Aspirin for thromboembolic prophylaxis

Listen to Andrew Duckworth, Ian A. Harris, Samuel J. MacDessi, and Fares Haddad discuss the paper 'Aspirin for thromboembolic prophylaxis' published in the July 2024 issue of The Bone & Joint Journal.

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Transcript

[00:00:00] Welcome everyone to our BJJ podcast for the month of July. I'm Andrew Duckworth and a warm welcome back to you all from your team here at The Bone & 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 take part in the series that highlight just some of the great work being published each month in the journal.

So today for our monthly podcast. I have the pleasure of being joined by three authors from an editorial published in this month's edition of the BJJ entitled 'Aspirin for thromboembolic prophylaxis: emerging from the uncertain world of observational evidence'.

So firstly, I'm very pleased to be joined by Professor Ian Harris from Sydney, Australia. Thanks for joining us Ian, it's great to have you with us. Thanks for having me. Ian is joined by one of his colleagues in Sydney and his co-author, orthopaedic surgeon, Professor Samuel MacDessi. Sam, great to have you with us. It's nice that you could join us. Great to be here too. And finally we're delighted to welcome back Ian and Sam's co-author and our awesome editor-in-chief at the BJJ, Professor Fares Haddad. Prof, great to have you back with us. Dux, thanks and thank you for doing this.

So guys, I thought we'd start off, I'd ask you all a similar question. Maybe I'll start with yourself, Ian. What is your institution's current standard VTE for prophylaxis for [00:01:00] patients undergoing routine primary total hip and knee replacement? And has that sort of changed over the past five to ten years?

No, it hasn't changed. My institution uses clexane, low molecular weight heparin, and has done for a long time. There was a period about 15 years ago when it was actually a state-level guideline. So it was kind of required by the government. And if you, if you didn't want to use low molecular weight heparin, you had to justify not using it. But that's only for the public hospital. So a lot of surgeons in private were using aspirin and aspirin use increased over time. But in my two institutions that I work, it's, it's always been low molecular weight heparin. So that hasn't changed. That's interesting. And how about yourself, Sam, is that similar sort of for your institution and yourself?

Yes, a little bit different to Ian. As Ian said, you know, clexane was mandated or not mandated, but highly recommended as the prophylaxis of choice [00:02:00] really up until 2012, 2014. But, but one of the big, big things we saw in our unit was, was a concern about the potential for incisional drainage from our wounds.

And so we were looking at this observational data emerging on aspirin as a potential option. This was prior to the use of tranexamic acid, so around that time the majority of our department switched about a decade ago to using aspirin, and we continued to using aspirin as a sole prophylactic agent up until the publication of CRISTAL. And we're going to get into why we changed back again tonight. 

Absolutely. Absolutely. Prof, if I come to yourself, finally, a similar question, you know, so your own practice, own institution, is that similar? Has it changed over time at all?

So I mean, I think very similar to Ian in that we have both public and private sectors in the UK kind of core, chemoprophylaxis has been a low molecular weight heparin with obviously as part of a multimodal system and as part of enhanced recovery, all of which I think are really relevant here overall. I think we've generally followed [00:03:00] NICE and we probably come back to that later on in the sense of in the hip, the standard is low molecular weight heparin in the knee.

We have shifted to using aspirin in the lower risk patients. So I think risk stratification is a big deal. The mixture between heparin and low molecular weight heparin is a really interesting one, but NICE did drive that in 2018 and we sort of moved with that at the time. And there's been a big push in the last decade from the hematologists to use the Factor X inhibitors. And I think that's a big driver here worth discussing further. Certainly in one of my institutions that is, you have to fight for that not to be the standard on discharge because of the difficulties with injections. 

Yeah, that's really interesting. And like you say, there's just so many stakeholders involved in this and actually that I maybe come on to that variance a bit later on. But so if we maybe move on, like, as you said, maybe yourself, Sam, you mentioned about, you know, that sort of observational evidence that was out there. And so [00:04:00] could you sort of give our listeners an overview of how VTE prophylaxis management has changed over time and how has that controversy and argument regarding the evidence evolved in your eyes?

