Protecting the Brain in TAVR

What are the concerns for the brain when a patient suffers from aortic stenosis and undergoes a transcatheter aortic valve replacement procedure (TAVR)?

From the brain’s perspective, aortic stenosis creates a problem because it decreases cardiac output. As the stenosis becomes more severe, the cardiac output drops to the point where blood/brain flow can be impaired, and that is a bad thing for the brain. Treatment of that aortic stenosis, with TAVR or other procedures, is aimed at increasing cardiac output and one would think brain function might well improve in that setting. The TAVR procedure risks relate to embolic material that is dislodged during the procedure, and for the brain, that really is the greatest risk of the procedure. The embolic material can lead to stroke and infarction in the brain. Once past the procedure, clearly this patient population has significant underlying cardiovascular disease; other issues such as atrial fibrillation can lead to a lower, but chronic, risk of embolic events even after treatment, but the chronic risk tends to be much lower than the procedural risk. 

Does embolic material coming into the brain always lead to damage?

Embolic material regardless of clinical symptoms has been shown to lead to permanent damage to the brain by several studies. The new Neurologic Academic Research Consortium (NeuroARC)  guidelines, just published in JACC¹, define new recommended guidelines on how we report strokes. When patients have clinical symptoms of a stroke and new lesions by diffusion-weighted (DW) magnetic resonance imaging (MRI), the guidelines recommend reporting the event as an overt stroke. Covert stroke is a stroke that does not cause clinical symptoms but the patient has new DW-MRI lesions in the brain. When the patient has neurological symptoms without new DW-MRI lesions, the new guidelines recommend reporting the condition as neurological dysfunction. The short- and long-term consequences of  new DW-MRI lesions resulting from emboli from cardiovascular procedures depend on the size, number, and the location of the new lesion(s). Even small lesions can cause major clinical symptoms if located in crucial areas of the brain. And even acutely clinically asymptomatic lesions will reduce brain reserve and expose the patient to increased risk of long-term neurological conditions such as dementia.

What is the current state of research into brain health as it relates to the TAVR procedure?

Clinically evident major strokes have been a big concern since the adoption of TAVR. In addition, numerous studies have shown that almost all patients suffer from new DW-MRI lesions. Until recently, little attention has been paid to less severe clinical symptoms and neurocognitive decline. Based on newly published data, the total volume of new DW-MRI lesions correlate with neurocognitive decline. In addition, other studies have shown neurocognitive decline after TAVR. The new NeuroARC guidelines address the need for more accurate assessment and diagnosis of all levels of brain damage, improving not just clinical science, but care for patients.

Measuring cognitive function is a much more difficult task than measuring paralysis, weakness, or visual loss. For many reasons, historically there has been less attention placed on trying to measure cognitive function and status. Research into cognitive function related to stroke and ischemic brain injury is now focused very clearly on careful looks at cognitive function. Neuropsychologists’ expertise, along with more detailed batteries of cognitive exams, are being applied to this question in the area of stroke research. I think it is going to be a major issue in stroke neurology for most of these lesions, whether the lesions occur in spontaneous stroke or in procedure-related events.

There has been some discussion about the overall definition of stroke.

People clearly have several concerns. Historically, stroke was defined purely as a clinical term, based on the neurologic exam looking at the deficits at the bedside, and if those deficits resolved within an arbitrary time — it was chosen as 24 hours — then it was a transient ischemic event and there was no stroke. Most of the early stroke studies used a very similar, functional definition. In the last 10 years, more attention has been paid to the fact that even these transient events are often associated with ischemic tissue injury to the brain and a tissue infarction occurs in many of these events, even though the symptoms went away. The idea that tissue injury in infarction is a bad thing for the brain, even if there are no obvious symptoms, has become a reason that many of the studies now use careful imaging as part of the evaluation of stroke. There is data to suggest that small, scattered infarcts can lead to cognitive impairment, even without stroke deficits. There is much more concern about imaging evidence of infarction than in the original definition. The newer stroke definitions being used in clinical research look at neurologic deficits, whether the deficits are transient or not, and associated areas of infarct seen on imaging, and then define those events as strokes. There have been several groups putting forward definitions. The Valve Academic Research Consortium (VARC) definitions and the new NeuroARC definitions mentioned previously look at a combination of the neurologic exam and imaging to define stroke. There is no doubt that these definitions are more sensitive and more events will be categorized as stroke, so that one will certainly find these research studies having higher rates of stroke. The more carefully you look, the more events you are going to find. There is yet another level of complexity around the question of so-called silent infarcts, where there could be no clinical events and yet imaging will demonstrate areas of tissue injury and infarction. These are often quite small, and while they are in no way restricted to TAVR, they have become subject to the conversation surrounding TAVR, because the frequency of these silent infarcts is extremely high. In almost all TAVR patients, DW-MRI imaging detects these tiny, diffusion-weighted abnormalities that represent little areas of ischemic damage. The potential impact of these small lesions on cognitive function has become a major focus of this research. It may be a much more important issue in cognitive impairment than we have appreciated. Research is aimed at understanding the clinical consequences of these small areas of infarction.

