 Welcome to Texas Heart Institute Educational Programs on Innovative Technologists and Techniques. My name is Von Merkrazier. I'm an interventional cardiologist at Texas Heart Institute and Baylor CHI Medical Center. The topic today is silent leaflet thrombosis, or SLT, after TAVR. What are the causes and how to treat it? Now, post-TAVR valve thrombosis has been described with different names. And the most common is silent leaflet thrombosis, or subclinical leaflet thrombosis, or hypotenuated leaflet thickening, or halt. Obviously, other names have been used to describe this problem. There are certain issues of importance related to silent leaflet thrombosis. And we will discuss several of them that are of importance. Number one, incidence, then predictors of silent leaflet thrombosis, the effect of antithrombotic therapy on silent leaflet thrombosis, consequences of this particular problem and complication, and issues related to a valve geometry and design that are playing a role in silent leaflet thrombosis. And then we'll talk a little bit more about the pathophysiology of silent leaflet thrombosis and why is it less common after SAVR and are procedural factors playing a significant role in this particular problem. Let's talk a little bit about incidence of silent leaflet thrombosis. Silent leaflet thrombosis in surgical bioprosthesis has been described to occur between 0.8% to 4% by several investigators. Now, silent leaflet thrombosis post-TAVR is significantly higher from previous publications and ranges between 4.5% to all the way up to 40%. So obviously, this could be a serious problem. There are numerous publications that were addressing this problem related to subclinical leaflet thrombosis in SAVR bioprosthesis and also TAVR. This particular study is an observational study, and it was analysis of silent leaflet thrombosis post-TAVR and SAVR bioprosthesis using a 4D CT or ultrafast CT. And they analyzed the effects of anticoagulation on valve hemodynamics and also clinical outcomes from two registry, SAVR and RESOLVE registries. The patients that were included in this study had to have interpretable CAT scans as shown here with 3D images and 890 patients qualified for this particular analysis. The data from this particular publication related to the use of 4D CT on the evidence to reduce leaflet motion in multiple prosthesis types is shown here. We can see that with adverse prosthesis, which includes the sapien XT and sapien III prosthesis, the incidence was 13%. With a newer generation, adverse sapien III prosthesis, the incidence was a little bit higher. It was 16%. Now, in comparison, evolut or evolut-core valve incidence of leaflet thrombosis was 6%, which is lower than from the publications related to Edwards and prosthesis. Lotus had a 14% incidence of silent leaflet thrombosis, and the highest one was reported by Portico with 30% incidence of silent leaflet thrombosis. Now, as we also mentioned previously, SAVR has a significantly lower incidence of subclinical leaflet thrombosis, somewhere in the range of 3% to 4%. Here we can see the CT images showing various types of prosthesis and also the incidence and appearance of the thrombosis in the leaflets. And we can see that actually the most pronounced abnormality is during systole, where the leaflet's excursion is limited, and that could affect one leaflet or two leaflets or all three leaflets. And therefore, a silent leaflet thrombosis can present itself with a variety of shades and severities from very mild and almost impossible to identify with imaging techniques to a very pronounced or severe where you have complete valve thrombosis that could lead to serious consequences. So from this particular study, silent leaflet thrombosis on anticoagulants was 4% versus 15% on dual antiplatelet therapy. Obviously, this is a significantly different number and carries a high statistical significance between those two modalities of treatment. Interestingly enough, in this particular study, silent leaflet thrombosis on newer anticoagulants was low. It was 3%. While silent leaflet thrombosis on the Coumadin was 4%. So silent leaflet thrombosis has serious consequences. We can see here, particularly related to stroke and TIA rates. So we can see that when there was a normal valve motion, the incidence was only 3% versus 10% when there was evidence on the CT with presence of silent leaflet thrombosis, which was statistically significant. Another study from Rashid that was presented at TCT in 2017, looked at the variety of predictors, potential factors playing a role in so-called hypotenuity in leaflet thickening or halt. And we can see that anticoagulants at discharge were the most reliable predictor, meaning that patients that did not receive anticoagulants had a higher incidence of thrombosis. Lotus valve also had a higher incidence of thrombosis from this particular study. Hansen and co-workers published in the Journal of American Cardiology in 2016 their data on antithrobotic therapy and the risk of thrombosis post-tabber. And as we can see, there is very interesting information that appeared from their study. The incidence of SLT was high when patients received only aspirin. But it was a little bit lower for patients that were treated with clopidogrel and significantly lower for patients that were treated on dual antiplatelet therapy and even lower on patients that were treated with warfarin or a combination of warfarin and aspirin. And the lowest incidence was for patients that were treated with warfarin, aspirin, and clopidogrel. Obviously, this combination of all three agents has a potential risk of bleeding, which should be taken into consideration. And in their study, NOAAX only also showed a low incidence of thrombosis. So from Hanson's study, using 3D CT, we can see that the incidence of thrombosis or silent leaf and thrombosis was 7% with sapien XT and sapien 3 trans-heart valves. And as far as predictors are concerned, they stated that larger valves had a higher incidence of silent leaf and thrombosis. And another very important factor was NOAA warfarin after TAVR. There was, in their study, no significant difference between different type of trans-heart valve generations. Further information related to treatment of silent leaf and thrombosis. This particular study from Resolve and Saver Registry showed that resolution on anticoagulants of silent leaf and thrombosis was seen in 100% of patients. And 91% of silent leaf and thrombosis persisted for those that were not treated with anticoagulants. Now, there was an interesting study that was carried on. And this was an international study, including 143 sites in 15 countries. Over 1,600 patients that under one TAVR were randomized to 10 milligrams of river oxyben and aspirin