Imperfect Evidence: How Strong Is the Case for Transcatheter Tricuspid Valve Interventions?

Despite the commercial availability of two transcatheter interventions for symptomatic severe tricuspid regurgitation (TR), uncertainty persists about the strength of the evidence supporting their approval and whether the data justify widespread use of the procedures.

Tricuspid transcatheter edge-to-edge repair (T-TEER) with the TriClip device (Abbott) and transcatheter tricuspid valve replacement (TTVR) with the Evoque device (Edwards Lifesciences) were approved by the US Food and Drug Administration in 2024, based on the results of the TRILUMINATE Pivotal and TRISCEND II trials.

The positive results in both studies were primarily related to health status, including improvements in Kansas City Cardiomyopathy Questionnaire (KCCQ) score, 6-minute walk distance, and NYHA functional class, rather than reductions in clinical endpoints like all-cause death and heart failure (HF) hospitalizations. Although extended 2-year follow-up of TRILUMINATE points to fewer heart failure (HF) hospitalizations in the TriClip arm, the high rate of crossovers complicates interpretation.

With the Centers for Medicare & Medicaid Services (CMS) agreeing to provide reimbursement for T-TEER and TTVR, US operators considering how to incorporate the procedures into their management of patients with severe TR now face two major questions. First, how substantial, and believable, are the health status benefits considering the lack of a sham-control arm in the trials and the possibility of placebo effects? Second, if the gains in patient-reported outcomes are real, are they enough to perform procedures that carry some risks and don’t have a big impact on harder endpoints?

The answers are not straightforward.

“If you’re going to focus on quality-of-life and symptoms, and we know there is a heavy component of placebo effect they have simply by participating in the trial, we need to at least have reasonably solid evidence that [these interventions] do make an impact,” Sanjay Kaul, MD (Cedars-Sinai, Los Angeles, CA), told TCTMD. “Without a sham control, I don’t think you can unequivocally say that they do.”

For Anita Asgar, MD (Northwestern Medicine, Chicago, IL), however, the evidence is convincing because the improvements in quality of life were proportional to the reduction in TR severity. “That’s the equivalent of a dose response,” Asgar told TCTMD. “The truth of the matter is people are going to be skeptical, and I don’t know that there’s any way to necessarily convince them. Those of us who treat patients, we see it.”

Better Health vs Placebo Effect

Since the trial results came out, experts have debated the changes in health status in the midst of likely placebo effects.

Suzanne Arnold, MD (Saint Luke’s Mid America Heart Institute, St. Louis, MO), who has done much of the research around patient-reported outcomes in this space, acknowledged that this question is complicated by the lack of sham-control arms in the trials but added that additional analyses indicate that the findings are at least partially biologically mediated.

“At least some degree of this is real,” Arnold told TCTMD.

Asgar, too, said that there could be an element of placebo effect at play with the quality-of-life outcomes, but “the reality is it’s a consistent benefit, regardless of the type of therapy that was used, whether it was repair or replacement. Improving the TR resulted in a quality-of-life benefit. So for me, that evidence is solid.”

David Cohen, MD (St. Francis Hospital & Heart Center, Roslyn, NY, and Cardiovascular Research Foundation, New York, NY), also is convinced that the improvements in health status with T-TEER and TTVR are legitimate. “I would qualify that and say the data may not be sufficiently convincing to skeptics who really want the perfect evidence,” he said. “We don’t have perfect evidence even for quality of life, because we haven’t done the proper placebo-controlled trials to assess that.”

Improving the TR resulted in a quality-of-life benefit. So for me, that evidence is solid. Anita Asgar

Cardiothoracic surgeon Steven Bolling, MD (University of Michigan Health, Ann Arbor), is more skeptical of the data to date. Referring to TRILUMINATE, he noted the trial was positive only on a “noncontrolled, placebo-affected, patient-reported endpoint.” He also worried about the unintended impact of performing TTVR with the Evoque system. “Although emotionally we all feel better that we deploy it and the TR goes away, it is so big—I like to say it’s the size of a Diet Coke can—and it distorts the ventricle so much that we may get rid of TR but it hurts the ventricle so much, we’re not going to see [much clinical benefit].”

The two trials should not be considered positive, Bolling said, pointing out that, in general, the placebo effects can be very strong. “I think a little bit of what we’re seeing is wishful thinking and hope that we have something [effective] out there,” he said. In the tricuspid intervention trials, “we’re seeing these super soft endpoints that are not controlled well and [are] very affected by placebo effects because they’re open label and the patient knows they had something.”

He is also not convinced by the additional analyses linking the changes in KCCQ score, for instance, with reductions in TR. “There’s a biological signal there,” Bolling acknowledged, “but is it overwhelmingly proven? No.”

TRILUMINATE and TRISCEND II did not provide definitive evidence of the beneficial impact of the procedures on health status, Kaul said. Even CMS recommended coverage provided there would be further evidence collected for both T-TEER and TTVR, he said.

