Can you tell us about your center and structural heart program?
I work at the EMO-GVM Centro Cuore Columbus and San Raffaele hospitals. Our cardiac surgery department, headed by Ottavio Alfieri, and the interventional cardiology department, headed by Antonio Colombo, work very closely together on the percutaneous structural heart disease program, located at San Raffaele Hospital. We were involved in some of the initial antegrade transcatheter aortic valve replacement (TAVR) procedures, and when the valves became commercialized in Europe, we were one of the first centers to become involved with TAVR. Currently, we do close to 200 TAVRs a year and the numbers have increased steadily. San Raffaele Hospital is probably one of the largest centers in Italy doing TAVR and this work has helped to grow other parts of the structural program, particularly work in other valves. We started doing MitraClip (Abbott Vascular) transcatheter mitral valve repair a few years ago, and in the last 2 years, we have also been doing CardioBand (Valtech Cardio), a direct annuloplasty procedure. We did the first-in-man procedure for CardioBand and are now doing it commercially. We were one of the first centers to start thinking about the tricuspid, and have been involved in percutaneous tricuspid therapies for almost 2 years. In that time, we have been fortunate to have exposure to several devices for treating functional tricuspid regurgitation. It is still a program in its infancy, partially because the tricuspid valve has been a “forgotten valve” by cardiac surgeons and cardiologists alike, since for many years, the feeling was that very little could be done to help patients with functional tricuspid regurgitation.
How is tricuspid regurgitation identified?
Tricuspid regurgitation is best identified on echocardiography. There are two types: primary and secondary tricuspid regurgitation. Primary is a problem with the valve or leaflets, causing damage to either, and secondary, also called functional, is secondary to left-sided heart valve disease, pulmonary disease, atrial fibrillation, or some other cause. Secondary or functional tricuspid regurgitation is probably about 85% of the cause of tricuspid regurgitation, with primary causing about 15%. The majority of patients who have tricuspid regurgitation have it in conjunction with other valvular disease that is treated or untreated, so patients that have mitral or aortic valve disease can develop tricuspid regurgitation. Even patients who have been treated for mitral or aortic valve disease with surgery, TAVR, or MitraClip, can have or develop tricuspid regurgitation. It is possible to have isolated functional tricuspid regurgitation only involving the tricuspid valve, which is usually caused by atrial fibrillation. Both interventional cardiologists and surgeons have just focused on the left-sided valves, the aortic and mitral valve, and we have forgotten about the right-sided valves, for a number of reasons. One, because the right side of the heart is a low-pressure system. Two, we thought that the therapy we had was fairly effective in making patients feel better. Tricuspid regurgitation can be symptomatic, resulting in: shortness of breath, tiredness, evidence of right-sided heart failure (fluid collection on the right side of the body), edema, liver swelling, and ascites. For years, the treatment has been to treat patients with diuretics to decrease the effects fluid congestion which initially helps with symptoms. Patients feel better with the diuretics, but this doesn’t do anything about the underlying tricuspid valve disease. The valve continues to be regurgitant. Decreasing the fluid volume may decrease the severity of the regurgitation, but the valve morphology or the dilatation of the annulus doesn’t change. Diuretics work for a while and then patients progress, and they need more and more diuretics until they get to the point where the diuretics aren’t working anymore. At that stage, we certainly don’t want to operate, because the right side of the heart has become dilated, dysfunctional, and weaker, and patients are at high risk for surgery. Once tricuspid regurgitation develops, its effects will, over time, create a vicious circle where tricuspid regurgitation begets tricuspid regurgitation. It is similar on the mitral side. The more regurgitant disease is present, the worse it will become with time. There is a real unmet clinical need here. If we think about how many patients are actually having isolated tricuspid valve surgery in the U.S., some numbers indicate maybe 6,000 cases/year. It is a minute amount. Obviously, there are also the patients whose tricuspid valve is operated on when they have their mitral or aortic valve operated on. The patients who just go for isolated tricuspid valve surgery are fairly uncommon. It is not a procedure that is done in isolation very often. The reason is that patients who need