Yeah, so, so let's just look back for over 40 to 50 years, you know, the standard in the 80s was subcutaneous heparin and then warfarin and warfarin stayed a very popular agent in the United States for quite a while. And even during my fellowship in New York, it was the agent of choice, difficult to monitor, patients didn't like it but, you know. They saw the worst of the worst of thromboembolic events in the early days of arthroplasty. And so they were highly aware of what the consequences were. And then in the 1990s, we saw the introduction of the low molecular weight heparins, even newer agents that were a little bit more targeted, hoped that there were going to be lower risk of complications, didn't need monitoring.

And then the oral agents came in, the Factor X inhibitors, the DOACs or the NOACs, as they were previously called. And then, at the same time, we saw the introduction of aspirin. And all these things, all these things have been evolving at the same time that we've had [00:05:00] ERAS protocols, we've had the introduction of VTE, which further complicates this issue as well.

Yeah, absolutely. And in terms of those observational studies, there has been a few other RCTs that have come out more recently. You mentioned in your, your editorial about the EPCAT II trial and the PEP trial. What did they sort of show?

Yeah, so, so really only, only there have been two adequately powered randomized control trials in the last 30 years on aspirin, which is quite astounding.

And the first one was the PEP or the 'Pulmonary Embolism Prophylaxis' trial. And this was published in 2000, but recruitment started from 1992 and went through to 1998. And in this study, what they compared was 160 milligrams of aspirin in one arm to placebo. Yeah. So they didn't actually have a comparator despite warfarin and low molecular weight heparin being around at the same time. They had about 4, 000 patients in this study. So it's a really good study for the time, but what they found was a modest improvement with use of aspirin, just [00:06:00] a modest improvement in aspirin. It was slightly underpowered really for looking at joint replacement because most of the patients were actually hip fracture patients.

And the other thing with this study was it was 30 years ago. I mean, when they were recruiting these patients, I was a medical intern. And I remember patients having a joint replacement, sitting around in bed for two days with three drains coming out of their thigh, being reinfused at the same time. And if you needed to get them up by day number two, you needed two physiotherapists and a crane to get them out of bed.

I mean, these were different times than what we're in now. So to generalize those findings of PEP to modern day arthroplasty is challenging. And we've got to be careful with that trial. And the second trial, which is also an excellent study, was EPCAT II. And, and this was out of the Canadians group in 2018, and this is the other highly cited study that people use in favor of aspirin.

But in this study, what they did was they gave every patient rivaroxaban for five days. Every patient got that for five days. And this is a time when patients [00:07:00] are at the highest risk for having a thrombotic event. And then after five days, they either got randomized to aspirin or rivaroxaban for nine days for knees and 30 days for hips.

And they followed them out for three months. And what they found in that study was there was no difference in VTE rates. So it's really not comparing what we're doing in 2024. Yeah. Where most people get aspirin as their sole form of prophylaxis from the outset. And this is really what's been recommended by the International Congress on, on VTE. They've come out and made the statement that aspirin is the most effective agent, the most effective agent, even in high-risk patients for thromboprophylaxis.

Yeah, we still don't have level-one RCTs proving this and the observational studies suggest that it's better, but we don't know until CRISTAL.

That's very, that's a really nice. I mean, like you say, it just highlights some of the issues, not only with the observation studies, but also designing a good trial in this area is hard, isn't it? And [00:08:00] there's a lot of stakeholders and there's a lot of opinion about it as well. I think that's what happens with some, some of these studies, isn't it? Is that it's hard to design them because people will, you won't recruit them unless you, you give a bit here and there. And that's what, why they, they, there will always be these little caveats to it. I think that's really interesting. 

Prof, from your sort of position as editor-in-chief as well, and sort of, of the journal and sort of watching this literature evolve over time and also your current guidance in the UK, what are your thoughts on that?

I think it's an area that has been driven by people who've been burnt by over anticoagulation and by the hematology lobby if you like. And I think it's important to bear that in mind. So aspirin has risen to prominence because of fear what anticoagulation can do. And I always kind of, if you like, try and remind everybody, take a step back and remind everyone that these rules should be based around a risk assessment. At any point in time, as a surgeon with a patient, you've got to risk assess the risk of bleeding [00:09:00] versus the risk of anticoagulation rather than blindly follow a set of rules.

