The July 2019 supplement of the The Bone and Joint Journal consists of papers from The Knee Society. In this episode, Mr Iain Murray (Associate Editor for Knowledge Translation at the BJJ) interviews two authors of one of the prize papers published in the supplement: Dr Craig Della Valle and Dr Yale Fillingham. The article "A multicentre randomized clinical trial of tranexamic acid in revision total knee arthroplasty: does the dosing regimen matter?" was the recipient of the 2019 Mark Coventry award.
Click here to read the article
Click here to view the table of contents for The Knee Society supplement
The July 2019 supplement of the The Bone and Joint Journal consists of papers from The Knee Society. In this episode, Mr Iain Murray (Associate Editor for Knowledge Translation at the BJJ) interviews two authors of one of the prize papers published in the supplement: Dr Craig Della Valle and Dr Yale Fillingham. The article "A multicentre randomized clinical trial of tranexamic acid in revision total knee arthroplasty: does the dosing regimen matter?" was the recipient of the 2019 Mark Coventry award.
Click here to read the article
Click here to view the table of contents for The Knee Society supplement
[00:00:00] I'm Andrew Duckworth and a warm welcome from your team here at The Bone & Joint Journal. As some of you may know for the months of June and July, we have released an overview podcast to accompany our supplements for the American Hip & Knee Societies closed meetings. For the month of July, we've already had a podcast with our editor-in-chief here at the journal, Professor Fares Haddad, and the guest editor for the July Knee Supplement, Dr. Brian Springer, where we hope to have provided you with a brief overview of the Knee Society, who the members are, as well as discussing how this collaboration came about and how it will benefit you as our listeners and readers.
We also hope to have provided you with a behind-the-scenes insight into how the studies within the supplements have been chosen, as well as a giving a brief discussion of our papers. With that in mind, over the next 15 to 20 minutes or so we will be discussing in more detail one of the prize papers from the American society closed meeting in 2018, which was published in this month's supplement.
As with previous BJJ Podcasts, we do utilize the invaluable insight of our guest interviewers for select papers. So today I have the pleasure of welcoming back for a [00:01:00] second time our guests interviewer, Ian Murray, who is my colleague here in Edinburgh, and also our Associate Editor for knowledge translation here at The BJJ. Welcome Ian and thank you so much for joining us.
Thanks Andrew. Pleasure to be here.
Ian and I have a real privilege today of being joined by two authors from the paper entitled A multicentre randomized clinical trial of tranexamic acid in revision total knee arthroplasty: does the dosing regimen matter? Which was the winner of the Mark Coventry award from the Knee Society that we published in the July supplement.
Firstly, I'd like to introduce the senior author for the study, Dr. Craig Della Valle, who is Professor of Orthopaedic Surgery and Chief of the division of adult reconstruction at Rush University Medical Center. Welcome Dr. Della Valle and a big thank you for taking the time to join us.
Thank you. Fun to be here and appreciate the opportunity to talk about our study.
Great. We're also joined by Dr. Yale Fillingham who is an orthopaedic surgeon in New Hampshire, and the lead author of the paper. Welcome Dr. Fillingham and likewise, thank you so much for taking the time to join us, to discuss your study.
Thank [00:02:00] you for hosting us. This is great.
So without further ado, I will hand over to Ian.
Thanks, Andrew. No, we're absolutely delighted to have you both with us today. So Dr. Della Valle, we will perhaps start with you. We know that blood management and conservation and joint arthroplasty has come a long way in the last four decades. I think it'd be very helpful for our listeners if you could outline, how do you feel we have moved from a time when transfusion rates were as high as 30% to where we are now.
Yeah. You know, it's been pretty amazing to watch and I think it's a real testament to how we as adult reconstruction surgeons have embraced change to improve quality of care for a patient. So I'm 49, so I did my residency training about 20 years ago and, you know, when I started residency, we would spend half of our day on the weekends checking haemoglobin levels and then calling the attending surgeons to find out if they wanted [00:03:00] testing of blood. And it was like, you know, literally like half your day on call on the weekend was worried about blood management. And, you know, went from there to having patients auto-donate blood and, I think for a lot of us things really changed at the American Association of Hip & Knee Surgeons meeting.
