with significant haemorrhage (systolic blood pressure <90 mm Hg or heart rate >110 beats per min, or both), or who were considered to be at risk of significant haemorrhage, and who were within 8 h of injury, were eligible for the trial."
I feel that the evidence is still compelling for this patient group, however now restricted to the first 3h after injury (as opposed to originally in CRASH-2 where it seemed that up to 8h was of benefit).
The original "CRASH" trial or CRASH 1 (Corticosteroids after Randomization after Significant Head injury) if you will, was corticosteroids for head trauma... Bottom line is that they do not work for this indication.
Regarding CRASH 2, there are many possible reasons why looking at transfusion requirements may be misleading. 1 out of every 6 patients died... so there may be some survival bias. In addition, the indications for transfusion were not standardized and are often quite subjective. So, I don't think we should be focusing on this so much as a negative aspect of the study.
The biggest limitation to the CRASH 2 trial (not mentioned in the podcast) is really external validity. The vast majority of patients enrolled in the study were from resource poor countries and not really similar to advanced western health care environments. Two thirds were penetrating trauma.
As Aaron above mentioned... there are a lot more recent studies on Tranexamic acid for trauma other than CRASH2 and it's slices of salami. But most are observational cohort studies in the military and not properly randomized.
We have looked at the data on tranexamic acid in quite detail and the bottom line is that it might help a little bit as an adjunct to usual care (definitely not a substitution for good resuscitation and hemostasis). It is probably not harmful. So, we give it when patients have the proper indications.
A lot was made of how big this study was... 20,000 patients. This really only gives a lot of statistical power to find small differences in outcomes. This does not get you past bias. You cannot "overpower bias." If there is systematic bias in a large study, it can only give you a biased study with a more powerful biased conclusion... So don't get to blinded by studies that have big numbers. Having said this... the CRASH 2 trial is quite good. There is no such thing as a perfect study.
It is interesting to see how much criticism the CRASH 2 trial has received. If this study was industry funded, you can bet that we would have direct to consumer advertising, billboards, pens, free lunches and everyone talking about how great it is. We might even get a "Surviving Trauma Campaign" instead of the Surviving Sepsis Campaign that all got created by the marketing arm of Eli Lily in order to promote Xigris.
So in the end, we have a cheap drug that probably helps a little bit and probably does not cause much harm... go ahead and give it... The best quality evidence we have is far from perfect but I think there is enough to give it a try. Think of it as a little shake of salt and pepper on a large pot of trauma management stew...
Episode 135Full episode audio for MD edition238:07 min - 100 MB - M4AEM:RAP 2012 December MP381 MB - ZIPEM:RAP December 2012 Written Summary677 KB - PDF
brendan c. - December 1, 2012 6:36 AM
I wonder if the after 3 hr group was a marker of poor protocolization and poorly delivered care and that early treatment was associated with better systems and overall better care, hence lower mortality.
The similar situation is if D2B >90 minutes being associated with greater mortality is also associated with more poorly delivered care vs <90 minutes in a hospital with better overall care i.e. marker of institutional excellence rather than cause and effect?
Timothy B. - December 4, 2012 7:04 AM
Curious if this could be extrapolated for head bleeds or other non-traumatic indications.
Maureen A. - December 4, 2012 3:27 PM
Hey Mel, I'm an emerg doc who also does some work in palliative care. I've used Tranexamic acid in patients who are bleeding from their airway tumor's (lung, throat etc) I nebulize 500mg and repeat if needed. We've had some good results using Tranexamic acid in this way.. I was able to find one case report in the literature. It's also great in dental bleeds and epistaxis. Just soak 500mg on 2x2 or 4x4 and get patient to bite down if it's a dental bleed and soak on gauze for nasal packing and leave the packing in the nare until you reasses. Another application I've used is to soak a gauze with transxemic acid and place it on bleeding tumors of the neck ,breast etc. Often these patients are not surgical candidates and starting IV's are not an option.