And I think if we as surgeons are thinking about patients, assessing our patients at every juncture, then actually it's much easier to then start making these decisions. So beyond that, I think the drivers for aspirin have been clear. They've been very loud and very popular. And this study now is really very welcome.

I mean, we're looking at two different pathways in hematology. So it's always kind of intrigued me that you're kind of knocking out one pathway, then knocking out the other in one protocol in some guidelines. So I think it needs, this is great work. But more work is needed. Certainly, I think from the UK perspective, we're really very fortunate in that we've got NICE and NICE, if you like, gives us a framework that most colleagues can understand and follow.

There is then local nuanced interpretation in different [00:10:00] organizations for their own guidelines and protocols in hospitals, but at least NICE for the hip has made it pretty clear that you need to go with low molecular weight heparin or a Factor X inhibitor, but you have the option in a lower risk patient to change to aspirin after ten days.

Again, whether we need to revisit that now or not is an interesting discussion. I think where surgeons are really going to want to ask questions is in the knee, where for the lower risk patients, NICE has allowed us to use aspirin. And I think surgeons have grasped that. Because it removes all the complexities and CRISTAL's now going to ask questions about that. 

Absolutely. And that sort of leads us very nicely back to you, Ian, obviously your great study, CRISTAL. So, I'm sure many of our listeners have are aware of it, but could you maybe tell us a bit about it in particular, maybe starting off about the design of CRISTAL and the reasoning for that?

Yeah. Well, we needed a large study. The design was to compare low-dose aspirin, which is the commonly used [00:11:00] form of aspirin, what most people suggest these days compared to low molecular weight heparin. And we'd previously done surveys around Australia showing that these basically were the two most common forms of VTE prophylaxis.

Interestingly, you mentioned the oral anticoagulants. They're also fairly popular. They figure around ten to 15%. And in fact, the main reason why they're not more popular is cost. Because we have an issue here where it actually costs the patients themselves a lot of money to get those drugs. And it's just a quirk of the Australian system, whereas aspirin and clexane are virtually free for the patients.

So they were the two most common, and they had not been compared in an adequately powered RCT. A lot of people say, oh, there's lots of RCTs comparing aspirin to clexane. There aren't. There's two which a total of about 500 patients. You know, hopelessly underpowered. There are other studies that compare aspirin to clexane, but for example they compare aspirin and [00:12:00] mechanical prophylaxis to clexane without mechanical prophylaxis.

To me, that gets included in systematic reviews. To me, that's not a fair comparison. So the literature wasn't there. And, and ever since I was an intern and attending orthopaedic conferences, I've seen people argue about aspirin versus low molecular weight heparin. And I just really wanted to settle this argument. And there was a lot of support. 

So, you know, we got 30 well, however many hospitals we got. And a lot of, you know, surgeons were pretty happy to recruit and we did a cluster randomized RCT. It's just a lot easier to do. That means you'd say to a hospital, okay, you're using, you know, we toss a coin, you're using aspirin, for the next, you know, 250 patients, and then you'll flip over and use the other one or vice versa.

And so, so that was the design and we nested it within the Australian Joint Replacement Registry which was actually a very efficient way of doing it because they already [00:13:00] recruit patients for patient-reported outcomes. So patients fill out all their outcome scores online. It's all automated with electronic follow up.

So we had this, you know, beautiful, efficient system to collect data from patients. And we really just sort of tapped into that. And so that's, that's why we were able to, to do it. 

That's great. It's like you say, it's interesting, isn't it? These common questions that for decades people argue about, but there's no real answer to it or there's no evidence to answer.

It's fascinating that it's throughout our specialty in medicine, isn't it? But, and in terms of you, you've alluded to, but the primary outcome for the trial, that was symptomatic VTE. Is that, that's correct?

Yeah. Most places don't routinely screen for VTE. I think in some private centers they do, but that's largely gone by the wayside because of recommendations that it's not actually helpful to routinely screen for it.

So it was only if the patients were symptomatic and it was any symptomatic VTE event up to 90 days, which is the usual [00:14:00] timeframe because as you know, these occur normally in the first few weeks and, and rarely after 90 days because patient's mobility is normally restored by then.