It was about 10 years ago, I can't remember the exact date. I remember John Callaghan was moderating the session. And there was Brian McGrory, an orthopaedic surgeon in Maine, had brought in this person who worked at a blood bank. And the two things that they talked about were tranexamic acid, as well as, you know, transfusion triggers. I think that really spawned a huge change along with some work being done at the Mayo Clinic, at about the same time. It really changed our views on blood management. Really tremendous and at this point, you know, it's [00:04:00] rare, I mean, extremely rare that we transfuse someone who has a primary total joint replacement, unless they're really starting with a haemoglobin level that's less than 10, which hopefully we can avoid in many patients by identifying that preoperatively and hopefully optimizing it.
Yeah. Well, that's also our experience over here. And how was the news of tranexamic received from the community? Were there concerns about safety and how's that been dealt with and moved forward?
Yeah, so that's a great question. You know, there's a couple of things there. It was really funny, you know, I brought this data back to my institution and the way that hospitals, at least in the US, are set up, you know, the pharmacy was like this is going to kills us. This is going to cost so much money. And I was like but it's going to save everybody else a lot of money and it's going to do a lot of good for a lot of people, you know, obviously avoiding [00:05:00] transfusions and all the problems related to them. And it was just a lot of resistance. I mean, literally, at an academic institution in the United States where you figured you'd have enlightened souls, you know, kind of looking at stuff and looking at data and say, Hey, you know, there's a bunch of data that says this stuff works. There was a real lot of resistance from it. Not only did we get resistance on a financial level, but there was, as you would suggested, a lot of safety concerns and all of a sudden, you know, we were going to be causing thromboembolic events in all of our patients and encouraging that. And well, I think there was a lot of misunderstanding on how the drug works and basically if the drug, you know doesn't cause blood clots. It prevents clots from being broken down. And again, I think there are, like a lot of things in medicine, just a lot of assumptions about who should and who shouldn't get this medication.
I think that the other big issue we had was with our anaesthesia colleagues, and frankly nursing, you know, [00:06:00] just again, I think, well-placed, but a lot of concerns about causing harm with this drug and who should and who shouldn't be getting it.
And I think I was at the American Academy of Orthopedic Surgeons meeting. It was probably four years ago and I had someone walk up to me who I really didn't know. He says Hey, you know, you're Craig, right. Yeah. Right. And he said, you are involved with OCAS. I said, yeah, what can I help with? And at that point I just entered the president's line. And he said, you know, OCAS should really come up with a position statement on the use of tranexamic acid. Because we're meeting a lot of resistance. I want to use it for most of my patients. I think it's safe for most of my patients to get, but we're really getting a lot of resistance from colleagues within the hospital. Can you help us with that? And I thought that was something that OCAS could really do, in a way to scientifically kind of come out with some recommendations on what is [00:07:00] the efficacy of this drug, what is the safety of this drug? Who should get it, who shouldn't get it and kind of, what are the risks of benefits?
Yeah. And yourself and Dr Fillingham, who's with us today were involved in, I think, bringing a few of the societies together in the development of the guidelines in the Journal of Arthoplasty last year. That must've been a challenge bringing all those groups together. How did that come about?
To be honest with you, it was quite a bit easier than I expected. I think there was a lot of appetite among again, I guess learned souls, that look at this drug as a drug that is helpful and that it probably could be used more widely. And, people really embraced the concept of working together on it. It was very refreshing that people were willing to work together again, just to kind of share with people what data suggests and what kind of, what's the right word, fantasy, or, you know, what's urban legend. [00:08:00] What's fact and what's myth. And, again, it was refreshing and fun to work on and Yale really was instrumental in making that whole thing happen.
Well, that's great to hear. And, coming to yourself then, Dr. Fellingham, could you tell us about how this particular study came about?
So I think that the catalyst for this study came from the recognition that we had a robust amount of literature on TXA and primary total joint arthroplasty, but we really kind of lacked any significant literature on revisions. In fact, actually, when we were going through the IRB process for this, we had a big roadblock from our IRB because the VAs practice guidelines on the use of TXA actually recommends against the use of it, or couldn't recommend the use of it for revisions because of the lack of literature that wouldnt support its use in primary. Kind of odd, right? We've got a drug that helps prevent [00:09:00] blood loss and you're saying that you can use it in the procedures that have less blood loss, but not in the procedures that have more blood loss.
