Thromboprophylaxis for the trauma and orthopaedic surgeon

Listen to Andrew Duckworth, Daniel Horner, and Xavier L. Griffin discuss the paper 'Thromboprophylaxis for the trauma and orthopaedic surgeon' published in the April 2024 issue of The Bone & Joint Journal.

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Transcript

[00:00:00] Welcome everyone to one of our BJJ podcasts for the month of April. I'm Andrew Duckworth and a warm welcome back to you all from your team here at The Bone and Joint Journal. As always we'd like to thank you all for your continued comments and support as well as a big gratitude to our many authors and colleagues who took part in the series that highlights some of the great work published by our authors each month.

So for today's podcast I have the pleasure of being joined by two authors from an annotation published in this month's edition of the BJJ entitled 'Thromboprophylaxis for the trauma and orthopaedic surgeon: tribulation and trials'. So firstly, I'm very pleased to be joined by Professor Dan Horner. He's a consultant in Emergency and Critical Care Medicine in Salford. Thanks for joining us, Dan. It's great to have you with us today. Thank you, and thanks for the kind invite. And secondly, I'm pleased to welcome back Dan's co-author, Professor Xavier Griffin, who is the Professor of Orthopaedic and Trauma Surgery at Queen Mary University in London. Xavier, great to have you back with us as always. Thanks very much. Pleased to be here. 

So Dan, maybe if I could start with yourself, you know your, you know, your annotation, as we've said, thromboprophylaxis for the trauma orthopaedic surgeon. I suppose a quick question first up, and I think it'll be of interest to our listeners. As an emergency medicine consultant, what's your sort of take [00:01:00] on this topic? Where, where do you come from, from, you know, the non-orthopaedic point of view?

Yeah, so probably worth digging into a bit of my history with VTE. I, I took a couple of years out of program for research as a mid-level registrar when I was pursuing a career in emergency medicine and my MD topic, I suppose, was VTE and particularly distal deep vein thrombosis. But as always, when you take on an academic project, other projects seem to appear out of nowhere and are placed on your desk. And one of those was the challenge of, of what we do about thromboprophylaxis for patients in lower limb immobilization. And we had a couple of index, very sad cases in the emergency department. 

And as you and your listeners will know, VTE continues to be a challenge for all of us. It's a diagnostic difficulty sometimes. You know, PE still has a case fatality rate somewhere between ten to 20%, depending on the timing that you look at, either 28 days or a year. So we kind of banged our heads together about that in the Royal College of Emergency Medicine.

We looked at the evidence base, we realized that was [00:02:00] real variation in international practice, and that's what first got me interested, I suppose, in the particular subjective thromboprophylaxis in lower limb, imobilization. That's really interesting. And in terms of, you mentioned that about the variation in practice, that is something that is, is really there, isn't it?

There is, there's various protocols from various centers, from various trusts, and there isn't really a standardization across the board. Would you say that's fair? Absolutely. Yeah. I mean, I think, perhaps the biggest evidence of that variation is the difference between us and North America. I think most US haematology guidelines don't particularly endorse the practice of thromboprophylaxis for ambulatory patients with lower limb immobilization, whereas in a lot of European countries like France and Belgium, it's, it's default essentially, and the UK settles somewhere in between basic practice on risk assessment.

But as you say, then that leads to variation because people use different risk assessment models. They have different percentages of prescribing rates and some hospitals even use different drugs for it. So a lot of that [00:03:00] reflects, I would suggest that the underlying lack of evidence, you know, that's something we wanted to highlight in this paper. And that's something we're trying to tackle with the TiLLI study, which I'll come on to later. 

Yeah, that's great. And, you know, we definitely will go on to those things and it'd be great to talk about TiLLI as well. But Xavier, if I maybe come to yourself, you know can I maybe, you know, again, your own clinical experiences with this topic and, and then move on, maybe talk about where you think we are with the current guidance on it?