isolated tricuspid valve surgery are patients who either have been operated on before, meaning it is a redo surgery and thus high risk, or these are patients who have just been treated with diuretics and who are now at a point where the right side of their heart is so weak that the risks of surgery, for morbidity and mortality, are present, with some studies showing mortality at 5% and others showing it at 30%. Regardless, it is high enough to be unacceptable. A number of physicians in the world, working alongside some startup companies, have identified an unmet need. We need devices that are percutaneous in order to treat these patients, because they get to a point where surgery is extremely high risk. Generally, when patients are operated on for their tricuspid valve, they get their valve repaired, rather than replaced. Ninety percent of the surgeries done for the tricuspid valve are repair and maybe only 10% are for replacement. When a surgeon repairs the tricuspid valve, what they are trying to do is an annuloplasty, either using a ring or sutures. I point this out because with percutaneous procedures, what we often attempt to do is simulate what our surgical colleagues have done in the past and shown to be effective. Percutaneous procedures that are similar to or reproduce a surgical procedure often have a high chance of success.
What devices have been tested in humans thus far?
At present, about 6 to 8 devices for tricuspid regurgitation are under development, but there only are 5 devices with actual human clinical experience. The devices can be divided into whether one tries to treat the annular dilatation, or attempts to bring the leaflets together, increasing the coaptation of the leaflets. If someone develops secondary or functional tricuspid regurgitation, their annulus and right heart dilates, and so the leaflets move away from each other and don’t coapt anymore. You can either address this problem by reducing annular dimensions to bring the leaflets closer together, or you can actually grab the leaflets and bring them closer together. There is no commercial device for the tricuspid at present. All the procedures that have been done in the world thus far have either been done inside a study or under compassionate use.
Of the 5 devices with human clinical experience, the first is called Trialign, produced by Mitralign in the United States. This procedure is performed via the jugular approach. The advantage of the Trialign procedure is that it has a surgical predicate. It reproduces a surgical procedure called the Kay procedure, where sutures are placed into the tricuspid annulus, and the annulus is decreased or cinched in an attempt to turn the tricuspid valve into a bicuspid valve. The tricuspid valve has three leaflets, but during this procedure, it essentially becomes two leaflets, so the whole posterior leaflet becomes redundant. The annular dimensions are decreased and thus the tricuspid regurgitation. Trialign is probably the device that is furthest advanced in terms of studies, with cases all over the world. SCOUT, an early feasibility study, has been approved by the FDA and is currently enrolling in the United States. Another study of compassionate use cases has been done in Europe, and there is a multicenter European Union study, SCOUT II, that is underway. I am the principal investigator for Italy. The second device is called TriCinch, from 4Tech Cardio in Galway, Ireland. We did the first-in-man about 2 years ago in Milan and have done a number of cases afterwards. TriCinch is a very unique device because it was developed solely for the tricuspid valve. You put a screw into the annulus near the anterior-posterior commissure, then pull on the annulus to decrease the annular dimensions, and when you have decreased the dimensions significantly, a stent is implanted into the inferior vena cava to maintain the tension. TriCinch also has an ongoing European first-in-man study that is enrolling. The third device with clinical experience in humans is the MitraClip. There are about 50 cases in the world where the MitraClip has been used on the tricuspid valve. Initial cases were done via the jugular, but cases are now being done transfemorally. It is a completely different mechanism than the first two devices I described. Trialign and TriCinch work on the annulus, while MitraClip works on the tricuspid leaflets. You grab two of the leaflets and bring them together, and in doing so, you try to decrease the valve area of the tricuspid regurgitation. Fourth is a device by Edwards Lifesciences called Forma, which is a balloon attached to a wire that gets screwed into the right ventricle (similar to a pacemaker), and then this balloon sits across the tricuspid valve (it comes in two different sizes). By the simple fact that it takes up space in the tricuspid valve, it decreases tricuspid regurgitation. There is less area for the regurgitation to occur. Forma