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CHRISTOPHER DESIMONE: Hello, and welcome back to the Mayo Clinic Medscape video series. I'm Dr. Christopher DeSimone, cardiologist and Director of Marketing. And today, we'll be discussing bioprosthetic valve thrombosis. I'm joined by my colleague, Dr. Sorin Pislaru, consultant and Professor of Medicine and an expert in this area. Welcome, Dr. Pislaru.

SORIN PISLARU: Thanks for having me, Chris. It's a great pleasure to talk about bioprosthetic thrombosis.

CHRISTOPHER DESIMONE: I know this is an area of passion for you, and you're an expert. So we just want to start off by asking, what is bioprosthetic valve thrombosis, and when do you find it occurring?

SORIN PISLARU: So this is a long story. Carpentier implanted the first xenograft in a patient in the '60s. And you can imagine, at that time, neither echo nor CT were available for routine evaluation. So it took a little while for the cases of bioprosthetic thrombosis to trickle into the literature.

And for a long, long time, the disease was considered to be a rare event. There's case reports of one or, at most, two patients or so who had bioprosthetic thrombosis through the '70s and '80s. And then people start to realize that this may be actually more common than what you think. We have a group here of several cardiologists and cardiac surgeons who became interested in the phenomenon early on, and we started looking deeper into our reports.

So what is it? Well, it's simple. It's thrombosis of a bioprosthesis. They are supposed to not have that event. We do anticoagulant routinely after implantation. So it was felt that, once you're past those three months in which the valve re-endothelializes, you're out of the woods.

And what we've seen, actually, is that you do have a thrombosis that occurs late after implantation, meaning in year two, year three, year four, post-implantation. And the latest we've seen was a little over 10 years after the initial event. But the bulk of them occur somewhere between years 1 and 3, so that would be the peak.

CHRISTOPHER DESIMONE: Perfect. And I know it's very difficult, depending on the study that you-- the population that you study, but in your population, what's the incidence of bioprosthesis? This seems like a very serious topic and could have lots of ramifications for our patients. So what's the incidence of bioprosthetic thrombosis?

SORIN PISLARU: So, Chris, just as you pointed out, I think you're largely depending on which population you look at and what's the methodology of looking at. So if you look retrospectively, like we started doing in early 2011, 2012, what we noticed is that the incidence was not very high.

So one of the first papers published from our group looked at patients who needed a reoperation for a bioprosthetic valve. And in that series, the presence of a thrombus on a bioprosthetic valve as a reason for the valve failure was present in about 10% of the patients. Now, of course, that's not the total number of patients. And if you say, during that study interval, how many bioprosthetic valves have been implanted at the Mayo Clinic? And you say, as a percentage of that total number, the incidence would be about 1%. So that's all retrospective.

Now, Raj Makkar had a huge impact on the literature with his paper in New England in 2015, where they looked systematically with 4D CT at patients who had transcatheter aortic valve replacement. And once you go to that study, you see that the incidence becomes much higher. So they quoted around 10% to 12% incidence at one month. And there are several registries from various groups that show an incidence of about 10% to 12% to 15% bioprosthetic valve thrombosis at one month post-implantation in transcatheter aortic valve.

So what's the difference between the two? Well, I guess we never look with CTs in a systematic fashion in our population. So could we have missed some patients? Yes. At the same time, remember that all TAVR valves in all the clinical trials did not require anticoagulation. So patients were placed on dual antiplatelet therapy.

So was that the problem? Is that the reason why they have more thrombosis? It's very hard to tell. My guess-- it's probably somewhere in between, between 1% and 10%, somewhere there.

CHRISTOPHER DESIMONE: Excellent. So that was one of my questions, was-- given now that we're doing lots of transcatheter valves, is there something inherently different about the valve, or is it just the antithrombotic, anticoagulant regimen?

SORIN PISLARU: It's a good question. And fortunately, we now have an answer. So for a long time, people said that transcatheter valves and surgical valves are different, meaning that, hey, there's Neosinus, because you have now the valve stent that's implanted there. You have the native valve that remains in place, whereas the surgical valve will require removal of the aortic valve-- native aortic valve.

So there was a lot of discussion why the incidence is so low in surgical valves and so high in transcatheter valves. And I always felt that they shouldn't be all that different. And I always thought that, well, maybe we don't find them in surgical valves because we don't look.

And just last year in spring, both the PARTNER group and the CoreValve group published their results in the randomized trial for low-risk patients. And they both showed that patients in surgical group and in transcatheter group had significant incidence of bioprosthetic thrombosis. That was quite a bit.

It was actually in the order of 10% to 20% for surgical valves, too, and not that different from transcatheter valves at one year term when the incidence was 20% to 30%. So I think they are just the same valves. It's just you start looking, you'll start finding.

CHRISTOPHER DESIMONE: Sure. Very interesting. So now, I guess the next question, to me, would be you have an episode of this valve thrombosis, and you treat it however you want to treat it-- with anticoagulation. You reimage the patient. They do fine.

