A Look at the SENTINEL Trial: Cerebral Protection in TAVR
Why has concern been focused on stroke post transcatheter aortic valve replacement (TAVR)?
TAVR has been shown to be the gold standard technique for treating high and intermediate risk patients with severe aortic stenosis. However, due to the nature of the procedure and the heavily calcified aortic annulae that are encountered, stroke is always a potential risk. Stroke post-TAVR is multifactorial, but more than 50% occur within the first few days and are embolic in nature, which raises the opportunity for cerebral protection devices to play an important role. Any stroke is devastating to a patient, and one stroke is one too many. In fact, research suggests that TAVR patients fear stroke more than any other outcome. Therefore, anything we can do to eliminate it should be explored. This is especially important as TAVR is increasingly being used in younger patients with lower surgical risk.
Across multiple trials in Europe and America, the Sentinel device (Claret Medical) has demonstrated its potential to reduce new brain lesions. For example, in the SENTINEL trial there is a 38% numerically lower stroke rate in the Sentinel-protected group, and a non-prespecified post-hoc analysis found a significantly lower number of patients with neurological symptoms at 72 hours in the protected group. Although previous TAVR studies have reported stroke rates to be 2-7%, the higher stroke rate of 9.1% in unprotected patients in this trial is likely due to several factors, including careful, prospective neurological exams before and after the TAVR procedure by neurologists, and adjudication of all events by certified stroke neurologists based on symptomology and cerebral imaging.
The focus has widened to look at lesions in the brain appearing post TAVR — can you describe what has been learned?
A brain lesion is a brain injury that shows up as an abnormal area on magnetic resonance imaging (MRI) or other brain imaging test. Up to 94% of TAVR patients were shown to have lesions after the procedure than pre-procedure across all patients in the SENTINEL trial, which indicates that the new lesions are caused by the procedure itself. The Sentinel-protected patients in the SENTINEL trial experienced 42% less lesions volumetrically in the protected areas of their brain than the unprotected group. While the definition of brain lesion encompasses cerebral infarction and includes clinically obvious stroke, it commonly includes smaller areas of brain injury that are not clinically apparent. It is these lesser injuries that are just beginning to be understood today. The literature tells us that lesions are associated with adverse neurological and cognitive consequences, including impaired mobility, physical decline, depression, cognitive dysfunction and dementia. An increase in the number and/or volume of brain lesions in a patient, therefore, is not a positive development. We as physicians should be very interested in the promise of a device like Sentinel that is showing potential in reducing brain lesions in TAVR.
What were the findings of the SENTINEL trial?
The Sentinel cerebral protection system was shown to be very safe, adding no risk to the TAVR procedure, and captured brain-bound debris in 99% of patients. It also demonstrated the ability to numerically reduce the stroke rate from 9.1% to 5.6% (38% reduction), and, more significantly, eliminated peri-procedural strokes in the protected territories of the brain. Even though the device also reduced the volume of cerebral lesions by 42%, it did not quite reach statistical significance due to several study limitations. This endpoint was a new and unvalidated surrogate imaging endpoint, and the pre-specified analysis did not account for a previously unappreciated key covariate (baseline lesion burden measured by fluid-attenuated inversion recovery [FLAIR] MRI), as well as variability introduced by the use of four different valve types throughout the course of the trial, which the trial was not powered for.
When you look at the amount of debris captured in virtually all patients, it is hard not to wonder about the potential damage that debris could cause if it traveled to their brains. Would it cause a stroke for my patient? Would it negatively impact their cognitive abilities, now or in the future? With the device showing exceptional safety, and stroke having such a negative impact on a patient’s quality of life, the benefits of using Sentinel regularly in daily practice clearly outweigh the risks. I also think about what patients might say if they knew Sentinel was available but not used in their procedure, and they had a negative outcome. I view Sentinel as somewhat of an insurance policy for TAVR.
With that said, the other authors and I also agree that there were some interesting things learned from the trial that may impact future research. Despite being the largest trial examining neuroprotection in TAVR to date, the sample size was too small to assess clinical and neurocognitive outcomes. There should also be stricter parameters around the use of quantitative MRI analyses, including controlling for or pre-specifying several factors, such as statistical analyses for adjustment, key covariates, and other confounding effects we are just now learning about.