Yeah, absolutely. So you know, I predominantly practice in trauma and I do a little bit of arthroplasty, low limb arthroplasty work. So. I have seen the two sides of the coin as, as most of our colleagues listening today would have done where we occasionally see DVTs and, and pulmonary embolus, particularly in multiple injured patients.

And so there's a real burden of, of clots, perhaps not from our perception, the same degree as, as the hematologists are seeing because they're clearly seeing a clinic workload, which is all made up of people with clots. But we also see the [00:04:00] flip side of it, and perhaps that doesn't reach through into other medical specialties, which is, or at least inpatient specialties, which is the bleeding side.

And often if the bleeding is, is not catastrophic, if it's wound-related, particularly incisional wounds, then you know, we run into problems with washing those wounds out, potentially infection. And I know there's a great fear that some of the anticoagulants that are used might increase the risk of those sorts of complications, which in the case of arthroplasty is a complete catastrophe for the patient and affected arthroplasty.

So, so I think it's a really difficult area because those two different types of risks are very different and, and they're probably in the ballpark of similarly common, I would say, overall across all populations and, and the consequences can be catastrophic on both sides and, and trying to peel apart what the best thing to do for, for individuals in front of you, I think is really difficult.

Yeah, no, I totally agree. And I think actually that's that equipoise we all throw it around, isn't it? Is that that risk [00:05:00] of, like you say, of VTE, which is a real thing, but also that risk of, like you say, if you get a haematoma after an arthroplasty and then that gets infected, it's, it's an equal disaster in many ways. So that's, I think that's, that's very well put. And in terms of, you know, you mentioned in the, your annotation about the NICE guidance in 2019, what, what did that sort of very briefly recommend or was there anything you would want our listeners to know? 

It's difficult to be brief about that NICE guidance. Mike Reed who was on, so we had an orthopeadic subcommittee, which made up of some really stellar people. And, and Mike took a picture, which I've used many times and I'm grateful to Mike Reed, of the entire document printed out on a desk and it's several volumes thick. So it's difficult to be brief about it, but I think there's a few things that when I was thinking about this is what are the key messages?

The first is that, VTE is a real phenomenon, but the degree to which we might be able to change mortality following VTE is highly contentious. And so, so we phrased the introductory text to make it clear that we believe that it's [00:06:00] potentially a modifiable event, mortality following PE and it's difficult because the trials are relatively small.

They're a few thousand patients and PE is very uncommon and mortality following PE, even less common. And so the trials typically are not powered to look for that as an outcome. They're typically powered to look for DVT and historically ultrasound proven DVT rather than clinical symptomatic DVT. And so we made the assumption that if you could reduce the DVT risk, then that would translate into reducing the more severe but less frequent complications.

But it is an assumption and that's laid out at the beginning with the NICE guidance. And then the other two things I would say is that we did incorporate a lot of orthopaedic data from the National Joint Registry linked with the Hospital Episode Statistics. And that's why you see so many changes between the previous iteration and this iteration.

Because we were able to incorporate much more real world estimates of [00:07:00] the real risk. And then use the trials to update the relative benefits of the drugs. Absolutely. Yeah. I guess the final thing I would say is that the absolute risk is very variable across different populations. So translating benefits into real risk improvements for patients and numbers that mean something like, you know, your risk goes down by two and a 100 or whatever it is.

That's really important. And so you must, must, must read NICE with a view to your particular population. And that's why the NICE guidance is laid out in that way, because some people have got less than one percent risk and other people in the same guidance have got 40 and 50% risk. Absolutely.

Yeah, that's, I know it was a big document. That was a really nice overview. And I think actually, I'd say the key key points that people need to take into account when they're, when they're looking at it, so maybe Dan, if I could come back to you and maybe if we maybe change tack it will become a bit more specific and move onto the sort of a key area, you know, of lower limb fracture surgery and immobilization, which, you know, we're all involved with. What are the [00:08:00] current thoughts and practices with regards the sort of risk assessment models? We sort of mentioned that already, but wondered if we could go in a bit more detail with that.

