Cerebral Embolic Protection Device Disappoints in TAVR/Stroke Trial
By Jeffrey Zimmet, MD, PhD
Associate Professor of Medicine, University of California, San Francisco; Director, Cardiac Catheterization Laboratory, San Francisco VA Medical Center
SYNOPSIS: In this largest-to-date randomized trial of stroke prevention in transcatheter aortic valve replacement patients, use of the Sentinel cerebral embolic protection device did not significantly affect the incidence of periprocedural stroke.
SOURCE: Kapadia SR, Makkar R, Leon M, et al. Cerebral embolic protection during transcatheter aortic-valve replacement. N Engl J Med 2022; Sep 17. doi: 10.1056/NEJMoa2204961. [Online ahead of print].
Transcatheter aortic valve replacement (TAVR) is a well-established treatment for aortic stenosis. In recent years, this procedure has become the predominant intervention for correcting this valve lesion. One of the feared complications of TAVR is peri-procedural stroke, which presumably occurs because of liberation of embolic material from the diseased valve itself, or from interaction of the valve delivery system with aortic atheroma. Multiple devices have been developed to capture emboli during TAVR procedures in the hope of preventing adverse outcomes. The Sentinel cerebral embolic protection (CEP) device received FDA approval in 2017 based on a trial that showed the device captured material in 99% of patients and generally was safe. However, that trial did not show a significant reduction in new cerebral lesion volume and was not powered to assess stroke. The device is placed from the right radial artery, and results in deployment of filters across the innominate and left carotid arteries.
The PROTECTED TAVR trial was designed to test the efficacy of this specific device in peri-procedural stroke prevention. The authors enrolled 3,000 patients undergoing transfemoral TAVR at 51 centers in North America, Europe, and Australia from February 2020 to January 2022. Interestingly, the Data and Safety Monitoring Board recommended the final sample size during an interim analysis after the first 2,100 patients had been enrolled, and was based on the sample size calculations and actual observed event rates.
Enrolled patients were a mean age of 78.9 years, 40% were women, and the average Society of Thoracic Surgery predicted risk of surgical mortality was 3.4% ± 2.7%. The heart team judged a little more than one-third of patients to be low surgical risk, with the remainder in the intermediate- and high-risk groups. Randomization was 1:1, with 1,501 patients assigned to the CEP group and 1,499 patients in the control group. The device was deployed successfully in 94.4% of patients in whom it was attempted. All patients underwent a neurologic exam at baseline and again after TAVR. Clinical stroke within 72 hours of TAVR occurred in 34 of 1,501 patients in the embolic protection group vs. 43 of 1,499 in the control group, a difference that the authors reported was not statistically significant (95% CI, -1.7 to 0.5; P = 0.30).
Among the 15 secondary endpoints measured, disabling stroke was diagnosed in eight of 1,501 patients in the device group and 20 of 1,499 patients in the control group (95% CI, -1.5 to -0.1). The absolute difference of 0.8% translated to a number needed to treat of 125 patients to prevent one disabling stroke. The authors concluded using the CEP device did not significantly affect the incidence of peri-procedural stroke in this trial. However, they emphasized “the results may not rule out a benefit of CEP during TAVR.”
Often, the biases of the observer heavily influence the interpretation of highly anticipated trial results such as these. Overall, this was a negative trial, since the results did not show a significant effect of CEP on early stroke after transfemoral TAVR. The trial was not powered for disabling stroke; therefore, most commenters would caution the reported significant reduction in this secondary outcome should be seen as hypothesis-generating in the context of an overall negative trial. One of the more disappointing aspects of this investigation is that at least in the initial analysis, the authors did not provide particular insight into which patients might benefit from selective CEP use, or any particular factors of the procedure itself (e.g., valve type, use of pre- or post-dilatation) that might suggest an advantage to the device.
This trial included a mix of patients that represents a good cross-section of patients undergoing TAVR today, with a combination of low-, intermediate-, and high-risk patients. A stroke rate of 2% to 3% matches expected rates from recent publications. Some have argued that as TAVR migrates toward younger and lower-risk patients, stroke prevention will become more important and might argue for more use of CEP devices. However, published results from low-risk TAVR trials refutes this concept. For example, the 2019 PARTNER 3 trial authors reported on the results of TAVR with the Sapien 3 valve in low-risk patients with an average age of 72 years. In that trial, despite negligible use of CEP devices, the 30-day stroke rate was only 0.6%. These data suggest the risk of stroke is related to the overall risk profile of the patient, which cannot be easily changed with using a device.1
Not every stroke can be prevented with embolic protection. Among the eight disabling strokes in device patients, two were hemorrhagic, and the Sentinel device would not have prevented these. Only a single event, an ischemic stroke in the left middle cerebral artery territory, occurred in what should have been a protected vessel.
Going forward, I do not expect this trial will change any practice substantially. Most likely, true believers of this technology will see enough of a glimmer of hope in these data to support continued use. Centers that are not using Sentinel routinely most likely will view the overall negative trial results as a reason to avoid the added costs and procedural time.
1. Mack MJ, Leon MB, Thourani VH, et al. Transcatheter aortic-valve replacement with a balloon-expandable valve in low-risk patients. N Engl J Med 2019;380:1695-1705.
In this largest-to-date randomized trial of stroke prevention in transcatheter aortic valve replacement patients, use of the Sentinel cerebral embolic protection device did not significantly affect the incidence of periprocedural stroke.
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