for 90 days versus just river oxyben or dual antiplatelet therapy for 90 days followed by treatment with aspirin. This study was terminated prematurely because they found that patients that were just treated with river oxyben had higher incidence of mortality, 6.8% versus patients that were treated with dual antiplatelet therapy where the incidence of death was 3.3%. So this was to a certain degree surprising because the previous smaller non-randomized trials revealed that dual antiplatelet therapy was inferior to treatment with NOEX. There is another study that's all going at the present time. It's also a multinational multi-center study, so-called Atlantis study, which is evaluating a different NOEX for a follow-up of patients with TAVR to determine if NOEX are beneficial in preventing silent leaflet thrombosis. So what are the consequences and importance of silent leaflet thrombosis? As we have seen, recent studies indicate that silent leaflet thrombosis may lead to earlier valve failure. And therefore, FDA has expressed their concerns and have called for prompt attention to this clinical problem. So American College of Cardiology and American Heart Association recommendations are based on the latest information related to SLT post TAVR. And their recommendations are the bioprostatic mitral and aortic valve should be treated with vitamin K antagonists for at least three to six months. In low-risk patients for bleeding, there will be class 2 level of evidence from the data that has been published so far. As far as TAVR is concerned, their recommendations are the use of vitamin K antagonists for at least three months in patients that are considered to be at low risk of bleeding. So let's talk a little bit about issues of importance related to silent leaflet thrombosis as far as valve design and valve geometry are concerned. We have at the present time three different TAVR prostheses approved in the United States for clinical use. Two of them that are most commonly used are shown here, sapien 3 and core valve. Sapien 3 is a balloon expandable valve and core valve is a self-expandable valve. Sapien 3 has a different design, therefore, than a core valve. And it consists of a metallic stainless steel frame, bovine pericardium leaflets, and also polyester material on the outside for prevention of a aortic peri-valve with a leak, and then suture material that integrates all those three components together. This valve is suited for an annular deployment versus core valve that is self-expanding with a nitinol stent frame and porcine leaflets with suture material. And the newer generation valve also has external porcine material wrapped around the nitinol frame for prevention of a peri-valve leak. This particular study that was published in Annals of Thoracic Surgery in 2017 looked at the deployment of the valves at the annular level and at the supra annular level, as far as turbulence is concerned, and stagnation of the blood flow, and a potential risk of thrombosis and silent leaflet thrombosis. And they found that supra-annual valve in valentification reduces blood stasis on the transcharteriotic valves. Now, a little bit more about analysis of so-called supra-valvular versus supra-annular versus annular prosthesis is shown here. For instance, surgical paramount prosthesis is a supra-annular deployment or suturing of the valve. And this one shows the lowest incidence of so-called neosinous formation and the problems with thrombosis versus sapien valve that is placed at the annual level where there is a creation of so-called neosinous, as is shown here schematically on the upper panel, where actually platelet deposition and fibrin deposition can occur between the leaflet and the stainless steel frame and also polyester material that's on the outside. There is no washout here, and that is a potential reason for blood stagnation and also the position of platelets and fibrin. So creation of the neosinous and narrowing of the old existing sinus is a potential problem with newer generation prosthesis, as shown here. So in their description, silent leaflet thrombosis risk factors include low deployment of the valve, over expansion of the valve, neosinous flow stagnation, and potential endothelial damage with balloon expansion of the valves that were suboptimally expanded or aggressively expanded or additional use of balloon expansion to achieve optimal results, as far as gradients are concerned and also in prevention and treatment of perivalvular leak. Further information from their data is shown here, where they show flow dynamics and stagnation of the blood in neosinosis. And they describe the geometric confinement of the taver by the calcified native valve or the failed by a prosthesis increases blood resistance time or stasis on the trans aortic valve leaflets. And they postulate that this may act as a factor in valve thrombosis. Further analysis of their data revealed that thrombus volume increased with the depth of core valve deployment height. But it did not change to any significant degree as far as sapien 3 valve deployment is concerned. And this obviously has something to do with design of the valve, while one can be placed in a supra-annular position and the other one is always in the annular position. They also show here in their study that sapien 3 valves without thrombus were under expanded on an average by 10% in diameter rather than when we see thrombus formation where the valves were overexpanded. So overexpanded sapien valves in their description were at higher risk of narrower neosinosis and formation of thrombus. No such relationship in their study existed among core valves. So in conclusion, silent leaflet thrombosis occurs frequently with bioprostatic valves, more frequently post-stavour than after-savour. Also, silent leaflet thrombosis is associated with higher gradients and higher incidence of TIA and stroke. Current evidence also indicates that SLT is minimized or eliminated with vitamin K antagonists. The risk-benefit profile of anticoagulation should be evaluated in future randomized clinical trials. However, current studies raise the issue of whether vitamin K antagonists or NOAACs are more appropriate in certain subsets of patients than dual antiplatelet therapy after TAVR. The benefits of newer antiplatelet antithrombotic agents for progression of silent leaflet thrombosis is still unknown, and the studies are ongoing at the present time. Silent leaflet thrombosis can be effectively treated with vitamin K antagonists, but not with dual antiplatelet therapy. And finally, the impact of valve geometry and its position on silent leaflet thrombosis varies according to the different valve types and may guide to better future in valve design. Thank you very much for your attention.