Neurological Complications With TAVR

Transcatheter aortic valve replacement (TAVR) is a rapidly growing therapy in the treatment of aortic stenosis (AS). Although its use was previously limited to patients with severe AS who were non-operative candidates, treatment with TAVR is now a Class I recommendation in the treatment of symptomatic patients with severe AS who are at high risk for surgical aortic valve replacement (SAVR) and a Class IIa recommendation in the treatment of intermediate-risk patients.1 Furthermore, additional trials are underway to evaluate the use of this therapy in treating low-risk patients and asymptomatic patients with severe AS. However, there is rising concern about cerebrovascular events that can occur after TAVR, which are associated with increased mortality after TAVR or SAVR.2,3 Thus, it is important to identify risk factors for neurological complications after TAVR in an effort to minimize and prevent these events. This review discusses our current understanding of neurological events associated with TAVR and current devices in development to minimize these events during TAVR procedures.

Epidemiology and Mechanisms of Neurological Events After TAVR

Severe AS is the most common valvular disease in the elderly, occurring in approximately 2-4% of patients.4 Although TAVR is a well-established therapy in the treatment of high-risk patients, early studies found that TAVR was associated with higher rates of stroke compared with SAVR.5,6 Although rates of stroke after SAVR have been reported to be between 0.7 and 6.5%, 30-day rates of neurological events have been reported to be approximately 3-6% after TAVR.6-8 The vast majority of neurological events occur in the peri-procedural period9,10 and are thought to be related to cerebral embolization and hypoperfusion.5 Studies suggest that the highest rate of embolism during TAVR is during valve positioning and deployment, and the second highest rate of embolism is during balloon aortic valvuloplasty.5 There have been conflicting data as to whether self-expanding valve devices or balloon expandable valves are associated with increased cerebral ischemic lesions.2,11-14

In addition to clinically apparent strokes, studies suggest that up to 84% of patients have new silent ischemic embolic lesions post-TAVR.15-17 These studies have shown that patients develop multiple cerebral lesions that are spread across both cerebral hemispheres, which is consistent with embolic showering events. However, the clinical impact of these imaging findings is unknown because only a few patients will develop clinically apparent strokes. Additionally, studies suggest that these silent ischemic emboli are not associated with changes in neurocognitive function, transient clinical symptoms, mental health, or quality of life assessments.18 Interestingly, some studies suggest that the majority of lesions that were detected initially after the procedure resolve by 3-month follow-up.15

Histopathology of embolic debris captured in embolic protection devices used during TAVR demonstrate amorphous calcium or valve tissue, collagenous tissue originating from the valve or aorta, thrombotic tissue debris, and foreign material detached from percutaneous devices.14,19 The likely mechanism of embolism during TAVR is dislodgement of debris during catheter manipulation within calcified and diseased aortas and from crushing the calcified native aortic valve (AV) leaflets to the aortic wall. Prior studies have demonstrated that manipulation of even small caliber diagnostic catheters had a risk of cerebral emboli.20 Thus, it is not surprising that TAVR, which involves stiffer and larger-caliber catheters that interact and disrupt heavily calcified valves, is associated with higher rates of stroke compared with medical therapy alone. Studies using transcranial Doppler have also supported this mechanistic theory by demonstrating that the peak rates of cerebral embolization occur during wire manipulation in the aortic arch, valve positioning, and implantation.21,22 Although the AV is also manipulated during SAVR, SAVR allows for additional removal of debris and cross clamping of the aorta in order to prevent embolism. Although there is no clear evidence demonstrating the difference in stroke rates between valve types (balloon expandable vs. self-expanding), the mechanism of embolic events may be different. Studies monitoring patients with transcranial Doppler suggested that balloon expandable valves create emboli during valve positioning along the annulus, and self-expanding valves cause emboli during valve deployment.21,22

