FDA Panel Takes a Positive View of TriClip in Tricuspid Regurgitation

Expert advisors to the US Food and Drug Administration offered little in the way of pushback against the TriClip (Abbott) transcatheter edge-to-edge repair (TEER) system as a treatment for symptomatic severe tricuspid regurgitation (TR).

By the end of yesterday’s advisory meeting, the Circulatory System Devices Panel’s take was overwhelmingly favorable, with members voting 13-1 that the benefits of TriClip outweighed the risks for use in patients who meet the proposed indication criteria. The panel voted 12-2 that TriClip was effective and voted 14-0 that there were reasonable assurances the device was safe.

Interventional cardiologist James Blankenship, MD (University of New Mexico, Albuquerque), who voted in favor of the device, said he was impressed with the improvement in quality of life seen in the pivotal trial. “The safety profile looks good compared to a lot of things that many of us do, [so] I have a lower bar for efficacy,” said Blankenship. “Even if it’s only helping symptoms, that’s what total hip replacements do—they help symptoms—so if we can help symptoms with [TriClip] at a low cost and low risk, I think it makes a lot of sense.”

“It’s important to consider what the alternatives are for these patients—their alternatives are quite limited,” added Bradley Bart, MD (University of Minnesota School of Medicine, Minneapolis), who also voted in favor of TriClip. “Overall, I think the totality [of evidence] is quite favorable.”

I still put a lot of faith in the KCCQ data, even though there is a potential placebo effect. David Yuh

For cardiothoracic surgeon Craig Selzman, MD (University of Utah, Salt Lake City), the benefits of T-TEER also outweigh the risks, but his vote carried some asterisks, particularly if the intervention will be performed in younger patients than those in the pivotal TRILUMINATE trial.  

“That concerns me,” he said, noting that once TriClip is implanted, surgery down the road becomes challenging. “When you put a clip in, and we’ve seen this with the MitraClip, it’s hard to re-repair those. Basically, once you put this clip in, if there is a surgical option [for repair], it takes it away and demands that [surgery] would be a [mitral valve] replacement.”

Data from the Society of Thoracic Surgeons (STS) national database has shown that surgical patients undergoing tricuspid valve replacement fare worse than those treated with repair, said Selzman.

The lone dissenter on the final question of whether benefit exceeds the risk, Paul Hauptman, MD (University of Nevada, Reno), said there were too many unknowns. “I felt the need to pull back on the unbridled enthusiasm,” he said. “We have a responsibility to better understand who is going to benefit, and that needs better definition.”

As an example, Hauptman pointed to patients in normal sinus rhythm treated with TriClip—87% of those in TRILUMINATE had atrial fibrillation—or treatment in those with significant left ventricular dysfunction—mean ejection fraction in TRILUMINATE was 59%. He encouraged the FDA to continue to study patients treated as part of the continued access protocol (CAP) “because those data could tip the scales, at least in my mind, and shore up what we know from the main cohort.”

Potential Placebo Effect

The proposed indication for the TriClip G4 system is to improve health status in patients with symptomatic severe TR despite treatment with optimal medical therapy. Eligible patients are those at intermediate or greater risk for surgery in whom T-TEER is deemed appropriate by a heart team.

The decision is based primarily on results from TRILUMINATE, which was presented last year at the American College of Cardiology/World Congress of Cardiology meeting and published simultaneously in the New England Journal of Medicine. In the study, the hierarchical composite endpoint favored T-TEER at 1 year, but there were no differences between the T-TEER and control groups in freedom from all-cause death/tricuspid valve surgery or freedom from hospitalization for heart failure (HF). The improvement in the Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary score—the third component of the primary endpoint—was significantly better with TriClip.

The data were supported by outcomes from a single-arm cohort of patients who were eligible for the trial but who had a low likelihood that TR would be reduced to moderate or less.

It’s important to consider what the alternatives are for these patients—their alternatives are quite limited. Bradley Bart

Even though TRILUMINATE met its primary endpoint, the advisory panel spent the day grappling with the data, with a particular focus on the fact that the benefit of TEER with TriClip was driven by the softer quality-of-life endpoint. TRILUMINATE was an unblinded, open-label trial, and FDA reviewers pointed out that patient-reported outcomes such as the KCCQ score “could be subject to the placebo effect.”

Still, the vast majority of the advisory committee felt the findings from TRILUMINATE were clinically significant, particularly the 15-point improvement in KCCQ score that favored the intervention.