Long-term, tell us, is there anything that these patients are at higher risk of? Are we more worried about these patients? Should we be imaging more seriously with them in parallel? What do you think? What are your thoughts?

SORIN PISLARU: I think this-- again, it's a field in motion. And our most recent study looked exactly at this question. What happens with those patients who were identified as having a clinical episode of bioprosthetic thrombosis, meaning that a clinician has recognized the event, has treated the patient with anticoagulation, and then what happens with that patient at follow-up after anticoagulation resolves the initial problem?

And it turns out that, in terms of strokes and peripheral embolic events, these patients do not do any different than patients who never had bioprosthetic valve thrombosis globally. Now, these are small numbers. So if you go large numbers, you may be able to pinpoint differences in these. But what we've seen are two important things.

One in four patients who had one episode of valve thrombosis will have a second, and sometimes a third or a fourth episode of valve thrombosis. So in other words, once you stop treating them with anticoagulation because you said, hey, we fixed your valve. You're home free. You need to be very, very careful.

And my personal feeling is that, if the patient who had a valve thrombosis is at very low risk for bleeding, it would not be unreasonable to consider long-term anticoagulation for these patients. So that's problem number one. One In four will have another episode of valve thrombosis.

The second problem is do you restore prostheses longevity? So you diagnose the disease. You treat effectively with anticoagulation. Are you going to restore the lifespan of the valve? And the answer that is probably not.

So what we did-- we took patients who had successfully treated bioprosthetic thrombosis and matched them to patients who had the same type of valve, same size, same gender, same year of implantation, and so forth. And then, if you go at long term follow-up, what we saw at 10 years was that, really, patients who did have valve thrombosis are more likely to need another intervention on the valve, be that a new valve in valve or a surgical re-intervention. So chance of that was close to 70% at 10 years, versus about 20%, 25% in control. So we think that bioprosthetic thrombosis hastens prosthetic degeneration, which you could imagine is related to the thrombotic event in the first place.

I hope that, once we see long-term data from randomized trials from PARTNER and CoreValve, those patients who were found to have valve thrombosis by 4D CT will be followed up, obviously, as part of the clinical trial. And we will see what happens at three years, five years 10 years time, in terms of a randomized clinical trial. That will be very interesting to see.

CHRISTOPHER DESIMONE: Very good. So it's really nice to have an expert like you giving us a glimpse into the future. If I had to just pin you down for our viewers and say, right now, if you had a patient that came in with bioprosthetic valve thrombosis, which anticoagulant, plus or minus antiplatelet, would you choose? And for how long do you need to treat them? I know you alluded to as long as we can as being safe, but what would you say is guidelines for our practitioners?

SORIN PISLARU: So in general, every patient has a bioprosthetic valve or a mechanical valve, for that matter. We recommend that they are on aspirin. The guidelines in 2020 and 2017, 2014, 2008-- all the recent editions of the valvular guidelines support the use of aspirin every type of prostheses. So aspirin is a go. Many times, aspirin has been replaced by Plavix in these patients who have concomitant coronary disease and had stents and so on and so forth. So that's a must.

Now, when you diagnose the thrombus on the valve, then the question is, do you go to warfarin or do you go with the novel anticoagulants? Because all our experience, or most of our experience, has been with the warfarin anticoagulation, we tend to go to warfarin anticoagulation. As you know, but the current guidelines allow use of novel anticoagulants for nonvalvular indications, such as atrial fibrillation and such in patients who have bioprosthetic valves. But there is no long-term evidence for that.

I was obviously very disappointed when the GALILEO trial was stopped prematurely because of excess bleeding and excess death in patients treated with rivaroxaban in bioprosthetic thrombosis-- in bioprosthetic valves after TAVR. So that was not a good thing. Now, is this across the class, or yes or no? Hard to tell.

We did use a novel oral anticoagulants in a small number of patients, and several groups have used successful DOACs with bioprosthetic thrombosis. But I would say, right this minute, there is more evidence with warfarin than with DOACs, in terms of treating bioprosthetic valve thrombosis.

And then the question is for how long. First of all, I would advise everybody who deals with a patient who has bioprosthetic valve thrombosis, be patient. We haven't published this yet, but it's currently under review and hopefully will come out eventually. We looked at how long does it take for the gradient to normalize if you put somebody on anticoagulation?

And it turns out that you need to wait for a little while. The mitral valve prosthesis respond relatively fast. So if you look at patients who have mitral valve bioprosthetic thrombosis, probably within three to six months, almost 100% of them will resolve.

But if you look at the aortic prostheses and tricuspid prostheses, it will take six, nine, 12 months, sometimes up to 18 months to resolve an event of bioprosthetic thrombosis, meaning that the morphological abnormalities on the valve by CT or by echo have disappeared and that the gradient has returned to normal. So it takes quite a while to obtain your full restoration of a valve function in the aortic and tricuspid position. So be patient.

CHRISTOPHER DESIMONE: Excellent. Well, thank you, Dr. Pislaru, for these very important Insights. And thank you for joining us on the heart.org Medscape Cardiology.

SORIN PISLARU: It's a pleasure participating. Thank you for the invitation, Chris.

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