Absolutely. And in terms of sort of, again, for our listeners, the headline sort of take home message from the, the CRISTAL paper, which was published in JAMA.

Well, fortunately we had nice round numbers that are easy to remember. So we had a 2% absolute risk difference. So it was 1.8% versus 3.5% for aspirin, but in the adjusted analysis was actually 1.96 or so it's 2% difference, which is a number needed to treat a 50. And it was a twofold difference as well.

And that was the same for PE as DVT, but of course, PE is much rarer. So the the significance for PE alone was not significant, but the difference was also a twofold rate with a wider confidence interval, favoring low molecular weight [00:15:00] heparin. 

Yeah, absolutely. And in terms of the subsequent studies, including the, you know, the paper you recently published just last month, 'Cost-effectiveness of aspirin versus enoxaparin', what did that show?

Yeah, we were published a few papers since then. That primary paper was just looking at primary unilateral hip or knee for osteoarthritis. So very narrow set. We've done other studies that look for, look at all comers, hip fractures you know, revisions, hemiarthroplasties, et cetera. We found pretty much the same results.

And then more recently, as you referred to, we've published the cost-effectiveness analysis. So low molecular weight heparin costs more. We know that. And one of the advantages of aspirin is that it's cheap. And it, it was a roughly, I guess, in US dollars, if you, because most people can equate to that, it was about 50 US dollars more expensive to use it. So you have to take that into account. But, you know, it depends on what your cost-effectiveness threshold is, but we found it likely [00:16:00] to to be cost-effective. And the, you know, the longer you stretch out your time period, the more cost-effective it is. But, you know, it's a, it's a legitimate argument. It does depend on what price you put on preventing VTE. 

Absolutely. No, I totally agree. And before we sort of, sort of round up with all that, you know, in terms of the trial itself, is there any limitations that you acknowledge with it or anything you would do differently now, you know, in such a massive trial?

Yeah, I probably wouldn't do a whole lot different. Certainly there's been a lot of criticisms and there was editorials in JBJS and Journal of Arthroplasty, which we were not you know, not given an opportunity to respond to until they were published. And then we found that they were really not very fair.

So we published a letter, which is buried in the back of one of the journals somewhere, which responds to the editorials. But yeah, the, the, there was a difference in recruitment rate between some hospitals, but that's life. And we analyzed for that and we found that, [00:17:00] high recruiting hospitals have the same results as low recruiting hospitals.

A lot of patients are already taking aspirin, which makes it difficult. We're trying to work out what to do with these people. It kind of confuses an RCT. And we thought, well, we've got to include them because I know there's going to be a lot of them. And it was roughly about 15% of all of our patients were taking aspirin. And so we thought, well, if they're taking aspirin and they're randomized to aspirin, we'll just keep them on it. 

But also if they're on clexane, we, we kept them on it. So that is confusing, but again, we knew this and it was built into the sensitivity analysis. And we looked at the patients who were already on aspirin and the patients who weren't on aspirin and we found the same results.

 So, you know, we've addressed a lot of the criticisms. I guess it's not a blinded study. I think that would have been just way too hard. You know, we would have been injecting saline in people and giving people tablets and logistically that would have been a nightmare. Yeah. You know, but that's that's another limitation.

No, that's very fair. And like I say, it's such a, an impressive study. Like you say, I can't do [00:18:00] those things, which are things which are real, aren't they, they just, what happened every day where you all have patients who come in and they're, they're on aspirin, you know, and, and what do you do? 

So, yeah, there's no such thing as a perfect study. I mean, every single RCT in the world, you can find fault with it. But what surprised me is that a lot of people have said, well, you know, there's a mismatch between hospitals or 15% of people on aspirin. Therefore, we will completely ignore the results of this high-quality study and continue to believe the observational studies, which is largely really the only thing that's supporting aspirin, is observational studies.

And these are studies that include people over a 20-year period. And we know that VTE rates decrease, have been decreasing over the last 20 years. Aspirin use has been increasing over the 20 years, yet many of these studies don't adjust. For the year, so they don't adjust for time. So really, they're just looking at more recent joint replacements compared to [00:19:00] joint replacements in the past. Yeah. And they're saying, oh, look at the more recent ones. They're more likely to get aspirin and less likely to get a VTE. Therefore, aspirin lowers the rate of VTE. That's not a valid argument based on observational studies.

