Bioprosthetic-Valve Thrombosis: Lessons From a Case Series

LaPrincess C Brewer, MD; Sorin V Pislaru, MD, PhD

Disclosures

January 20, 2015

Editorial Collaboration

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Bioprosthetic-Valve Thrombosis

LaPrincess C Brewer, MD: I'm Dr LaPrincess Brewer, an advanced cardiology fellow at Mayo Clinic. During today's Mayo Clinic talks, we will be discussing bioprosthetic-valve thrombosis (BPVT). I am joined by Dr Sorin Pislaru, consultant and associate professor of medicine, who specializes in valvular heart disease.

We are here to discuss the very relevant and timely topic of the diagnosis and management of BPVT. Although a rare occurrence in clinical practice, when present, it can be life-threatening. Dr Pislaru and colleagues have recently published a nice case series of the Mayo Clinic experience with BPVT in an article titled, "Misconceptions, diagnostic challenges, and treatment opportunities in bioprosthetic valve thrombosis: Lessons from a case series," published in the European Journal of Cardiothoracic Surgery in May 2014.[1] The study provided excellent insight into the diagnostic challenges of BPVT and offered clear recommendations on improving echocardiographic diagnosis. We are eager to hear your expertise. First, can you provide us with background on BPVT as a medical issue, and does it exist beyond isolated cases or patients with a known high risk for thrombosis?

Sorin V Pislaru, MD, PhD: This is a difficult question, because it has been quite hard to diagnose the condition in the first place. If you do not know a problem exists, you will not find it. You know what they say: "The eyes will not see what the mind doesn't know." The first troubling issues came with the realization that many patients who had bioprosthetic valves implanted came back for redo surgery early on. Dr Hartzell Schaff, our lead surgeon for many years now, published his experience with aortic BPVT spanning almost 12 years.[2] They did more than 4000 prosthetic aortic-valve implantations; and of those, about 3000 were porcine valves. The incidence of BPVT was actually quite low, just about 0.18%. At the same time, we do not know how many patients had valve thrombosis and were never diagnosed or were outside the 2-year window that was predefined for the search that they performed.

A more troubling signal came from a very systematic review from Denmark published in JAMA.[3] This study encompasses every aortic-valve replacement that has been performed in Denmark. They have a registry that every hospital in the country subscribes to, and they also have data on every medication that these patients have taken. The troublesome finding was that if patients discontinued warfarin within the first 6 months after aortic-valve replacement, they were more likely to die, have a stroke, or have a thromboembolic complication. It is hard to not associate this finding with the possibility of aortic-valve thrombosis being a common reason for all these events. With that in mind, we thought we should look at our own experience with BPTV, and this is what we plan to talk about today.

Raised Thrombogenic Risk

Dr Brewer: Thank you for that insight on the current medical literature in this realm. Which valve position is at higher risk for thrombosis?

Dr Pislaru: We usually think that the valves that are at lower gradients and lower flow rates are at increased risk for thrombus; and typically, the tricuspid valve is at the highest risk followed by the aortic-valve position. With the pulmonary valve, we do not have enough data points; but certainly, we have seen pulmonary-valve prosthetic thrombosis in our series, so that exists too. It is probably the same degree of risk as aortic valve. It is just that the numbers are much smaller. Fewer patients have a pulmonary prosthesis compared with the other three valves.

Dr Brewer: What about porcine vs pericardial valves?

Dr Pislaru: A common report in the literature is that porcine valves are more thrombogenic than pericardial valves, and the question is why. Many hypotheses have been formed. One hypothesis generated by the Schaff paper was that the porcine valves actually have a rail that is by design. The porcine tissue has to be sewn into the valve ring, and that creates an area where, perhaps, there is some stasis. That being said, is it that we see more porcine bioprosthetic valves thrombosed than pericardial valves because they are more common and because they have been around longer, or is it because they thrombose more? We have also seen pericardial valves thrombose, but there was a lower number of these in our series.

Dr Brewer: What about stented vs stentless designs? Are there any differences there?

Dr Pislaru: The stentless design is thought to be less thrombogenic, but there are so few, because these are still very new, that we cannot really comment. No stentless valves thrombosed in our series, so we are waiting to see.

Dr Brewer: From an epidemiologic standpoint, when is the peak incidence of BPVT?

Dr Pislaru: I want to emphasize the misconception about when BPVT occurs. Everyone knows that the first 3 months after implantation is the high-risk period because it takes a long time for the valve to be reendothelialized. For that reason, most centers will systematically anticoagulate patients for mitral, tricuspid, and pulmonary prostheses (plus/minus aortic procedures) for the first 3 months. Beyond 3 months, people usually do not think of the valve as being thrombogenic and perhaps let their guard down. We noticed in our series that the peak incidence was the second year after implantation, and the longest in our published series was about 7 years after implantation. We keep active surveillance on this issue. Just a few months ago, we identified a patient 10 years after implantation with a confirmed BPVT, successfully treated with warfarin.

Thickened Leaflets and Increased Gradients

Dr Brewer: How can we diagnose BPVT, and are there any specific echocardiographic findings that we should be looking for?

Dr Pislaru: This is the biggest challenge of all. The most important thing is to be aware that the condition exists. We looked at our series. We identified patients with BPVT based either on surgical data (they had surgery for one reason or another; and at pathology, there was confirmed thrombus on the valve) or on clinical grounds. The active cardiologist involved with the patient thought of the possibility, treated them with a vitamin-K antagonist, and the gradient across the valve decreased. But when you look back at our echocardiographic data in this 31-patient series, we notice that in only a minority of patients did the initial echocardiogram suggest the possibility of BPVT. All the echocardiographic reports described abnormal valves. The common findings are thickened leaflets and increased gradients. These are the two common findings on an echocardiogram report. When you see these, you need to be aware that BPVT is in the differential diagnosis. So what we suggested was to consider the possibility whenever the gradient is more than 50% above the baseline value or above the published reference value (if you do not have the postimplant data) and you have thickened leaflets. Whenever you see those findings, you probably should consider obtaining a transesophageal echocardiogram (TEE) as a confirmation test for BPVT.

