Tricuspid Valve Intervention - tricuspid procedures are going to become a standard therapy within the next 2 or 3 years

27 July 2016

Interview with Azeem Latib, MD - San Raffaele Scientific Institute, Milan, Italy

Tricuspid Valve Intervention - tricuspid procedures are going to become a standard therapy within the next 2 or 3 years
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.

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.

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