That's, that's really interesting. And I think maybe that, that brings us to sort of, sort of our wrapping up. And in terms of Sam, if I could come back to you, you know, given all that and, and, and, and the data from CRISTAL, what do you feel for arthroplasty surgeons are the real key learning points from that and, and maybe practice changing points?

Yeah, well, I think for the first time, we actually have a really precise estimate of what the true symptomatic VTE rates are in arthroplasty. We really didn't know this comparing aspirin to a low molecular weight heparin. We can say with a certain, with a high degree of confidence, if you take aspirin, you'll have a 3.5% risk. And if you take a, use a low molecular weight heparin, that'll be halved. We haven't had that. And, and that pertains to all, both hip and knee arthroplasty, revision arthroplasty, and the results are, or the, the odds difference are even higher if you're, if you're at [00:20:00] high-risk have had, had had DVT before.

And so for us as surgeons, this is really useful information that we can hang a hat on it. And you can decide what you want to do with this information as a surgeon, how heavily you want to weight a below knee DVT in terms of clinical concern, that's up to you. If you don't think post-thrombotic syndrome is not a major issue, then, you know, keep using aspirin.

But in my practice, I believe it is, and I've seen people with significant venous ulcers after having a DVT. The second thing I think is, you know, as we start developing further consensus statements, it's really important that the experts on those panels, weight the evidence in terms of the hierarchy of the evidence.

So if you're using observational data in hundreds of thousands of patients and weighting based on sample size, you're going to continue getting skewed data as we continue to see in observational studies, even up to this year on the use of aspirin. 

And the third thing is, look, this is really world-class research. I'm extremely proud to be an Australian, to have Ian Harris ,Vinny [00:21:00] Sidhu, who was the the, the other leader author of this study, the registry in Australia and the AOA behind this study. This is world-class research. This is practice changing research. And they need to be commended on that. And, you know, if you're listening to this podcast, you haven't read this, make this part of your next journal club, make this paper part of your reading to see how a really well design study is conducted.

I think that's great, Sam. And I think that's a really nice summary of that and the implications of it. And I'm just conscious of time, maybe Prof, if I could finish with you, you know, what, what do you think, you know, what's your summation of all this and, and where do you think we need to sort of go, go next? What's the next move forward in, in this, in this arena?

Well, I think this is a really important piece of work. I think NICE, you know, we're very fortunate in the UK for those UK listeners that NICE will look at this and they primarily look at level-one data and, and really treasure that above anything else.

So I think that it will figure and it will come into thinking in the UK. I still think we've got a [00:22:00] lot of other things to consider here. I think the rate will continue to go down as we continue our multimodal approach from that perspective. I think this has completely changed the landscape for below knee DVTs. Everybody needs to rethink the significance of below knee DVTs. That will change a lot of surgeon thinking, but we've also got to consider stratifying, you know, if somebody is already on aspirin when they come in, does it really make sense that that's their VTE prophylaxis? Surely they should be on something else beyond that.

So I think surgeons need to really take this study on board and it's going to lead to more usage of low molecular weight heparin. I guess the challenge will be that patients don't like injecting. Hospitals don't like sending patients home with injections and the push will come back as to whether we should be looking at Factor X inhibitors again in a different way.

And it'll come back to that balance for me, for each surgeon making a decision of how hard do I want to risk, reduce my risk of VTE versus how much am I willing to accept [00:23:00] my risk of bleeding? That's, that's a, that's the real equation that I think will come back down to individual decision making.

That's great Prof. I think that's a really nice point in where we can sort of wrap up. 

Well, well, I'd like to thank you all for taking time to join me today and congratulations on a great editorial, which has given a really clear overview of the subject and congrats, Ian and the team, on an awesome trial and awesome data that's really, really added some really needed high-quality evidence in the area.

And it was great to have, have you all with us and to our listeners, we do hope you've enjoyed joining us and we do encourage you all to share your thoughts and comments on the various platforms, feel free to post about anything we've just discussed here today. And thanks again for joining us. Take care everyone.