Can you describe the TriGuard embolic cerebral protection device?

The TriGuard (Keystone Heart) is a fairly simple device with a nitinol frame and mesh that is self-expanding. The device is placed transfemorally prior to deployment of other catheters and devices, and the mesh then serves to protect the great vessels across the top of the arch that lead to the brain. The porosity of the mesh is such that the pressure perfusion across it is adequate to supply blood flow to the brain and the embolic material is then deflected downstream. The mesh covers all of the vessels that supply blood flow to the brain, making it a device that is optimally suited to protect brain from this material.  

So the mesh deflects embolic particles downstream?

The majority of the emboli are deflected downstream, but clinical data has shown no risk of peripheral emboli, for example, to kidney function, which has been monitored carefully. Unlike the brain, other peripheral circulation can withstand small emboli without any clinical consequences. Other options include devices that are filters rather than deflectors, and I think the challenge with filters is that the porosity has to be adequate to allow flow through it in order to perfuse downstream. If material is accumulated and impairs flow, there is always that risk of diminished flow. The deflection process tends to not to be associated with decreased flow, and it makes it easier to cover all of the vessels that supply the brain. The other options also involve a third access point. The TriGuard doesn’t have the need for the third access point. 

Are some patients more at risk than others, or should it be used across the board for all TAVR patients?

The risk of stroke has not been shown to reduce post TAVR, even as we have moved to a lower-risk patient population. In addition, the risk of embolic material from a calcified aortic valve is the same. However, younger patients may have less atherosclerosis in their aortic arch, which may reduce the risk of brain emboli as the TAVR devices are passed through the arch to the heart. On the other hand, younger patients can suffer more from even mild neurocognitive symptoms such as difficulty to focus, memory issues, social skills, and overall decline of executive functions, potentially having a major impact on their quality of life and ability to continue working.  The data that is being accumulated suggests that neuroprotection is going to be very important.

Considering the ongoing risk, patients with chronic atrial fibrillation have been shown to have increased risk of brain emboli and thus in this patient population, any additional brain emboli should be prevented.

Could you speak to the data surrounding the TriGuard thus far?

In the several trials that have used this device^2-4, the data shows not just the safety but also benefit of brain protection with TriGuard. When all the data from the smaller studies were pooled, complete coverage of all three cerebral branches showed a significant reduction of the strokes and other neurological outcomes.  The larger, prospective, randomized REFLECT trial is underway in the U.S. and European Union for U.S. regulatory approval. This study will gather a robust data pool both of clinical events and of imaging outcome, with the hope of confirming the need for cerebral embolic protection during TAVR. All prior data suggests that there is stroke protection associated with this device.

What are your thoughts on the involvement of the neurologist with the heart team?

Clearly, many of the research trials that we have been talking about, while involving cardiology procedures, are, in essence, also stroke prevention trials. Having neurologists and interventional cardiologists together in these research efforts is going to be important. In order to have careful neurologic evaluations, neurologists will be useful in these studies. These trials really are stroke prevention trials in many respects. Having neurology more closely involved with interventional cardiology will produce better quality research and be more effective in the long run.

Any final thoughts?

First, stroke prevention and brain protection devices in interventional procedures such as TAVR are going to be very important. It probably goes beyond simply TAVR. Many of these procedures, whether you are talking about simple coronary angioplasty and stenting, or atrial fibrillation ablation, have risk of embolic events that would be amenable to these same brain protection strategies. I think this is going to be a major focus in the next few years. Second, I simply want to emphasize that these are important procedures for the patients we are talking about. These procedures clearly have beneficial effects and save lives. Focusing on the stroke risk isn’t meant at all to be critical, but simply to support efforts to make these procedures safer. That really is our overall common goal.

Recommended websites:
www.iheartmybrain.com
www.reflectneurologists.com

References

1. Lansky AJ, Messe S, Brickman AM, et al. Proposed standardized neurological endpoints for cardiovascular clinical trials: an academic research consortium initiative. JACC. 2017; 69:679-91.
2. Giustino G, Mehra R, Veltkamp R, et al.  Neurological outcomes with embolic protection devices in patients undergoing transcatheter aortic valve replacement: a systematic review and meta-analysis of randomized controlled trials. JACC. 2016; 20:2124-33.
3. Baumbach A, Mullen M, Brickman AM, et al. Safety and performance of a novel embolic deflection device in patients undergoing transcatheter aortic valve replacement: results from the DEFLECT I study. EuroIntervention. 2015;11:75-84.
4. Lansky AJ, Schofer J, Tchetche D, et al. A prospective randomized evaluation of the TriGuard™ HDH embolic DEFLECTion device during transcatheter aortic valve implantation: results from the DEFLECT III trial. Eur Heart J. 2015;36:2070–78.

Disclosure: Dr. Daryl Gress reports he is a member of the Scientific Advisory Board for Ornim Medical, Keystone Heart, and Silk Road Medical, and is a consultant for Medtronic.