John M. Mandrola MD: Hi, everyone. This is John Mandrola from theheart.org on Medscape. I am here at the American College of Cardiology sessions and I am very pleased to have Dr Raj Makkar, who is principal investigator and senior author of an important paper looking at the RESOLVE and SAVORY registries and the possibility of subclinical leaflet thrombosis on bioprosthetic valves. It was simultaneously published in the Lancet. Welcome.
Raj R. Makkar, MD: Thank you, John.
Dr Mandrola: Can you tell us about the background of this study?
Dr Makkar: From our previous work and the work of others, we know that there is this phenomenon of reduced leaflet motion in bioprosthetic valves which was ultimately attributed to formation of clot on top of leaflets. We wanted to find out how common this is in a large cohort of patients, if this is a finding that affects clinical outcomes and the functioning of a valve and valve hemodynamics, and whether it is something that is treatable with anticoagulation, especially using the novel oral anticoagulants.
Dr Mandrola: You have a previous study looking at incidence, but it was smaller, and this was a larger study.
Dr Makkar: That is correct. In our first publication in the New England Journal of Medicine, the incidence varied depending on the cohort of patients we looked at. It was a total of 187 patients. The incidence was high at 40% in the Portico IDE cohort. Then in the two registries, which are now expanded, the incidence was about 11%-12%. One of our major goals was to find out how prevalent this finding is in a large cohort of patients. The current sample size is close to 900 patients; we thought that was a good number to come up with a reliable estimate.
Dr Mandrola: Tell us about these 4D CT scans.
Dr Makkar: Putting it very simply, 4D CT scans are done using high-resolution (second-generation) CT scanners, which most companies have. The difference is in the acquisition protocol; you have to have a technologist who knows how to acquire these images. Basically, you acquire images at different time points in a cardiac cycle, so you can actually see the leaflets open and close. That tells you whether the leaflet motion is restricted or not.
Dr Mandrola: How did you define subclinical thrombosis? It's not just seeing a clot, is it?
Dr Makkar: The first thing we do is look at the 2D ECHO, 3D volume-rendered images, and also 4D. You are looking for reduction in leaflet motion of at least 50%, so the leaflet has the inability to open. Then corresponding to that on the 2D and 3D images, you are looking for presence of what are called hypoattenuated lesions. They look like black blobs on top of leaflets.
Incidence and Clinical Consequences
Dr Mandrola: You asked a number of clinical questions, so let's get into the results. What is the incidence?
Dr Makkar: We found in this cohort of close to 900 patients that leaflet thrombosis was present about 12% of the time. The second thing we observed was that this was present more often in transcatheter heart valves than in surgical aortic valves. Now, it is important to point out that these patients were different. Patients who got surgical aortic valves were younger and had fewer comorbidities. It is quite possible that the comorbidities affect the clotting system and lead to this phenomenon. It is an unmeasured confounder. Knowing whether this is truly more common in transcatheter versus surgical valves will come from some of the imaging substudies that are incorporated in the low-risk studies that are ongoing.
Dr Mandrola: Theoretically, there are reasons why it may be more common in transcutaneous valves.
Dr Makkar: The theoretical reasons could be crimping of the leaflets, the fact that you leave the old valve behind and there may be alterations in flow patterns, etc. I think it is very important to put these findings in proper context. When you look at the results of randomized clinical trials that test surgical aortic valve replacement versus transcatheter aortic valve replacement, if anything, there are better outcomes, lower death rates, and lower stroke rates with transcatheter aortic valves, and equal durability.[4,5] You have to look at this as one variable.
Dr Mandrola: Tell us about the anticoagulation and antiplatelet effects.
Dr Makkar: As you know, the 2012 American College of Cardiology guidelines say that you should use dual antiplatelet therapy. It is not based on a lot of evidence, but that is the recommendation. What we found in our analysis was that dual antiplatelet therapy did not really significantly reduce the incidence of this problem. This was prevalent 15% of the time in patients who were on dual antiplatelet therapy. In contrast, when patients were treated with anticoagulants, the risk was about 3.5%/3.6%, so, significantly lower. New/direct oral anticoagulants (NOACs/DOACs) have traditionally not been very good at treating valve-related issues. True, those were mechanical valves. These are tissue valves, so for the first time in a large dataset, we can say that NOACs at least prevent this finding of subclinical leaflet thrombosis.