“In their opinion, the quality and strength of evidence were insufficient to make the determination that these devices are reasonable and necessary, which is not necessarily a very high bar, and they couldn’t identify any specific patient characteristic or comorbidity that would make patients more or less likely to benefit” from intervention, said Kaul.

We know there is a heavy component of placebo effect they have simply by participating in the trial. Sanjay Kaul

Indeed, “you cannot say there is unequivocal evidence that there is a placebo-resistant benefit from these devices,” which would take a sham-controlled trial to obtain, Kaul said.

There are many examples of researchers failing to replicate large treatment effects observed in open-label studies when they perform subsequent sham-controlled trials. These include studies of percutaneous laser myocardial revascularization in patients with severe coronary disease, PCI in stable coronary artery disease in ORBITA, renal denervation for hypertension in SYMPLICITY HTN-3, trials of interatrial shunting in heart failure, and others.

“Examples like these make you take pause as to whether we are identifying a true effect or whether there is some component of a placebo effect in the tricuspid intervention trials,” Kaul said.

Is Quality of Life Enough?

Several physicians indicated that achieving a clinically meaningful improvement in health status, assuming one exists after accounting for potential placebo effects, would make the interventions worth pursuing in patients with severe TR, even in the absence of effects on harder clinical outcomes.

“My feeling is that there’s going to be a population of people in the scientific community that—without seeing a mortality, or what they consider a hard endpoint, benefit—will feel that it’s not justifiable. Personally, I don’t agree,” Asgar said.

Arnold pointed out that interventions in other areas of medicine, like joint replacement or back surgery, are performed to improve patients’ function, ease their symptoms, and help them maintain independence and not to help them live longer.

When it comes to severe TR, “one of the things that we have realized in some of the qualitative work is how important some of these symptoms and functional limitations really are, particularly to these elderly patients who . . . just want to get out and go grocery shopping and visit with family and friends. That’s really important,” Arnold said.

Cohen agreed that for these patients, who are typically older and poor surgical candidates, “really what they prioritize is not how much longer they’re living but how much better they’re living.”

One of the things that we have realized in some of the qualitative work is how important some of these symptoms and functional limitations really are. Suzanne Arnold

In her experience, Arnold noted, patients are eager to undergo an intervention to get relief. “They usually have been struggling with shortness of breath and fatigue for a long time,” she said. “And if there’s something that can potentially make them feel better, they seem pretty darn motivated to have a procedure to do that.”

When it comes to safety, T-TEER appears to have an advantage over TTVR. For example, TRISCEND II showed an early risk of mortality (the 30-day rate was 3.5% with Evoque, with no deaths in the control arm). The difference between the TTVR and control groups lessened by 1 year (11.6% vs 10.5%), although Evoque-treated patients had higher rates of severe bleeding (15.4% vs 5.3%) and of needing a new pacemaker due to arrhythmias and conduction disorders (17.8% vs 2.3%).

“Evoque has a larger health status benefit but increased risk for complications, whereas TriClip has minimal complications but a more modest improvement because you’re not reducing TR as much,” Arnold said. “I think that that’s where shared decision-making is really important.”

Cohen noted that there will be data from the TVT Registry presented at the upcoming TCT meeting that will provide information on the commercial use of Evoque, and he’s hopeful there will be reductions in pacemaker rates with greater operator experience.

He agreed that shared decision-making is key. “It’s incumbent on us as clinicians to explain those issues to patients and patients will help us to decide if their symptoms are enough to warrant taking on some of those risks,” Cohen said. “I don’t think the clinician is in the position to make that decision for any individual patient by themselves. It has to be shared with the patient.”

Refining Patient Selection

Before considering T-TEER or TTVR, all patients should be seen by a heart failure specialist to rule out any reversible causes of severe TR and optimize medical therapy, said Cohen.

“Because we don’t see a mortality benefit, at least at present, with T-TEER or with TTVR, there isn’t a tremendous urgency to getting them treated like there is with aortic stenosis, for example,” he said. “We can take some time, make sure that their medications both for left- and right-sided heart failure are optimized, and [ensure] that any issues potentially with pacemakers and leads that could be causing TR, if they have those already, should be dealt with.”

After that step is complete, “if the patients are still quite symptomatic, and the patient is the best judge of that, then we look at the anatomy and try to assess which therapy is going to be better,” he said.

Cohen tends to go with T-TEER if he thinks he can get an excellent anatomic result, both because of its better safety profile compared with TTVR and because it doesn’t require ongoing anticoagulation. “Those are important advantages when we’re not saving lives with these procedures,” he pointed out.

There’s a biological signal there, but is it overwhelmingly proven? No. Steven Bolling

On the other hand, if the anatomy is unfavorable—if there are large coaptation gaps and a very large ventricle, for example—TTVR may be a better option to achieve an adequate reduction in TR. “But again,” Cohen said, “we have to discuss the need for long-term anticoagulation and the issues with a possible pacemaker.”