Yeah. So I think the premise of risk assessment is a very logical one, isn't it? And Xavier's really eloquently highlighted the trade off here between prevention and VTE whilst also trying to mitigate the, the, I suppose, the costs and potential harms of using a drug for a low event rate population. The challenge with risk assessment is that it's very badly studied and derived. Lower limb immobilization is a very good example of that. So there's numerous scores that abound internationally. If you look in detail at them, there's very little validation work, very little work on reliability, hardly any implementation work.

So, you know, hardly any studies looking at the introduction of the score compared to, the gestalt of an emergency or an orthopaedic surgeon. So, you know, we tend to grasp risk assessment quite quickly, but often without the same kind of reliable evidence-base that or critique that we would apply to trial data when we're considering [00:09:00] whether or not to use a drug or intervention.

We were commissioned by NIHR to look at this, really with a systematic review of risk assessment tools and a decision analysis model in 2018, 2019. We found you know, the evidence for risk assessments to be very, very weak. But interestingly, the decision analysis model and the cost effect of this work did suggest that, that thromboprophylaxis was likely to be overall cost effective based on the estimates of, of relative risk reduction using thrombo prophylaxis I know, we can talk about that in more detail if you like, but again, that was a fairly lengthy document. Since then, there's been a number of kind of slightly more refined and better validated risk assessment models published. And I don't know, I suspect many of your readers might have seen the recent publication in The Lancet, I think it was this month, looking at the evaluation of the TRiP(cast) score in this particular population.

And that's probably one of the better studies in this area, really a group from France and Belgium looking at stepped-wedge plus the randomized trial where they, they assign different sites to continue [00:10:00] their normal practice and then interject use of the TRiP(cast) risk assessment model for this particular clinical situation and based on the prophylaxis prescribing decisions on that.

And yeah, the suggestion from from that paper is that TRiP(cast) is probably one of the better models that it can reduce the amount of thromboprophylaxis we use, that it had a relatively high accuracy and that in the right hands, it might be good. And luckily enough, that's the risk assessment model we've chosen for TiLLI, because we've been working with Delphine Douillet, who's the lead author for that Lancet study as part of the, an actual replication.

So we've evolved, I would say, from, you know, where we started. In 2012 with the Royal College of Emergency Medicine, GEMNet guidance on this, which was essentially, you know, good old people around the table trying to decide what they thought might incur risk, highlight that in some sort of pro forma. I know John Keenan and others, you know, from orthopaedic surgery have introduced rules like the Plymouth rule, you know, they're used in certain geographical locations, but I think we've kind of gone through that work. We've [00:11:00] now got to slightly more reliable and better validated scores. And we're now using those to discern risk in randomized controlled trials, which is really what we need to be sure. 

Yeah, yeah, no, that's that's a really nice overview, Dan. I think like you say about the TRiP(cast) score in that study, I think what like you really nicely highlight is that, and I think probably it's reassuring, I suppose, to a orthopaedic decision is actually that it could potentially reduce the amount of chemo prophylaxis we may need to use.

And I think that's the thing is it's actually finding who we need to use it in, isn't it as much as anything. And I think if we get a really good score like that, or we hope to have like that, that's one of the keys to it. And maybe Xavier, if I come to you sort of moving on from that, you know, when we're talking about lower limb, lower limb surgery and immobilization, there's two sort of recent RCTs you highlight in that area. That's the the prophylaxis in non-major orthopaedic surgery and then The PREVENT CLOT trial. Can you just sort of summarize again what they really showed and what the listeners should take home from those?

Yeah, absolutely. So first of all, both these trials are top end, out the gate, stellar pieces of work. And [00:12:00] we are you know, I would say we are duty bound to dig into these and understand them and apply them in our practice as best we can because the quality of these, these data is, is fabulous. So they're both around largely fracture related populations.

