As Stroke Rates Fall, Questions Mount for Embolic Protection Devices in TAVR
Rates of stroke following transcatheter aortic valve replacement have declined significantly since the landmark PARTNER trial, and while cerebral injury remains a concern among implanting physicians, it’s still unknown what role cerebral protection devices will play in future clinical practice.
The risks and benefits of adding embolic protection to TAVR procedures, the increased costs associated with the device, and the clinical significance of particulate debris captured by the embolic protection devices are all ongoing concerns that still need to be addressed, according to a new review published March 7, 2016, in Circulation: Cardiovascular Interventions.
"I think the concept is very appealing,” senior author Ron Waksman, MD (MedStar Washington Hospital Center, Washington, DC) told TCTMD. “When you see a lot of debris in those baskets post-procedure, in the cases in which you participate, you say I’d rather have this in the basket than in the brain, but the proof of the concept remains to be seen."
The initial neurological complications reported in the PARTNER randomized trials, which included patients ineligible or at high-risk for surgery, ranged from 5.5% to 6.7%. These rates, said Waksman, were considerably higher than rates reported among patients undergoing surgical aortic valve replacement (SAVR). Since then, though, stroke rates have declined, with registry data showing stroke rates after TAVR ranging between 1.7% and 3.4%.
To TCTMD, Waksman said that with the advent of low-profile devices, increased physician awareness of stroke risks, improved techniques, and better patient selection, stroke rates for TAVR match those observed in valve-replacement surgery. "The question is whether there is still a merit to have these [embolic protection] devices since we were able to get the stroke rate to similar rates as we seen with SAVR,” he said.
Clinical Usefulness of Embolic Protection Still Unknown
In their review, Waksman along with Arie Steinvil, MD, and Richard Benson, MD (MedStar Washington Hospital Center), survey the current state of the embolic protection device field, summarizing the data to date for four investigational devices: Embrella and Embol-X (Edwards Lifesciences), TriGuard (Keystone Heart), and Sentinel (Claret Medical).
So far, none of the devices are approved by the US Food and Drug Administration, but Embrella, TriGuard, and Sentinel all have CE Mark approval in Europe. The Embol-X device was initially developed for use during open-heart surgery and requires direct access to the ascending aorta via a midsteronotomy for transaortic TAVR procedures.
A number of clinical trials testing these embolic protection devices have wrapped up or are ongoing, nearly all small and using a surrogate endpoint to assess effectiveness. In many of these trials, including CLEAN-TAVI, one of the larger trials to date with 100 patients, the primary endpoint was the rate of new cerebral lesions in diffusion-weighted magnetic resonance imaging (DW-MRI). In the ongoing SENTINEL trial, sponsored by Claret Medical, the primary endpoint is new lesion volume assessed on days 4 through 7 after TAVR with DW-MRI. Studies testing the Embol-X and TriGuard devices are also using DW-MRI as the primary efficacy endpoint.
To TCTMD, Waksman said stroke rates in TAVR are so low now that a trial using clinical stroke as an endpoint would need to be very large. As a result, a surrogate-endpoint study is more likely.
However, the clinical relevance of lower rates of cerebral lesions detected with DW-MRI is unknown, and in order to show clinical utility, sponsors and investigators would likely need to move beyond this surrogate endpoint alone. As pointed out in the review, the clinical relevance of silent brain ischemia is not known—DW-MRI lesions were previously considered a valid surrogate marker for clinical stroke in cerebrovascular procedures, but that is no longer the case. Indeed, American Heart Association now recommends against using clinically silent cerebral lesions of undetermined onset as the primary or secondary endpoint in stroke studies unless all patients undergo standardized imaging at specific time points.
What Happens Next?
In terms of the future, Waksman said the embolic protection device companies have a number of tasks in front of them: they need to show the device is safe, that it reduces cerebral infarcts detected on DW-MRI, and that the reduction in silent infarcts translates into a clinically meaningful result, such as better neurocognitive performance. Neurocognitive testing is no informality either, as it requires testing by trained and experienced examiners. However, given that there is an array of tests available to clinical investigators, standardization of neurocognitive testing in TAVR trials may be difficult.
"Let’s assume the devices will show safety and will be approved for use based on the surrogate endpoint, which could be controversial for other reasons because there is no consistency in terms of measurement of the DW-MRI across the board,” said Waksman. “So, I think it brings us to a very interesting question. Assuming the device is safe, should we use it in every patient? Should we use it only in high-risk patients?”
Identifying the subset of patients most likely to benefit from embolic protection is yet another challenge. Given the changing demographics of TAVR—from the early days of older high-risk/surgery-ineligible patients to use in younger patients with a lower risk profile—Waksman said it’s unknown if embolic protection would be required for everybody. The studies testing TAVR in low-risk patients are ongoing, and with that, the risk of stroke/neurological complications remains to be determined in this population. It’s possible such patients might have less atheroma in the arch resulting in less risk of embolization, but that remains to be seen, he said.
Waksman told TCTMD that even if embolic protection devices are shown to be safe and effective, the cost hurdle isn’t inconsequential either.
“The margin on all these TAVR cases being done in the US is relatively small, and if you add to that the cost of the [embolic protection] device, then that makes the whole procedure challenging from a financial aspect,” he said.
- Steinvil A, Benson RT, Waksman R. Embolic protection devices in transcatheter aortic valve replacement. Circ Cardiovasc Interv. 2016;Epub ahead of print.
- Waksman reports receiving research grants and consulting with Biotronik, Medtronic, AstraZeneca, Boston Scientific, Biosensors International, Abbott Vascular, The Medicines Company, Edwards Lifesciences, and St. Jude Medical.