In addition to making sure patients are truly symptomatic, Arnold is looking for patients who are more functional. Those who are debilitated due to arthritis or a prior stroke, for instance, may not have much to gain from a quality-of-life perspective. It will be hard to see a benefit from intervention in patients with more severe RV dysfunction, too, she said.

The problem with trying to decide who to treat with T-TEER or TTVR is that there are no highly predictive risk models that can help identify those most likely to benefit, said Kaul. Until the evidence base gets stronger, he’d consider one of these procedures as a “last resort” for patients who have recurrent heart failure admissions related to severe TR or who require repeated thoracentesis for draining pleural effusions.

Bolling suggested that treating severe TR would be more likely to yield positive results earlier in the course of the disease before patients get too sick, although he indicated that the current transcatheter devices, which are large, might not be well suited for that task. “If we had some magic way to snap our fingers to get rid of your TR, we would do it,” he said. “But we don’t have that. Certainly, the devices that we have right now are not going to apply upstream, which is where they need to be applied.”

For now, operators should select patients using the inclusion criteria from the pivotal trials, Asgar advised. For asymptomatic patients with identified TR, “I don’t think there’s a role in treatment for those patients at this time.”

Mulling Sham Controls

In hindsight, the pivotal trials of T-TEER and TTVR probably should have included a sham control to address questions about the impact of placebo effects, several physicians said. At this point, although it might be possible to design a sham-controlled trial, it doesn’t seem likely that one will be performed, at least in the United States, where TriClip and Evoque have been approved and given reimbursement from CMS.

“I don’t think it’s realistic that we’re actually going to get it,” Asgar said.

If a sham-controlled trial in severe TR were to be done, it would probably have to use TriClip because of the lower risk for complications, Arnold said, adding that such a study would need only a few hundred patients and a short duration of follow-up (maybe 3 months) to assess impacts on patient-reported outcomes.

“Because there has not yet been any sort of mortality benefit, that makes us a lot more comfortable with doing some of these sham controls,” she said. And the equipoise is there, according to Arnold. “I feel like there’s enough of a remaining question out there that from a clinician side, people would be willing to randomize patients as well.”

The results of a sham-controlled trial would help increase confidence in the quality-of-life benefits observed in the trials of T-TEER and TTVR, Arnold added.

When the evidence is not as strong, it’s really harder to advocate strongly for the procedures as much as we otherwise might. David Cohen

Kaul agreed that a sham-controlled trial with a short duration of follow-up for bias-prone outcomes is feasible, but said it would need to discourage crossovers for 2 to 3 years to allow for a cleaner comparison between the intervention and control.

A trial with a sham control is both possible and needed, Cohen said. It’s unlikely to be done in the US “because the FDA and Medicare have opened the door wide open,” he specified, but it could be performed in parts of the world where access to and reimbursement for these procedures is not as widespread.

Cohen is currently working with a group led by Michael Mullen, MBBS, MD (Barts Heart Centre, London, England), in the United Kingdom to help plan a sham-controlled trial. If positive, he said, that study would be “sufficiently convincing to say we have certainty with respect to the quality-of-life benefit.”

The Future of Transcatheter Tricuspid Interventions

Both Asgar and Cohen stressed that high-quality evidence is needed to move the field of transcatheter tricuspid interventions forward.

“These therapies are here to stay and they’re going to continue to expand,” Asgar said. “It’s our responsibility as a scientific community to better understand the patients that are going to benefit most, so that we can choose those patients appropriately and not forget the other therapies, such as treating their arrhythmias to maybe prevent some of these things from happening.”

Some people might be afraid that these expensive technologies will be misused in large numbers of patients, and that’s always a concern, she added. “We just have to be stewards of the technology and make sure we’re treating the right patients.”

As with TAVI for aortic stenosis and TEER for mitral regurgitation, these interventions for TR require well-done foundational trials to allow the field to flourish, Cohen said.

“When the evidence is not as strong, it’s really harder to advocate strongly for the procedures as much as we otherwise might. It’s harder to get the payers to pay. It’s harder to get the entire field, including heart failure specialists and cardiac surgeons and all the people who really are involved in caring for patients with tricuspid valve disease, to really buy into the therapy,” he said. “So I think that if we get a single well-conducted sham-controlled trial done, the field will take off as I always hoped it would.”

Several questions still need to be answered, Kaul said, citing, for one, whether these interventions are altering the natural history of TR or simply providing a “cosmetic benefit.” In addition, research is needed into determining which patients are most likely to benefit, and with which device; developing risk-prediction scores; and homing in on the optimal time to intervene.

Bolling predicted that over the coming years, operators will continue to get better at performing T-TEER and TTVR and a second generation of devices specifically designed to treat TR will emerge, both contributing to better clinical outcomes. Easier-to-use and smaller devices could eventually be deployed earlier in the progression of TR, he suggested. “We’ll start to go upstream and then we’ll start to see better results.”

Though skeptical of the results seen in trials so far, Bolling said “we’re all happy that [the devices] got approved.” It would have been a “disaster” if TriClip and Evoque hadn’t been made available, which “would’ve put a huge damper on the field in general,” he said.