And they're both what's called a noninferiority design study, which is a really important consideration when you're thinking about what this means for your practice. So we're not asking, is one treatment better than the other? We're asking the question, is one treatment no worse than the standard of care?

So it's our new test treatment, not worse than the standard of care. And it's an appropriate design. If you've got a standard of care, which is expensive or really cumbersome for the patient to use or unpleasant or has a lot of side effects. And what you're searching around for is something that is not worse in terms of its effectiveness at reducing the clot risk, but is more amenable in some way.

And, and because low molecular weight heparin is our standard of care typically for fracture [00:13:00] surgery and lower limb fracture surgery, you know, the patients hate it. And it's actually quite expensive because a proportion of patients can't self-administer. And so when you work out the cost associated with low molecular weight heparin is quite, it's quite pricey, much more expensive than the actual cost of the drug when the health economists spin up those costs with nurse administration and things.

So I think it's an appropriate design, but it's got a bad reputation because if you design a study, which is looking for a benefit, the worst case scenario is you fail to find a true benefit and you default to back to what you were starting with, which was probably safe and relatively effective.

But if you ask the question in a way that is not necessarily ideal about, is it not worse? Then you can make conclusion that it's not worse, even if it is worse. And this starts to get a bit complicated because the terminology is, is horrible, but noninferiority designs need to be really cautious because you can incorrectly come to the conclusion that we'll [00:14:00] switch to this different treatment because it's no worse.

And I think these two trials illustrate that really nicely. So PRONOMOS is about is non-major orthopaedic surgery, but it's mostly learning fracture surgery. And they said, okay, our control group, our standard of care is, is low molecular weight heparin. We want to know whether an oral anticoagulant, which in this case was rivaroxaban is not worse in terms of producing clots.

And so they looked at PE related to death, DVTs, proximal DVTs. It was all clinically based. It wasn't driven by ultrasounds. It was in thousands of patients. And they found really, really obviously that it was not inferior, didn't cause any more bleeding. And then when they did a subsequent secondary test to see, is it actually better in terms of reducing blood clots? They found it was better. And they did a really lovely comparison right at the end, which was they lumped together all the bleeds and all the clots in the two groups, and they showed that even when you take into account bleeding and clotting in the two groups, you [00:15:00] get a net clinical benefit with rivaroxaban.

So you get fewer bleeds, you have fewer clots, so overall your patients are about a 50% reduction in bad outcomes. Now PREVENT-CLOT is a different question. Now they were saying, okay, well, our standard of care is low molecular weight heparin, but you know, we don't really believe necessarily that we need to give heparins or, or DOACs.

I think aspirin is just as good. So we're asking the question, is aspirin, which is cheaper and oral and more amenable for patients. Is that not worse? But here, they did something that was really important. They looked at the outcome of mortality, all-cause mortality. If you got a treatment that we don't think really changes mortality, and I said that right at the beginning in the NICE guidance, that we know that our trials are not really adequately powered to look for big differences in mortality, because it's really uncommon death.

If you set the trial up to find a difference in an outcome that you don't really think gets changed, you skew the trial to finding a positive finding for noninferiority. And [00:16:00] so what they found was it doesn't change death. It's noninferior for death. And therefore they said aspirin was safe. When you dig into the secondary outcome measures, it's about double the risk of proximal DVT.

But of course the primary analysis and what the whole trial is geared up for in the discussion is all around death. Yeah. So, I, I am nervous that PREVENT-CLOT, because of the way it was designed, it's still a lovely trial, it's beautifully reported. You've got to understand that the question's all around mortality, and if you don't really think it changes mortality, why would you ask the question around mortality?

Yeah, that's really, that's a really interesting take on it, I mean, I think actually, like you say, the importance of actually delving a little bit deeper to those other secondary outcomes, so to speak, but actually are very important. So Dan, if I may come back to you in terms of, obviously, we're talking about that, a lot of that was about lower limb fracture surgery. There's also some data about lower limb immobilization after injury as well, isn't there? And there's some recent studies in that area, which are probably worth highlighting as well, that you discuss in your annotation. 