So I think that that really kind of helped highlight that although we had a lot of literature in the primaries and we knew that it was an effective drug, there was still some roadblocks to possibly getting it more broadly used in revisions.
Plus this study was kind of one of those Holy Grail studies whereby regardless of what you'd found statistically or not statistical differences, you have something that's a meaningful outcome. So for instance, if we found no difference then we know that we can actually kind of reduce the number of doses that we're giving patients. Give them less drug, which is always a nice thing and then also reduce the cost of utilizing that drug. But if we found a difference then it actually we'd be doing something where we could find out that we were maybe under dosing these revision patients, and we needed to increase the dose could [00:10:00] have a positive effect of reducing blood loss and transfusion.
Great. That's very helpful. And for those listeners who haven't yet come to read the article, I'm sure everyone will, could you give them an overview of how the study was set up in the question that you were specifically asking?
Right. So we set this up as a sixth centre, multicenter RCT. So we were trying to compare four treatment groups. Those treatment groups included a single dose of IV TXA, which was a one gram dose before incision. The second group was a double dose of IV TXA, where they got one dose the same time preoperatively, and then a second dose around the time of closure. And then the third group was the combined IV topical. That was where they got the one dose of IV TXA preoperatively. And then they got an [00:11:00] intra-articular injection after they had closed their arthrotomy, but before skin had been closed. And then the fourth group was the multidose oral TXA. So they got approximately a two gram dose, so 1,950 milligrams, about two hours before surgery, and then they got it six hours post-op and then the morning of postoperative day one.
So we were comparing those four groups together. And I think that one of the big challenges that you have in a revision when we're looking at revisions is how do you take something that's an incredibly heterogeneous mix, right? I think everybody would agree that both component revision is very different from a single component revision and different from a spacer type procedure.
So what we did was we had each site have their own randomization chart for each type of procedure. [00:12:00] So that we could kind of ensure that there was an equitable distribution of all of these different procedures in each treatment group to hopefully not have one treatment group have a tonne of two components and one have a tonne of one component of revision.
So with that design, we ended up essentially finding out that there was no difference in any of the outcomes, whether we looked at it from a per protocol analysis or an as treated analysis. And the reason why there's the difference there is that unfortunately some of the patients ended up getting a treatment dose, like for instance one institution their standard was to give two doses. So the patient accidentally got a second dose of IV TXA, just because they kind of had fallen into their standard pathway. Or some patients ended up [00:13:00] just getting a single dose and somehow the pharmacy got mixed up because they didn't use the topical TXA wasn't administered. So that patient would have been kind of moved over to our single dose IV group.
But regardless of how you splice the data and look at the patients, they all demonstrated the same outcome regardless.
And you were quite comprehensive in the outcome measures you looked at weren't you? You looked at change in haemoglobin, calculated blood loss, transfusion rates. There was no difference in any of those things. Am I right?
Correct. And I think the other thing to kind of highlight with this, that somebody could kind of say, well, this isn't a double-blinded study. I think that my response to that would be that we did a very good job of kind of working with our medicine colleagues to develop a strict transfusion protocol that everybody would adhere to for the more subjective [00:14:00] outcome of transfusion, but really our primary outcome that we powered to and everything was the reduction in haemoglobin. And it's hard to argue with something at such a laboratory value. And we can't sway that value regardless of whether I know what the patient got.
And as we've already discussed the use of TXA, everyone's using different doses, what made you decide on those four specific regiments?
So our study was actually initiated prior to the development and completion of that recent clinical practice guidelines on the primary total joint arthroplasties. But shortly after Dr. Della Valle and I had finished investigating oral versus IV TXA in primaries and the treatments that we came up with were those that, and our literature review had shown that there were a handful of RCTs that I [00:15:00] demonstrated. There was potentially improved outcomes in terms of blood loss and transfusion with these other doses.