Dr Mandrola: There was also an effect seen with initiation of anticoagulation in patients who had the thrombosis.
Dr Makkar: This was an observational study. I believe that is the beauty of the study, because it allowed us to do different things based on what the patient, the doctor, wanted done, or needed to do. We were able to look at different things. We had 36 patients who had leaflet thrombosis and who were treated with anticoagulation, and t we found that when we treated them with anticoagulants, this finding disappeared in all of them.
Dr Mandrola: All of them?
Dr Makkar: Yes, all 36 patients. In contrast, we had 22 other patients with leaflet thrombosis who were not treated with anticoagulation for a variety of reasons, and in 20 out of 22, the finding persisted. That tells us that if you do not treat this, it is likely to persist.
Dr Mandrola: What if you treat them for a period of time and then you stop—what happens?
Dr Makkar: The data are limited. I want to start with that statement. What we know is that when we treated these patients for 3 months (because that is what we did) the finding disappeared, but disturbingly there were eight patients who we brought back for repeat CT, and in half of these patients the leaflet thrombosis actually came back. That tells me that 3 months of treatment may not be enough in all of these patients. "How long" is a big question that needs to be answered.
Dr Mandrola: Small numbers but provocative nonetheless. Let's go into the effect on valve function and possibly even in clinical outcomes.
Dr Makkar: When you look at these images of leaflet thrombosis, they look very dramatic. The question is, does it really show up on echocardiogram, which is what we normally use for surveillance. We observed that you can have a leaflet completely stuck but the ECHO gradients may be normal. What we observed was that there were small increases in gradients, so the gradient went up in patients who had this phenomenon, by about 5 mm Hg. We also showed that it was more common for a new increase in gradient, so 15% of patients who had this finding had a new increase in gradient by 10 mm Hg compared with 1% of patients who did not have this finding.
Looking at the other side of this equation tells us that almost 85% of the patients had gradients that would be considered normal. If you are just using echocardiogram, you are going to miss this finding.
Dr Mandrola: Then there were some data on clinical outcomes and associations.
Dr Makkar: For me, as a very busy TAVI operator who uses this technology, it is a relief that there was no impact on death and MI. There was no significant difference in terms of strokes; the strokes were numerically higher but not statistically different. You could say that if you cannot show a statistical difference in almost 1000 patients, that is reassuring. However, the rate of TIAs was higher. They were statistically higher irrespective of how we looked at it, be that time since TAVR, excluding the first 72 hours; whether the TIAs and strokes may have other causes; or just counting the TIAs that occurred after the CT scans were done. Nonetheless, these are just associations. We did not prove causation here in terms of leaflet thrombosis and TIAs.
Dr Mandrola: You had some interesting clinical implications. Let's go over some of those.
Dr Makkar: My first takeaway is that if you are doing TAVI/TAVR in patients who are elderly and at increased risk of bleeding, you could make the argument that monotherapy was as effective as dual antiplatelet therapy. You could do away with dual antiplatelet therapy—quite a conclusion to derive from a study that actually talks about more anticoagulation being effective.
The second conclusion is that in younger patients, I cannot make the recommendation that we should routinely give anticoagulation, but I think it's time to start thinking about using anticoagulation in some of these patients. The right thing to do is to do clinical trials that test routine anticoagulation, routine CT strategies, and see what actually makes sense.
Dr Mandrola: I want to get you to think about the most provocative question, and that is, if there are gradients in subclinical thrombosis, does this say anything about longevity of tissue valves?
Dr Makkar: It is very interesting that you bring this up because we can put this in context of, for example, a study that came out of Brigham and Women's and the Mayo Clinic a few months ago looking at the valves that the surgeon had explanted for clinical reasons. In about 12% of those valves, the primary reason ended up being thrombus. So after the surgeons took out the valve, they realized there was thrombus. Just being aware of this finding is important because you can treat these patients with blood thinners and then you do not have to explant the valves.
That brings us to the issue of durability. The data are thought-provoking. Given that there is a small increase in gradients and given that patients with this finding had a greater increase in gradients, does this affect long-term durability? I think it is an open question. I would like to speculate, but I do not think I can.
Dr Mandrola: Very good. It is a real pleasure to talk to you, and congratulations on your study.
Dr Makkar: Thank you very much, John.
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Cite this: Implications of Subclinical Leaflet Thrombosis in TAVR/SAVR - Medscape - Apr 05, 2017.