Yeah, thanks. I mean, just to pick up the point about death in [00:17:00] particular, as well, if I may, as an emergency and critical care physician, I suppose I would argue that, you know, a lot of VT outcomes are later down the line in these kind of studies, and actually, we have fairly robust pathways within NHS care, certainly to diagnose and to treat VT. So looking only at those mortality episodes, you know, gets you really down into the very, very fine detail of outcomes, but there are lots of other things that patients can experience, which are bad related to VT. Yeah. Moving on to the specific trial data around lower limb immobilization in ambulatory patients, so patients who are put into some form of immobilization and discharged from hospital.

I think we talk about POT-CAST in the annotation, which was a great trial, again, published in the New England Journal of Medicine, authors from the Netherlands, really, looking across multiple sites and randomizing patients to low molecular weight heparin versus no pharmacological intervention.

And finding no real difference in the incidence of symptomatic VT between those two groups. It kind of [00:18:00] shone a real light on the discussion around whether these patients need any kind of thromboprophylaxis. When you look at the detail of that trial, I suppose the concern from the thrombosis community were around the open label design.

Some of the strict exclusion criteria. So people with previous VTE were excluded, people with any kind of recent active cancer were excluded, there were other exclusions. So you really drill down then onto a very low-risk cohort that perhaps don't stand to benefit. And the worry always, I suppose, is that when people generalize this kind of findings to the broader population, you end up with, you know, people with very high VTE risk who are then, I suppose denied thromboprophylaxis for want of a better word because of a single trial that excluded their type of population.

And then the dosing use was, was actually lower than we would use in the UK. So you know, it's externally generalizable. I suppose some questions around there that we just need to, to bear in mind. And interestingly, when you put POT-CAST alongside other trials on this topic You do still see [00:19:00] a net clinical benefit or evidence of clinical effectiveness for thromboprophylaxis.

So a recent updated Cochrane review, you know, will tell you that thromboprophylaxis reduces the overall risk of VT as will our systematic review published, as will the, the NIHR monograph published in 2019. So, you know, POT-CAST is one trial amongst many, and I think we probably need to look at the body of evidence overall.

Yeah, and I think, and that's a really important point you raised there Dan, and talking about the inclusion exclusion criteria, I know they're obviously they're very important for any trial, but I think particularly for these, you know, even with we're talking about the PRONOMOS trial, you know, there was a comment, you know, you make about how they were a relatively young population and actually, the danger, like you say, is you get a result from these and then you stretch it to the population it hasn't really looked at. And I think that's such a really important point, isn't it? I totally agree. Maybe that sort of takes us on nicely done to talk about, you know, we've talked about lower limb and then you talk briefly in the the editorial about, you know, the other types of the fragility fractures of the pelvis hip and proximal femur.

Well, you [00:20:00] know, the, the much frailer population may be, you know, and the risk benefit profile somewhat different. Where, where, where is the evidence with that really at the moment? Do you feel Dan? 

Yeah, this is probably more in Xavier's territory than mine, but just to comment briefly, I suppose. But we've recently just published a another, an NIHR monograph around the use of risk assessment models to predict who, which inpatients hospitalized inpatient should benefit from, from pharmacological thromboprophylaxis.

Yeah. And again, there's detail in there to perhaps, you know, raise eyebrows about the use of risk assessment models internationally. And there's interesting data there on the cost-effectiveness of thromboprophylaxis for all type strategies. Some of that undoubtedly comes from the fact that the risk of VTE almost exponentially increases with increasing age.

And I'm not just a reflection of the age, of course, it's a reflection of additional comorbidities limited mobilization, the likelihood of secondary complications in hospital. So, you know, that frail population with fragility fractures are right at the top end [00:21:00] of the VTE risk spectrum. So, you know, we need to think very, very cautiously about withholding thromboprophylaxis in that population.