What were the types of debris found?
Across three different randomized studies encompassing more than 600 patients, the Sentinel device has captured and removed strikingly consistent histopathologic debris in more than 80% of patients undergoing TAVR. This debris includes arterial wall, calcification, valve tissue, acute thrombus with tissue elements, and even “foreign material” – usually polymers used in the TAVR valve delivery systems and their accessories, which are found in over 30% of patients and create local cerebral inflammation. In the SENTINEL study, about 20% of this material was greater than 500 microns in size, so not insignificant. This tells us that the TAVR procedure itself liberates a great deal of material into the circulation that would, if not for the Sentinel, go straight to a patient’s brain with the potential to cause a stroke or accelerate longer-term cognitive deficits. The prevalence of debris suggests that overly aggressive TAVR device manipulation, especially in repositionable TAVR platforms within the aortic valve environment, should be avoided whenever possible.
What do you see as potential advantages of the Sentinel device?
All three randomized studies, but especially the SENTINEL trial, showed one of the key advantages of the technology, which is to not only capture embolic debris that would otherwise enter the circulation of the right innominate and common left carotid arteries, but to remove it entirely from a patient’s cerebral circulation to decrease the potential for stroke. Alternative embolic protection systems in development use a deflection approach with a shield that sits in the aortic arch, but this may lead to the debris diversion towards the arteries supplying the mesentery or kidneys in patients who are already are renally compromised.
The trials show us that the device is also extremely safe — in the SENTINEL study, the device met its primary safety endpoint, which was a very low major adverse cerebrovascular or cardiac event (MACCE) rate of 7.3%, as compared to a historical performance goal of 18.3% and the control arm rate of 9.9%, and it had an access site complication rate of only 0.4%.
Since it is designed to be positioned out of the aortic arch and avoid contact with the devices used to perform TAVR, it does not interfere with the passage of the TAVR system and adds only a few minutes to the overall TAVR procedure. With experience and planning, placement can be achieved without additional contrast use and the procedural success rate of 98% was achieved.
Finally, the Sentinel is the most-studied device in the field of TAVR cerebral protection, and there are several other studies either reported or in process to add to the compelling body of evidence for this technology. This includes studies looking at the role of Sentinel in left atrial appendage occlusion, MitraClip (Abbott Vascular), and thoracic endovascular aortic repair (TEVAR), as well as the role of Sentinel in failed TAVR valves, which will be a new market as the TAVR technology matures. Other technologies in development will need to meet or exceed the high bar set by Sentinel.
What about exploring the nature and incidence of neurocognitive decline?
The SENTINEL trial showed us, for the first time, the strong link between frequency and size of new brain lesions and neurocognitive deterioration post TAVR. It will be very important to more closely study this connection in order to understand the true value of cerebral protection on a patient’s cognitive state. This is especially important as TAVR has moved from extreme to high, and now to intermediate risk patients, and is expected to soon move into low risk patients that could otherwise undergo open valve replacement surgery. None of these patients should have to tolerate stroke as a complication and the resulting neurological deficits that accompany it, nor should they tolerate increased risk of future neurocognitive decline. So this makes further exploration of cerebral protection even more important.
What do you envision as the role of neurologists for heart teams in the future?
As we have seen in several studies of the Sentinel device, there is value in having neurologists engaged as part of a heart team to understand the nuanced clinical effects of a patient’s lesion burden, which the SENTINEL trial showed was closely associated with neurocognitive decline. Their involvement would also be important to review scans and match them to clinically relevant symptoms post procedure, in order to understand the impact of TAVR on a patient’s brain and help guide clinical decision making.
Disclosure: Dr. Axel Linke reports that within the past 12 months, he or his spouse/partner have had a financial interest/arrangement or affiliation with the following organization(s): Grant/research support – Claret Medical Inc., Medtronic, Bard. Consulting fees/honoraria – Medtronic, St. Jude Medical, Edwards Lifesciences, Symetis, Boston Scientific, Bard. Major stock shareholder/equity – Claret Medical Inc.
Dr. Axel Linke can be contacted at axel.linke@medizin.uni-leipzig.de
