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FDA staff questioned the evidence for clinical benefit with the TriClip G4 transcatheter edge-to-edge repair (TEER) system for severe tricuspid regurgitation (TR) in documents released ahead of the agency's Circulatory System Devices Panel meeting on Tuesday.

Manufacturer Abbott has proposed an indication for improvement of health status in patients with severe TR that is symptomatic despite optimal medical therapy and who are at intermediate or greater risk for surgery and deemed appropriate TEER candidates by a heart team.

Approval appears to hang on the open-label TRILUMINATE trial.

While that pivotal trial successfully showed that TriClip improved health status for patients on Bayesian analysis (win ratio 1.44, 95% CI 1.03-2.08), the only individual component of this primary endpoint to significantly favor the device was the Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary score. Hard outcomes such as mortality showed no impact compared with medical therapy alone, and heart failure (HF) hospitalization was actually numerically higher with TriClip.

FDA staff expressed concerns about relying on the patient-reported KCCQ outcome, which could be subject to the placebo effect in an unblinded trial like TRILUMINATE.

Also, the primary endpoint was met in the intention-to-treat and as-treated analyses but not in the per-protocol analysis, the FDA reviewers also noted in released before the advisory meeting. "In addition, COVID-19 related deaths and HF hospitalizations as well as subsequent primary endpoint events, if any, were excluded from the primary analysis. When these events were included in the primary analysis, the primary endpoint was not met."

On top of the questions of the robustness of the evidence for TriClip, the advisory panel will be asked to interpret the finding that the TEER device's primary benefit in TRILUMINATE did not extend to participating sites enrolling fewer than 10 patients. This result could indicate lack of broad generalizability.

FDA staff found that safety was not a sure bet with TriClip, either. They cited numerically higher event rates in the TriClip group versus controls:

• All-cause mortality at 12 months (8.1% vs 7.0%)
• Cardiovascular mortality at 12 months (5.3% vs 3.8%)
• Tricuspid valve intervention at 12 months (2.5% vs 1.0%)
• Major bleeding at 30 days (3.9% vs 1.7%)
• New-onset renal failure at 30 days (1.4% vs 0.3%)

While the FDA just approved the Evoque tricuspid valve replacement system for tricuspid regurgitation in early February, TriClip proponents have argued that TEER addresses an unmet need for a patient population with few treatment options, since surgery is often high-risk due to a typically older, sicker patient profile.

A host of other transcatheter TR treatments are in development, including Medtronic's Intrepid valve replacement device and the Pascal repair system from Edwards Lifesciences. Pascal's pivotal trial, scheduled for completion by the end of this year, will show whether it can follow through with the early success of the CLASP TR single-arm study.

TriClip got the CE Mark from European regulators in 2020. The device was adapted from the MitraClip, which is FDA approved for the treatment of primary and secondary mitral regurgitation.

If the TriClip makes it to the U.S. market, its position as an alternative to surgery may be informed by unexpected positive results from a non-randomized single-arm cohort of TRILUMINATE: the patients with complex anatomies predicted to be unlikely to achieve a TR reduction down to moderate or less at baseline.

In fact, 81% of this group achieved moderate or less TR with TEER, which is comparable to the 89% in patients who got TriClip for more favorable anatomies as part of the randomized trial (though the latter group achieved more mild or trace TR). Quality-of-life score improvements on the KCCQ were similar between these cohorts as well.

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