In terms of the evidence base, you know, my reading of NICE is that it's relatively weak. You know, there are some trials around hospitalised surgical patients and, and data from those was applied to some of the thinking. But that's one of the reasons that we need direct, I think, which Xavier is trying to move forwards.

So, anything you would add to that, Xavier, at all?

No, I think I totally agree with Dan, and this is why population specific guidance is so crucial, and it's one of the difficulties with trials that have been put together where the population stray across quite a big risk spectrum, because, you know, an absolute, sorry, a relative risk reduction of half, so if you half someone's risk, that means a hell of a lot if your risk is 40%.

It doesn't mean so much if your risk is 0. 5%. You know, you go from 0.5 to 0.25. Well, was that worth 42 days of injections? I don't know. And actually there's some work from the guys who did clot prevent about sorry, PREVENT-CLOT about [00:22:00] about how patients value each of the different outcomes and what they would do in terms of which medication they prefer, how much better it would have to be before they switch from tablets to injections.

So that's just some really nice background work that that put together why they were aiming for the effect sizes they were. But I think population specific trials are going to be really crucial. Clearly it's more difficult to recruit to a trial that's got a smaller population and that's why we need to use somewhat smarter ways of doing trials at a scale.

Which is what we're going to try and do with DIRECT. And indeed, TiLLI, which we'll no doubt come on to talk about in some more detail, is another monster trial. I think in the arthroplasty space, which is another group, and you know, the hip and knee arthroplasty are a higher risk as well. It's interesting because Goulage and Mike from from Bristol put a lovely meta-analysis together. And they did that back in early 2020, I think, and the sort of upshot was that the risks of bleeding and VTE seem to be quite similar between aspirin and low molecular [00:23:00] heparin, probably the two leading contenders that we'd like to use in, in orthopeadics, perhaps not shared across all of the medical specialties, but certainly a commonly commonly sought after intervention that we'd like to see in the guidance.

But actually when you look at the confidence intervals around those estimates, they're really quite big, relatively speaking. And, and so my take from it was that actually that, that review really helpfully put in place a question which was, well, is aspirin or low molecular heparin the right way to go for lower limb arthroplasty?

And those of you who have read your NICE 2019, can see we've kind of sat on the fence a bit because there seemed to be uncertainty, so we recommended a few options for people, but the CRISTAL trial came out recently from Australia. We talk about that in the annotation and, and this is another top drawer trial.

So every one of them that we've mentioned in the annotation is really a fabulous study. And I would say to everyone that's got journal clubs, they're all free to [00:24:00] download. Just get in there, get, get into the annotation and go to the go to the links and download the papers and read them and, and really interrogate them in your journal clubs because they're really top drawer.

But CRISTAL is a, is another great trial. It's a cluster crossover. So now we're randomizing hospitals. Not patients. Yeah. So if you turn up in a hospital and it's randomized to aspirin, you're going to get aspirin. And it's crossover, which means that at the beginning of the study, you get aspirin and then you, and then the whole hospital moves over to low molecular weight heparin and you can cross over multiple times, actually.

So the whole thing can get quite spicy and difficult to coordinate. But they're beautiful designs and they, they really ramp up the power and so you get a lot of information out. This trial was was planned for sort of ballpark 15,000 patients, and they terminated it early. This is really critical.

They didn't just stop because they couldn't recruit. They stopped because their independent safety monitoring committee enforced them to stop against some pre-specified safety rules. And that was because [00:25:00] the risk of DVT after proximal DVT and, and other complications was three times higher in the aspirin group.

So they got stopped by an external independent safety committee, and there's no differences in the bleeding risks either. So they just couldn't complete because they were told stop. And you've got to think, that is a really hard stop. So, and when you look at what the rules were, it wasn't a five percent. It wasn't like our typical p-value where we say we're aiming for five percent.

