The TriClip G4 transcatheter edge-to-edge repair (TEER) device received a strong endorsement Tuesday from a U.S. Food and Drug Administration (FDA) advisory panel. The Circulatory Systems Device Panel of the Medical Devices Advisory Committee positively answered questions posed by the FDA on the device’s safety, effectiveness and whether the benefits outweigh the risks in the treatment of symptomatic, severe tricuspid regurgitation who are deemed to have at least intermediate surgical risk and who are considered appropriate candidates for tricuspid TEER. On whether the device, manufactured by Abbott Medical, is safe, the panel voted unanimously, 14-0, that it was. The vote was 12-2 that the device was effective, and the vote was 13-1 that the benefits outweighed the risks. In deciding whether to grant approval, FDA generally follows the advice it receives from its advisory panels, but the agency is not obligated to do so. Abbott’s presentation largely relied on data from the TRILUMINATE pivotal trial. The primary analysis population was 350 patients randomized to receive either TEER with the TriClip (47% of these patients received the first-generation; the remainder received a newer iteration, the G4) or optimal medical therapy. The primary endpoint was a hierarchical composite including all-cause mortality or tricuspid valve surgery, heart failure hospitalization and an improvement in Kansas City Cardiomyopathy Questionnaire (KCCQ) score of at least 15 points at 1 year post-TEER. The Finkelstein-Schoenfeld rank test and win ratio were used to evaluate the primary endpoint. With this method, patients were paired in all possible combinations between the TEER and control groups, and the number of pairs in which the TEER-group patient has a better outcome is divided by the number of pairs in which a patient in the control group has a better outcome. All-cause mortality or tricuspid surgery was at the top of the hierarchy, meaning ties here would go to the heart-failure hospitalization outcome, and the remaining ties would go to the KCCQ outcome. This analysis yielded a Finkelstein-Schoenfeld test statistic of 2.16 (p=0.0311) and a win ratio of 1.44 (95% confidence interval: 1.03, 2.08), meaning the device met the primary endpoint. The full randomized controlled trial cohort of 572 patients yielded similar results, and a single-arm cohort of patients who were considered unlikely to achieve moderate or better TR after TEER did end up with 80% of them achieving that level of TR. The significance in the trial results was largely driven by the KCCQ score, as there was no significant difference in the death/tricuspid surgery and heart-failure hospitalization rates between groups. On the KCCQ score, 50% of patients in the device group saw at least a 15-point improvement at 1 year, compared to 26% of the control group. The FDA’s presentation largely reflected these results but added an item that caused a great deal of discussion during the meeting, with no certain answer as to why: sites that enrolled more patients had higher win ratios than sites with fewer patients. This was largely driven by worse heart-failure outcomes after the TEER procedure in the smaller sites. In the end, though, the significantly greater KCCQ score improvement among patients in the device arm was enough to convince most panel members that this improvement could not be explained by a “placebo effect” alone – which is a concern given that patients were unblinded as to whether they underwent the procedure or received medical therapy. The proposed indication for use (IFU) reads: “The TriClip G4 System is indicated for the improvement of health status in patients with symptomatic severe tricuspid regurgitation despite being treated optimally with medical therapy, who are at intermediate or greater risk for surgery and in whom tricuspid valve edge-to-edge repair is appropriate as determined by a heart team.” FDA staff asked the panel about two phrases, “improvement of health status” and “as determined by a heart team.” There was some disagreement among panel members as to whether “improvement of health status” was too broad. Amy M. Cizik, PhD, MPH, a research assistant professor of orthopedics at the University of Utah School of Medicine, for example, said maybe it should be as specific as “a moderate to large improvement in KCCQ.” John W. Hirshfeld Jr., MD, an emeritus professor of medicine at the University of Pennsylvania Perelman School of Medicine, disagreed, saying the indication should be general. “We can get too far into the weeds to micromanage it,” he said. Nearly all the panel members voted yes to answer all three questions: safety, effectiveness and risk-benefit ratio. Everyone agreed that the device clearly demonstrated safety. James C. Blankenship, MD, a professor of medicine and the director of the cardiac catheterization laboratory and of the division of cardiology at the University of New Mexico, said he based his “yes” for safety by comparing the safety demonstrated by TriClip with that demonstrated by the recently approved EVOQUE device (Edwards Lifesciences), which is a tricuspid valve replacement system for severe tricuspid regurgitation, noting that both devices’ safety data were “in the ballpark.” Bradley A. Bart, MD, a professor of medicine at the University of Minnesota School of Medicine, addressed the “placebo effect” in explaining his “yes” for effectiveness. “I think that patient-reported outcomes are important,” he said. “And although there definitely is a placebo effect, I think the sponsor provided enough information that the benefit was not related to placebo alone.” If FDA does ultimately approve the device, Abbott has committed to initiate a postapproval study to continue to evaluate the safety and effectiveness of TriClip in a prospective, single-arm, multicenter real-world study with a proposed sample size of 2,000 patients. Consecutive patients entered into the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry would be analyzed annually. FDA staff and advisory panel members agreed that the KCCQ completion rate must be better than it has been for previous postapproval studies involving the TVT Registry. They also stressed the importance of having a patient population that is more representative of the U.S. population, as the TRILUMINATE trial patients were 85% white. Abbott officials pledged to make every effort to have better KCCQ response rates, and they agreed with the need for a more diverse patient population in the real-world study. Image Credit: Screenshot by Jason Wermers/CRTonline.org Image Caption: Circulatory System Devices Panel members discuss the TriClip G4 device during an online meeting Tuesday.