In cardiology, the admixture of new tools plus an unmet medical need often brings zeal. Indeed, new tools can be a positive; think transcatheter aortic valve replacement (TAVR). But new devices can also be a negative; think the dissolving stent.
Whispers heard in our cath lab about percutaneous approaches for patients with tricuspid regurgitation (TR) sent me looking at the evidence for these procedures.
The first thing I noticed were the headlines: "The Tricuspid Tragedy: From Cinderella to Celebrity." And this: "Percutaneous Therapy for Tricuspid Regurgitation—A New Frontier for Interventional Cardiology." Multiple sources mentioned that the tricuspid valve is no longer the "forgotten" valve.
When I reviewed the evidence underpinning these new approaches, I began to worry. When I thought about how often an echocardiogram report notes TR, I worried a bit more. And when I thought about how much of cardiology is already low-value practice, I worried a lot.
What follows is a critical appraisal of the state of percutaneous approaches to the forgotten valve.
The case for fixing a leaky tricuspid valve goes like this: TR is common, symptoms can appear late in the course, and medical therapy is limited to diuretics. Observational studies show that TR is associated with higher mortality. Primary surgical repair of the tricuspid valve has a high rate of morbidity and mortality and is not associated with long-term benefit compared with medical therapy. Thus, transcatheter approaches offer a chance to fill an unmet need.
TR most often (~80% of cases) stems from functional or secondary causes. In the presence of pulmonary hypertension, left-sided pathologies (such as left ventricular disease and mitral or aortic valvular disease), the tricuspid annulus dilates and the leaflets tether. These forces impair adequate leaflet coaptation and TR ensues. Just as mitral regurgitation can contribute to left ventricular dilation and failure, TR has the same effect on the right ventricle. Primary causes of TR, such as infective endocarditis, Ebstein anomaly, or pacemaker leads, are far less common.
As it is with all regurgitant lesions, quantitative assessment of TR severity is difficult. The valve's noncircular anatomy makes the annulus hard to measure, and the degree of regurgitant flow is highly load dependent. The conundrum of grading TR severity is especially relevant because the supportive evidence for percutaneous repair thus far has assessed severity of TR, not clinical endpoints.
The surgical literature suggests that repair of the tricuspid valve (using a rigid annular ring) at the time of left-sided valvular surgery improves outcomes. I use the verb suggest because the evidence is observational; there are no randomized trials. Adding tricuspid valve repairs to left-sided surgeries is different from primary repair because the heart is already open, the ring can be placed in minutes, and the extra surgery confers little added risk.
Preliminary results from the Abbott-sponsored TRILUMINATE study gained significant attention last year. The Lancet published the single-arm uncontrolled study of 85 patients who underwent implantation of the novel TriClip system—a variant of the MitraClip designed for the tricuspid valve. TR was reduced by at least 1 grade at 30 days in 86% of patients. The unblinded study also found improvements in patient functional capacity and quality of life, and there were minimal adverse effects. In April 2020, the TriClip received a CE mark in Europe.
A research team from the University of Zurich has compiled the TriValve Registry, an international multicenter registry of percutaneous procedures—with various devices--on the tricuspid valve. This has led to a trove of observational studies of this procedure. The most common device in the registry is off-label use of the MitraClip for edge-to-edge tricuspid repair. A report on 1-year outcomes in 249 patients from the registry found reduction of TR by at least 2 grades in 72% of patients. These were sick patients: unplanned hospital admissions for heart failure occurred in 35%, and 20% died.
By email, interventional cardiologist Alan Zajarias, MD, from Washington University, St. Louis, Missouri, wrote that catheter-based strategies for the treatment of TR are in various stages of study in the United States. Edwards Lifesciences has multiple devices in development: its PASCAL Transcatheter Valve Repair System is in feasibility studies, and its percutaneous annular-ring Cardioband system has encouraging 6-month data available. Medtronic is starting a compassionate use study of the Intrepid Valve in the tricuspid position. And the Cardiovalve has earned an FDA breakthrough nod; a feasibility study is in the planning stages.
While it is clear to any cardiologist that untreated TR can be associated with adverse outcomes, it is not clear whether TR is causal or a marker of other heart disease. By definition, functional TR stems from left-sided disease, and both lesions worsen with age.
Rare is the echocardiogram on an older patient with established heart disease that does not find significant degrees of TR. Consider also that simple diuresis can massively improve TR in a patient with vascular congestion. These challenges make patient selection a core issue for future trials of percutaneous intervention. But even more than the valve itself, the degree of associated left-sided heart disease, pulmonary artery pressures, right ventricular dysfunction, and overall frailty of the patient complicate the decision to intervene.
Then, once the decision to do a tricuspid valve repair is made, the endpoints to assess remain on open question. The studies to date focus on the degree of TR—which is a difficult-to-measure, non–patient-centered surrogate endpoint.
If I had to bet on the future of percutaneous repair of the forgotten valve, the low rate of procedural complications combined with super-careful patient selection gives me some optimism. That said, I remain concerned that if percutaneous tricuspid procedures earn regulatory approval, patient selection may become less robust. That's a problem because TR in the real world is tricky: while there are occasional patients in whom severe TR is the main problem, most TR is simply a marker of other forms of advanced heart disease.
At the risk of repeating myself, the way forward is obvious: the burden of proof lies with those who believe percutaneous approaches to repair of TR are beneficial. Single-arm unblinded studies tell us little. The MitraClip and TAVR trials randomly assigned patients in proper trials that measured hard outcomes, such as admission for heart failure and mortality. The same should be done for patients with TR.
The data thus far tell us that patients with advanced TR have high rates of morbidity and mortality. If TR is causal in the decline of these patients and percutaneous repair reduces TR as has been reported, hard clinical outcomes will improve.
Whether or not regulators force randomization, it is the right thing to do. Otherwise, we will be the same situation we are in with COVID-19: many thousands treated and little idea which therapies work.
John Mandrola practices cardiac electrophysiology in Louisville, Kentucky, and is a writer and podcaster for Medscape. He espouses a conservative approach to medical practice. He participates in clinical research and writes often about the state of medical evidence.
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Cite this: John M. Mandrola. Let's Not Move at a Rapid Clip to Repair the Forgotten Valve - Medscape - Jun 24, 2020.