This was down in fractions of a single percent. I can't remember if it's one in a thousand or if it's one percent, you can have a look at that when we review the literature themselves, but that is a massive, massive margin and the chances of that occurring due to sampling or some other random error and not being true difference between aspirin and low molecular heparin, I think is essentially zero. Yeah, absolutely. So, you know, I personally, and I'm not, I'm not on the NICE committee, but I would personally be surprised if that does not feature heavily in the next NICE guidance. It's rich and make its way in. And I agree.

We're going to go just [00:26:00] maybe just to finish up. We've mentioned it already. And I think just conscious of the time Dan, I'll come to yourself. We've mentioned it a few times, but to we've wound it up now. So we let our listeners know about TiLLI, which is about to start. 

Yeah, great. So TiLLI, I suppose this is the culmination of the work we've done on temporary lower limit mobilization, the NICE research recommendation. I think it was an RCS research recommendation as well, and all that fed into the NIHR that then commissioned a pool to try and tackle this, this problem, and then different ways of of approaching it. But we opted for a pair of linked randomized controlled trials with large sample size, because I think Xavier has been mentioning all along, you know, these are different subpopulations we want to look at, and we want large, robust levels of data really in the UK population to inform our practice going forward.

So we're proposing, at this pair of trials we're going to use the TRiP(cast) score to ascertain VTE risk and assign people to low or high-risk, if you like. And then we're going to have different [00:27:00] tiers of interventions for those risk populations. So I'm also representing two different designs, interestingly.

In the high-risk population, we're really going to be looking at a noninferiority design, aiming to compare oral anticoagulant agents, either rivaroxaban or apixaban versus conventional low molecular weight heparin, which is recommended in NICE guidance at the moment, as you know. For the lower risk population we were quite surprised to see the NIHR commission a trial in that group, you know, our feeling was what we need to identify the high-risk group and then look at different drugs. And NIHR said no, you know, we think the evidence base is is so weak, it might be that the lower risk group would also benefit. It may be that patients will find that acceptable and one of the really interesting things that that we discovered when we talked to our patient public representation group when designing TiLLI is their ideas around risk consequence.

So we talk a lot about absolute risk, don't we, and relative risk reductions when we're, when we're thinking about interventions and trials. Some of the patients, you know, particularly mentioned, [00:28:00] well, what, what, what is the absolute consequence of that risk? You know, if the risk of VTE is very low, but the consequence of that might be death within 28 days, up to the levels of 10, 15, 20%.

I really want to know about that risk and I want to mitigate it even if you don't think that's a very high-risk, you know, I would like to be told and that kind of stuff is fascinating, isn't it? I didn't see that coming at all, but we had a really interesting discussion about that and it informs some of the design and perhaps why that's why the NIHR wanted us to investigate that low-risk group.

You know, so we're launching that. We've already got ten, I think, pilot sites signed up, which is fantastic for a 12 month period to look if we can demonstrate feasibility. And then we're looking to expand to 30 sites. So we will hope to be in touch with many of your listeners, I'm sure. And we would really encourage them to participate in generating this evidence base so that we know who this intervention will work in and what the most acceptable version of it is.

And that's, that's, that's great. And it's an amazing amount of work as well. I know to set something like that up and get information, like you say, it's the PPI stuff is always so fascinating, isn't [00:29:00] it? Cause it's, it's, it puts a lot of our myths in our own head to bed. And actually it's really important what they think is actually what they've got to live with it. I think that's exactly right. 

Well, both, I think that's all we have time for and I wish you all the best. And well, first of all, thank you so much to you both for taking the time to join us. It was a really great annotation. I find it very, very informative and actually, simulated quite a lot of complex information data into a really nice annotation and really, really clear overview of of what can be a really complex topic and, and really why, you know, we need more data in this area and I wish you all the best for the trial moving forward.

It's been great to have you with us. And to listeners, we do hope you've enjoyed joining us. We do encourage you to share your thoughts, comments on the various platforms about what you've listened or read in the journal and feel free to post about anything we've discussed here today. And thanks again for joining us.

Take care of everyone.