Matthew Z. - December 5, 2012 6:46 PM
I presented this paper in residency and if I remember correctly the crash-2 study did NOT take all comers, the patients randomized were those in which the treating physician was UNSURE if TXA should be utilized, but the study never gave criteria for when they thought that's its use would be obvious, nor were those patients included. That makes the study much more difficult to interpret.
Aaron R. - December 10, 2012 8:28 AM
Interestingly, my program recently did a journal club on TXA. The CRASH-2 and subsequent data re-analysis are not the only papers on TXA in trauma. I know that it's a completely different cohort, but the MATTERs study is another good one to look at when reviewing the data. My take - the MATTERs study used it on the really sick, with benefit, showing that it works. The CRASH-2 trial excluded the really sick (unsure if the patient would need TXA), and showed no increase in adverse (VTE) events, showing that it is safe. Both ends of the spectrum seem to be covered.
Michael S. - December 10, 2012 8:18 PM
It's important to note that the CRASH-2 trial criteria were:
"Adult trauma patients with significant haemorrhage (systolic blood pressure <90 mm Hg or heart rate >110 beats per min, or both), or who were considered to be at risk of significant haemorrhage, and who were within 8 h of injury, were eligible for the trial."
I feel that the evidence is still compelling for this patient group, however now restricted to the first 3h after injury (as opposed to originally in CRASH-2 where it seemed that up to 8h was of benefit).
Carla F. - December 12, 2012 4:22 PM
I have a question for Maureen A. If you use it for dental bleeds or epistaxis do you use the iv ampul to soak the gauze with?
Brian D. - December 13, 2012 1:09 AM
A few things...
The original "CRASH" trial or CRASH 1 (Corticosteroids after Randomization after Significant Head injury) if you will, was corticosteroids for head trauma... Bottom line is that they do not work for this indication.
Regarding CRASH 2, there are many possible reasons why looking at transfusion requirements may be misleading. 1 out of every 6 patients died... so there may be some survival bias. In addition, the indications for transfusion were not standardized and are often quite subjective. So, I don't think we should be focusing on this so much as a negative aspect of the study.
The biggest limitation to the CRASH 2 trial (not mentioned in the podcast) is really external validity. The vast majority of patients enrolled in the study were from resource poor countries and not really similar to advanced western health care environments. Two thirds were penetrating trauma.
As Aaron above mentioned... there are a lot more recent studies on Tranexamic acid for trauma other than CRASH2 and it's slices of salami. But most are observational cohort studies in the military and not properly randomized.
We have looked at the data on tranexamic acid in quite detail and the bottom line is that it might help a little bit as an adjunct to usual care (definitely not a substitution for good resuscitation and hemostasis). It is probably not harmful. So, we give it when patients have the proper indications.
A lot was made of how big this study was... 20,000 patients. This really only gives a lot of statistical power to find small differences in outcomes. This does not get you past bias. You cannot "overpower bias." If there is systematic bias in a large study, it can only give you a biased study with a more powerful biased conclusion... So don't get to blinded by studies that have big numbers. Having said this... the CRASH 2 trial is quite good. There is no such thing as a perfect study.
It is interesting to see how much criticism the CRASH 2 trial has received. If this study was industry funded, you can bet that we would have direct to consumer advertising, billboards, pens, free lunches and everyone talking about how great it is. We might even get a "Surviving Trauma Campaign" instead of the Surviving Sepsis Campaign that all got created by the marketing arm of Eli Lily in order to promote Xigris.
So in the end, we have a cheap drug that probably helps a little bit and probably does not cause much harm... go ahead and give it... The best quality evidence we have is far from perfect but I think there is enough to give it a try. Think of it as a little shake of salt and pepper on a large pot of trauma management stew...
Patrick S., M.D. - January 2, 2013 8:18 AM
Nice talk Sanjay, with good feedback. I just hope everyone can relearn how to say tranexamic. Duude...