has been used in a number of compassionate use cases in Canada, and Edwards is starting an early feasibility study in the United States. The fifth device is a dedicated self-expanding valve, Tric Valve (Vertriebs GmbH, Germany) that has been designed for implantation in the superior and inferior vena cava. In this case, the valves decrease the regurgitant volume going back into the caval veins without any impact on the actual tricuspid regurgitation, thus allowing the right ventricle and right atrium to essentially become a single chamber. About 4 compassionate use cases have been performed with this device. As you can tell, all 5 devices are fairly early on in terms of clinical development. We need to create awareness in the medical community, in the cardiology community in particular, that we are going to have devices available for truly difficult to treat conditions. One of the frustrating things right now is that even though I am being referred tricuspid regurgitation patients, these patients are often so advanced in their disease that they may not benefit from percutaneous therapy. Already they won’t benefit from surgical therapy, but I am seeing them at a point when even percutaneous therapy may not be of benefit. Part of creating awareness is the hope that physicians will send patients earlier to be evaluated for these new devices, rather than waiting until the patient gets to an end stage with this disease.
How does the anatomy of the tricuspid valve create challenges for device development?
The challenges are different than with the mitral valve, because we are working on the right side of the heart. We are going through a vein. We don’t have to do transseptal puncture, as with the mitral. Size is not a major issue. The annular tissue on the tricuspid side is different than with the mitral valve. There is less annular tissue, and the tissue is more friable and fragile compared to the mitral valve or the mitral annulus. The tricuspid leaflets are also more fragile than the mitral leaflets. One of the concerns about doing the MitraClip on the tricuspid is that the leaflets that are slightly more friable than the mitral valve leaflets. I do think that is an issue. Another issue is the proximity of the right coronary artery (RCA), which can be quite close to the annulus, and so for the devices that work on the annulus, the proximity of the RCA needs to be taken into account.
What about imaging?
One of the biggest challenges is the imaging: getting repeatable, reproducible imaging of the tricuspid valve that allows us to perform these procedures safely. Similar to most percutaneous valve procedures, computed tomography (CT) and echo planning are used to decide if the patient is treatable with these devices, if the patient has anatomy that is suitable or not, if there is sufficient annular tissue to implant the device, the location of the RCA and proximity to annular target site, while fluoroscopy and transesophageal echo are used to perform and guide the procedure. However, standard views and standard imaging aren’t available for the tricuspid valve, because it hasn’t been taught very well, nor do we have much experience. One of the echocardiographers who has been very fundamental in this standardization process is Rebecca Hahn from Columbia University in New York. She has probably been the one person who has helped us all in learning how to image the tricuspid valve. It is completely different to the mitral. We need to be able to see the leaflets and annulus extremely well in order to be able to perform the procedure. I think it is a question of time, learning, and more procedures before we will get a very standardized imaging.
Will heart failure specialists grow in importance to the heart team?
Compared to TAVR, where heart failure specialists have not been an important part of the heart team — it has been mostly surgeons, echocardiographers, and interventional cardiologists —for the mitral and particularly the tricuspid valve, it will be essential to have heart failure specialists as part of the team. Heart failure specialists will help us decide on two important things. First, the indication. The most difficult thing in most of these procedures is the timing. Second, heart failure specialists will help us identify the correct endpoints. These patients are chronically sicker with several comorbidities and are a very different group of patients than TAVR patients. Endpoints will focus on showing a reduction of tricuspid regurgitation, but also on showing an improvement in quality of life, an improvement in 6-minute walk distance, and a reduction in hospitalization, a common problem in tricuspid regurgitation patients. Rather than looking at mortality, these are the most important endpoints. In contrast, for TAVR, mortality has been a very important endpoint, particularly in the initial studies, where we wanted to compare TAVR to medical therapy.