So there've been a couple of studies that had shown double dosing of your IV TXA or providing multiple oral doses or even doing your combined IV topical are potentially going more efficacious than like a single dose of IV TXA.
So that was kind of the catalyst for those. We unfortunately didn't have the insight that we have now from the much broader systematic review of the literature for the clinical practice guidelines.
Well, I think you did well to take on a multi-arm study like that in so many centres. So I think you've really covered a lot of basis with those options. So as we've already discussed with both yourself and Dr. Della Valle, there is not a [00:16:00] lot of data out there in the revision etting. In fact, I think yours is one of only two perspective, randomized trials evaluating TXA and revision total knee replacement. How do your findings compare with the previous retrospective series and also the recent Chinese study that looked at revision TKR.
Yeah. So our study is a bit different from those retrospective studies because efthey had compared to essentially a control to a treatment TXA treatment group. And in those studies, they investigated either a single dose or a double dose of IV TXA. So for us, we did not include a peer control arm. The thought behind that is there's been some rumblings in the literature and people have started to kind of raise the question of, when we're looking at tranexamic acid in total joint arthroplasty, it's such a proven drug that [00:17:00] is it unethical to actually withhold such a good drug from patients?
So, there's kind of started to be some mention of us utilizing a pure treatment, a pure control group is unethical for the patients. So for that reason, we did not actually include a pure control group, but those retrospective studies all show that there was favorable for the TXA.
I think in terms of the recent prospective RCT, they had investigated a combined IV topical to only a topical TXA. And they actually found that there was a synergistic effect between the combined, formulations of TXA. And when you kind of break down their data and compare their data to our data, we had actually had very similar reductions in haemoglobin between our IV and [00:18:00] topical combined groups. But where we really differed in between those groups was our transfusion rate. So for instance, our transfusion rate was 2.1% compared to theirs at 16.7%.
So, when we kind of begin to, I think this highlights that that difference between something being a subjective and an objective outcome and their transfusion triggers were far different than ours. So we had a much lower haemoglobin - our patients had to get to a much lower haemoglobin transfusion, which probably answers a lot of why we saw such a big difference between our rates of transfusion.
And then lastly I think our findings are similar to that of the clinical practice guidelines, where we found that essentially based upon the dose amount or the number of doses there is no difference in the [00:19:00] ethicacy of the drug. Whereas they're citing a difference between the number of doses that you give the patient.
Great. So, it's a very clear, clear study with clear take home messages. My question to Dr. Della Valle is so now we've got this data how should that influence the practice of our listeners? And how do you think this will affect the community now that we have this very valuable data?
Before I forget, I just want to thank, you know, The Hip Society kind of sponsored this study and helped us get organized with it. Many thanks to the society. I organized both the hip and the knee study so that was very helpful and I also wanted to make sure we recognize there were a lot of people who really contributed to this study. And, you know, as you pointed out, it's always topical to a multicentre study and everybody was very gracious in terms of working together to get this all done. So I just want to make sure I don't forget that.
I [00:20:00] think the bottom line is, is that you have to look at your own system and see what's going to work for you. It seems to us that you should use, well, A. You should use TXA because it works. But there doesn't seem to be a clear winner in terms of, you know, giving more of it to improve the outcomes. So, you know, kind of our take home is use the lowest dose that's gonna be most cost-effective in your health system. In our health system oral TXA is very inexpensive and that's what we use. But you know, in another system IV might be cheaper or topical might be cheaper. I mean, those are basically the same thing, but, you know, use the lowest dose that works. I think that's our take home.
Great. Well, I'm afraid we are going to have to stop there cause we're running out of time, but I encourage everyone who hasn't had a chance to read that article to download it and read it because it's very interesting, not [00:21:00] only from a methodological point of view, the setting up the RCT in this complex setting, but also just has a very clear, important message.
Thank you, Ian. And thank you so much to you all for what has been a really excellent and informative discussion and congratulations, particularly to Dr Della Valle and Dr Fillingham. A really great study and clearly an invaluable addition to the current literature. To our listeners we do hope you've enjoyed joining us, and we encourage you to share your thoughts and comments through Twitter, Facebook, and a like, and feel free to post or tweet about anything we've discussed here today. And thanks again for listening.