That being said, even the TEE is not perfect, because imaging, especially of a bioprosthetic valve, is extremely challenging. You have to image across the valve ring, and that creates acoustic shadowing. In our series, nine out of 12 patients with thrombosed aortic valves had been diagnosed by TEE, but in three out of 12 we were not able to identify it, even if there was confirmation at pathology of the thrombus being present. So it is quite a challenge. We do not know how well CT fares, so CT is another possibility to look at this. Other modalities are unlikely to play a role in the diagnosis.

Dr Brewer: What are the differential diagnoses?

Dr Pislaru: The common problem is early valve degeneration, for a host of reasons. We know this occurs. We do not know whether some of the valve degeneration starts as valve thrombosis. This is pure speculation, so we cannot make this claim, but you could imagine that if a valve thromboses and that thrombus gets organized, that can lead to valve degeneration later on. Looking at all the echocardiogram reports, we often struggle to explain findings of increased gradients with other sources of high gradient such as high flow. If somebody has anemia, is hypothyroid, has sepsis, or has high flow, sometimes the gradient is increased because of the secondary condition rather than because of a valve problem. Even then, you should keep in mind that you could have valve thrombosis under those circumstances as well. Just because a patient has anemia does not mean he or she cannot have a thrombosed aortic-valve prosthesis, for instance.

Scant Treatment Guidelines

Dr Brewer: Moving along to therapeutics, can you tell us about the current options, such as surgery vs thrombolytics vs anticoagulation?

Dr Pislaru: This is a very important treatment decision. Because there is a lack of data on BPVT, the European and American guidelines[4,5] both discuss mostly how to treat mechanical-valve thrombosis, and there is virtually nothing on bioprosthetic valves. People assume that because you have a valve thrombosis, you should use the treatment that is designed for mechanical valves. That treatment in the United States favors surgery and thrombolytic therapy for left-sided valves (if there is occlusive thrombus) and vitamin-K anticoagulation (plus/minus heparin and aspirin) if the patient is stable. European guidelines also talk about optimal anticoagulation if there is a low thrombus burden or no evidence of heart failure and favor an intervention such as thrombolytics or surgery if those conditions are present.

In our series, 17 patients were treated with either thrombolytics or surgery and about 15 patients were treated with just warfarin, a vitamin-K antagonist. They did equally well. So 13 of 15 patients treated with warfarin had improvement in their gradients and resolution of their symptoms. We suggested that vitamin-K antagonists should be considered for first-line therapy whenever the patient is stable enough for longer treatment. If the patient has hemodynamic instability, a large thrombus burden, or a mobile thrombus that you are afraid may embolize, then obviously you need to consider surgery or thrombolytics.

Dr Brewer: What about novel oral anticoagulants for bioprosthesis? Do these agents have any role?

Dr Pislaru: This is a complete unknown, and the reason is that novel anticoagulants are not approved for use in patients who have bioprosthetic valves. They were never studied in this population; and there are no data to support or refute their use for this indication. One study has been conducted to evaluate whether novel anticoagulants could be used instead of warfarin to treat patients with freshly implanted bioprosthetic valves. The results have not been published yet, so we have no data. I would discourage anybody from treating with novel anticoagulants until we have some sort of evidence that they work. The mechanical valves and novel anticoagulants was a disaster story.

Risk Factors and Awareness

Dr Brewer: Can you define the incidence based on surgical registry data?

Dr Pislaru: We have to be more aware of what we have. As a next step we plan to examine our entire surgical population and look at all the patients who have increased gradients within the first 5 to 10 years after implantation to see whether this is a problem of greater magnitude than we have appreciated before. Retrospective studies are always hard. It's always important to keep the awareness high; and over a period of less than 1 year, we accumulated more cases treated with a vitamin-K antagonist than in the first 16 years of our previous study. So the disease exists. If we know about it, we can treat it. We want to make a push to raise the awareness about this condition.

Dr Brewer: What are the risk factors for BPVT?

Dr Pislaru: If you have a hypercoagulable state, you are at high risk of having a thrombosed valve. If you have a very low left ventricular systolic function, you are probably at high risk of thrombosing your valve. Atrial fibrillation is a risk factor. Are these the only important risk factors? We don't know. There are not enough data to propose other factors, such as porcine vs pericardial, stented vs nonstented, and small valves vs large valves. We do not have enough data points to make any significant judgments. We are looking actively at the patients who had confirmed thrombosis and had their valves replaced vs the ones who had their valve replaced for degenerative disease. We are looking to see whether there is anything to differentiate them or identify risk factors, but that is going to be a long-term project.

Dr Brewer: You have alluded to its importance, but how do we raise awareness in the cardiology community on BPVT to guide clinical-practice change?

Dr Pislaru: A key point is to send the message out, and this is a wonderful opportunity through our collaboration with theheart.org. I hope that people tune in and hear what we have to say, and we will link to our materials and presentations. We have presented the data at various meetings already, and we will try to show our data in the future at European and American society meetings. Word of mouth goes a long way.

Dr Brewer: Thank you, Dr Pislaru, for these very important insights, which will definitely change our clinical practice. Thanks to our listeners for tuning into Mayo Clinic talks at theheart.org on Medscape.

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