SILVER SPRING, MD — Unanimously disappointed with the end point used to determine clinical benefit, advisors to the US Food and Drug Administration (FDA) agreed the Sentinel Cerebral Protection System (Claret Medical, Santa Rosa, CA) is safe for use during transcatheter aortic-valve replacement (TAVR).
"Because I think preventing any stroke or potential for cognitive dysfunction in a patient population that is one, already full of comorbidities, and two, moving to lower- and lower-risk patients, as an interventionalist, I would use this device. I can't tell you that it is effective in reducing clinical end points, but I believe the totality of the data suggests that it might, and the outcome when it occurs is so devastating that I would want to prevent it," Circulatory System Devices Advisory Panel member Dr Joaquin Cigarroa (Oregon Science and Health University, Portland) said.
The panel struggled with the evidence from the pivotal SENTINEL trial in elderly TAVR patients, which met its primary safety end point but failed to meet its primary efficacy end point of reduction in brain-lesion volume on diffusion-weighted MRI (DWI). Some have reported that DWI lesions may be seen in more than 80% of patients after TAVR, although many of these lesions are not apparent as clinical strokes and their clinical significance is unclear.
Neuroradiologist Dr Donna Rae Roberts (Medical University of South Carolina, Charleston), however, said, "I see those DWI signals as injured brain tissue, and so to me that's extremely important to protect the brain tissue, particularly given the fact this device is safe. Really, there is no large risk associated with this, so why would you not want to protect this brain tissue?"
Echoing sentiments from TAVR patients who testified, Dr John W Hammon Jr (Wakeforest University School of Medicine, Winston-Salem, NC) said, "I'm just 5 years from being 80, and I want something to help me, so I'm very much in favor of having this device go forward."
Dr Kevin M Duff (University of Utah, Salt Lake City) offered a dissenting voice, remarking, "Although I understand the concept and very much wanted to see positive results, I didn't in the primary first outcome measure." Other outcome measures were not convincing, he said, adding, "I hope the work continues in this, but I don't feel as strongly about it."
The sponsor noted that after adjustment for baseline lesion volume and valve type, there was a significant reduction in new lesion volume in protected territories in the SENTINEL trial. Also, both filters in the device were able to be implanted in 95% of patients, there was uniform debris capture independent of valve type, and one in four patients had an average of 25 particles collected that were at least 0.5 mm in size and visible to the naked eye. Still, the panel struggled with how to correlate the findings with clinical benefit, missing data that may have left the trial underpowered, and the lack of coverage in the left posterior inferior cerebellar artery with the device, although the sponsor said this supplies just 2% of brain tissue.
Because the Sentinel device is on the FDA's de novo classification pathway, no formal vote was taken, although the panel's deliberations will inform the agency's decision on whether to grant clearance. The device is already available in Europe, having received European CE Mark approval in 2013.
Panelist Dr John C Somberg (Rush University Medical Center, Lake Bluff, IL) remarked that there is considerable pressure to modify the FDA drug- and device-approval process toward safety predominantly, but that "we in the FDA need to be data driven, and that is a major problem with this device."
Somberg suggested the FDA harvest additional data presented by the sponsor from a meta-analysis of the SENTINEL trial plus the German CLEAN-TAVI and European MISTRAL-C trials showing a nonsignificant trend for improved 72-hour and 30-day stroke rates with the filter.
He added, "Altogether, it gives us an overview that there is enough benefit here and very little risk to favor a risk/benefit assessment in favor of the device's approval."
Dr Erick Magnus Ohman (Duke University Medical Center, Durham, NC) said it's unlikely this type of study would ever be done again and advocated future trials return to clinical end points. "It's a harder study, but you don't have to squeeze elderly patients into MRI machines and try to figure out what it means and you can make the study very simple and get the information that is meaningful to us."
Other suggestions by the panel included the need to establish long-term follow-up of randomized patients and a postmarket registry to track clinical outcomes in new patients and standardized neurologic end points in future cardiovascular trials.
Commenting to heartwire from Medscape, Dr Jeffrey Popma (Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA), who was not involved in the meeting, said the 8-hour panel discussion was one of the most thoughtful and thorough FDA reviews he's witnessed in 20 years.
"At the end of the day, I think everyone came to the same conclusion that the device is extremely safe, that it captures debris, that there's a lot of complexity in correlating MR scans with clinical benefit, but nevertheless the trends for the nondisabling strokes were clearly in the right direction," he said, adding, "Dr Ohman's comment that perhaps we should fall back to clinical end points that are much easier for us to understand may be one of the ways to move in the future. I thought it was just a fantastic panel."
In his concluding remarks, panel chair Dr Richard Page (University of Wisconsin, Madison) noted the panel's frustration over the nonsignificant efficacy outcome, but said, "I think we're all in agreement that we'd much rather have that debris coming out of the body than going to our brains, so for that reason, I would favor this."
He added that TAVR is an evolving, imperfect procedure, and "this is an iterative step. Our interventional colleagues, I believe will want this to be available, and I would postulate it will be used frequently, if not universally."
Popma reported institutional grants from Medtronic, Boston Scientific, Abbott, and serving on Boston Scientific's advisory board.
Heartwire from Medscape © 2017 Medscape, LLC
Cite this: FDA Advisory Panel Cautiously Optimistic on Sentinel Embolic-Protection Device for TAVR - Medscape - Feb 24, 2017.