When you say the timing of the procedure, what does that mean?
The European and U.S. guidelines tell us what we should do with the tricuspid valve when someone is already having surgery for the mitral and aortic valve. According to the European guidelines (from the European Society of Cardiology), anyone with annular dilatation undergoing mitral or aortic valve surgery, meaning their annulus is larger than ~40 mm, even irrespective of tricuspid regurgitation, should have the tricuspid valve repaired. That is not currently true for the American guidelines. The European guidelines adapted this recommendation based on retrospective and prospective data, but also because patients who have had surgery for their mitral or aortic valve who don’t have severe tricuspid regurgitation at present, but do have some annular dilatation, are one of the hardest groups to treat. We know now that these patients will get worse with time and develop late onset tricuspid regurgitation. The other issue with timing is that we are going to start seeing more heart failure patients with mitral and tricuspid disease, or they will have aortic and tricuspid disease. The tricuspid regurgitation is secondary to what is happening in the left side of the heart, and won’t change. Finally, for me, the biggest issue for timing is that patients are being sent or referred to our center for surgery or percutaneous consideration too late. By too late, I mean they already have severe pulmonary hypertension, severe dilatation of their right ventricles, and/or their right ventricles are dysfunctional and weak. It is so troubling, because often there is nothing we can do for these patients. We will need the heart failure specialists to help us in trying to get to these patients a little bit earlier, before they get to a point where they are not going to benefit from a corrective procedure.
Where does the early experience with tricuspid percutaneous therapy stand currently?
The collective number of tricuspid percutaneous procedures in the world at present is probably under 100, using the 5 different devices described earlier. We are early in the learning curve and are trying to show that the procedures are, first, safe and not associated with serious procedural complications, and second, that they are efficacious. In general, all the devices have shown efficacy in selected patients with greater efficacy for some of the devices. I believe that it is still too early to know which device will be the most efficacious and probably we will discover that some devices work better in certain anatomies or patients. A surprising finding has been that even modest reductions in tricuspid regurgitation has resulted in significant improvements in symptoms and quality of life.
Any final thoughts?
The number of tricuspid regurgitation patients is greater than people realize. Many tricuspid regurgitation patients can benefit from percutaneous therapies. It is early and this is pioneering, but I think tricuspid procedures are going to become a standard therapy within the next 2 or 3 years. We have been lucky enough to get involved early on, and we are seeing some interesting results with the devices we are trying now. In the future, we will hopefully be able to treat patients at a much earlier stage and prevent progression of tricuspid regurgitation and avoid the negative effects it has on the heart.
Disclosure: Dr. Latib reports consulting or receiving research grants or speaking honoraria from Mitralign, Millipede, 4Tech, Abbott Vascular, and Valtech Cardio.
Dr. Azeem Latib can be contacted at firstname.lastname@example.org.
- Latib A, Agricola E, Pozzoli A, Denti P, Taramasso M, Spagnolo P, et al. First-in-man implantation of a tricuspid annular remodeling device for functional tricuspid regurgitation. JACC Cardiovasc Interv. 2015 Nov; 8(13): e211-e214. doi: 10.1016/j.jcin.2015.06.028.
- Latib A, Ancona MB, Agricola E, Giannini F, Mangieri A, Regazzoli D, et al. Percutaneous bicuspidization of the tricuspid valve. Percutaneous bicuspidization of the tricuspid valve. JACC Cardiovasc Imaging. 2016 May 12. pii: S1936-878X(16)30129-2. doi: 10.1016/j.jcmg.2016.03.008. [Epub ahead of print]
- Rodés-Cabau J, Hahn RT, Latib A, Laule M, Lauten A, Maisano F, et al. Transcatheter therapies for treating tricuspid regurgitation. J Am Coll Cardiol. 2016 Apr 19; 67(15): 1829-1845. doi: 10.1016/j.jacc.2016.01.063.