“In terms of the efficacy, in terms of what the patient is really experiencing, I still put a lot of faith in the KCCQ data, even though there is a potential placebo effect,” said panel member David Yuh, MD (Stamford Health, CT), a cardiothoracic surgeon. “I’m very comfortable with the safety. It’s still the reality to the patient and to discount that does them a disservice.”

Mitchell Krucoff, MD (Duke University Medical Center, Durham, NC), who also voted in favor of TriClip, said that when TRILUMINATE was designed, it was “inevitable” that heart failure hospitalizations and mortality would be included as part of the primary endpoint. However, TriClip was unlikely to have an impact on mortality over the relatively short follow-up. Additionally, it’s possible that patients weren’t sick enough at the time of randomization to see a reduction in heart failure hospitalizations.

Krucoff, for his part, was untroubled by the trial’s design.

“To me, the placebo issue, understanding that it’s unblinded, I would not have supported doing a sham procedure,” he said. “I think this level of significance and the durability of the impact of [TriClip] is clinically significant.”

Post hoc analyses from TRILUMINATE, which were presented during the advisory panel meeting, showed that lower TR severity at 12 months and larger TR reductions with treatment correlated with greater improvements in the KCCQ score. For some committee members, the association helped offset any concerns about the potential placebo effect.

Others, however, like cardiothoracic surgeon Marc Katz, MD, MPH (Medical University of South Carolina, Charleston), weren’t persuaded of the procedure’s overall effectiveness, noting that while it did decrease TR and improved the KCCQ score, hard endpoints were unchanged with treatment.

“Additionally, the patient’s medications didn’t change much,” he said. “They may or may not have had a better response to their diuretics, but it didn’t decrease their overall level of medications. Then, looking forward, I have real concerns about the [indication] creep that’s going to occur. It will be sicker patients who will be [treated] and that’s not going to help the results overall, especially as less experienced teams get involved.”

To me, the placebo issue, understanding that it’s unblinded, I would not have supported doing a sham procedure. Mitchell Krucoff

Just last week, the FDA took many by surprise when it approved the Evoque tricuspid valve replacement system (Edwards Lifesciences) for the treatment of severe TR without convening an advisory committee. That approval was based on results of the TRISCEND II study, which showed the device significantly improved TR grade and led to meaningful improvements in functional status and symptoms in patients with severe TR.

This approval must be factored in, too, Katz continued: “Given that there is now an approved tricuspid valve replacement, once the tricuspid is clipped, you take that [therapy] off the table in the future.”

Postapproval Study

Although the vote was overwhelmingly in favor of TriClip, panel members expressed concerns about outcomes in patients who may require an implantable cardioverter-defibrillator or pacemaker in the future, and also questioned the generalizability of the TRILUMINATE results. For example, it was noted that the “win ratio” result for the primary endpoint was better in sites that enrolled 10 or more patients. At sites that enrolled fewer than 10 patients, HF hospitalizations were higher in the device arm.

Some panel members felt that the better outcomes at sites that enrolled more patients was possibly attributable to better HF care.

“I think there’s something to learn [here],” said Krucoff. “It’s not so much about the technical procedure but caring for patients with this truly right-sided disorder and not caring for them like they have left-sided heart failure.”

I felt the need to pull back on the unbridled enthusiasm. Paul Hauptman

Panel member Mladen Vidovich, MD (University of Illinois, Chicago), agreed, suggesting there’s an unmeasured confounding variable impacting results at lower-volume centers. Even at sites that enrolled fewer than 10 patients, operators were experienced with MitraClip, he said. “And this is right-sided [with TriClip], so it should be easier,” he said.

Patients in the TRILUMINATE randomized study, as well as those in the single-arm cohort and those treated as part of the CAP, will be followed for 5 years. So far, 360 patients have been treated as part of the CAP, but no study results are yet available. In addition to these patients, Abbott is proposing a registry-based, postmarket surveillance study of TriClip-treated patients. They will be enrolled in the STS/ACC TVT registry and data will be linked to claims data from the Centers for Medicare and Services and tracked for at least 5 years.

“As a breakthrough device, the postmarket [study] takes on added importance because the job is not done on the point of approval on something that is this novel, this new,” said Krucoff.

The FDA does not have to follow the advice of its advisory committees but takes their opinions into account when deciding on drug and device approvals.