Few studies have determined the predictors of cerebrovascular accident during/after a TAVR procedure. The PARTNER (Placement of Aortic Transcatheter Valve Trial) cohort A study found that smaller AV area index was associated with an increased risk of early (<30 days) neurological events, and increased functional impairment and history of stroke were risk factors for long-term neurological events.10 In addition, studies have found that pre-existing atrial fibrillation or the development of new onset atrial fibrillation after a TAVR was associated with a fourfold increased risk of in-hospital and late strokes.23,24 From a procedural standpoint, balloon post dilatation of the valve has been associated with increased stroke risk.24

Embolic Protection Devices

Despite improvements in TAVR device technology, rates of neurological events appear to be consistent over time.25 These events can undermine the ability of TAVR to improve a patient's quality of life. As a result, multiple cerebral embolic protection devices have been developed for use during TAVR in order to reduce embolic strokes. The goal of these devices is to prevent embolic debris from embolizing to the major head vessels by either filtration or diversion. Filtering systems capture the embolic debris travelling toward the head vessels within nets. In contrast, diversion systems deflect emboli away from the cerebral circulation toward the systemic circulation. The efficacy of these devices is dependent on their ability to cover the aortic origins of the three major head vessels, the stability of the devices intra-procedurally, and the filter characteristics (e.g., pore size).

Embol-X

Embol-X (Edward Life-Sciences; Irvine, CA) is a single-filter net that is inserted via a mid-sternotomy into the distal ascending aorta but proximal to the right brachiocephalic artery. This device can be used during transaortic TAVR and protects all three major head vessels. A preliminary study demonstrated a trend toward a lower rate of new cerebral lesions and decreased lesion size.26 However, this study was terminated early because of unavailability of study devices; the study was underpowered for efficacy.

Embrella Embolic Deflector

The Embrella Embolic Deflector (Edward Life-Sciences; Irvine, CA) is inserted via the right radial artery and, once in the aorta, is deployed over the right brachiocephalic artery and the left common carotid artery. It deflects debris from these vessels. In a study containing 52 patients, patients treated with the Embrella device unfortunately had higher rates of transcranial Doppler signals during device deployment and during TAVR valve deployment. In addition, patients receiving the Embrella device had more lesions detected by magnetic resonance imaging than patients who did not receive the Embrella device during their TAVR.27

TriGuard

The TriGuard system (Keystone Heart; Tampa, FL) is an embolic deflector system advanced from femoral access that covers all three main aortic arch branches. In the DEFLECT III (A Prospective, Randomized Evaluation of the TriGuard™ HDH Embolic Deflection Device During TAVI) multicenter trial, 85 patients were randomized to TAVR with and without the TriGuard system.11 Patients receiving the TriGuard system had fewer new ischemic brain lesions than those who did not receive protection; however, statistical significance was not provided. Furthermore, there was a significant reduction in median lesion size when patients received the TriGuard system, but total lesion volume was similar between the treatment arms. In addition, although neurological assessments were worse among the patients without embolic protection at discharge, there were no differences seen at 30 days. Thus, the clinical benefit of the TriGuard system is still unclear. A randomized trial (REFLECT [Cerebral Protection to Reduce Cerebral Embolic Lesions After Transcatheter Aortic Valve Implantation]) that was powered to evaluate the neurocognitive impact of the TriGuard system was underway; however, it was terminated early after enrolling 258 patients because a newer iteration of the device became available. The results of the REFLECT trial as well as additional data regarding the new device iteration are not yet available.

Sentinel Cerebral Protection System

The Sentinel Cerebral Protection System (Claret Medical; Santa Rosa, CA) is the latest iteration of the previous Montage Dual Protection System. It is inserted via the right radial artery and consists of two interconnected filters. One filter is deployed in the proximal right brachiocephalic artery, and the second filter is deployed in the proximal left common carotid artery. The left vertebral artery is not protected with this system. This device was studied in the CLEAN-TAVI (Claret Embolic Protection and TAVI) trial, which was a single center study containing 100 patients randomized to TAVR with and without the Sentinel device.28 Patients who received the Sentinel device had a 50% reduction in the number of new lesions compared with patients who did not receive the Sentinel device during the TAVR procedure. However, rates of stroke and neurocognitive outcomes were similar between the 2 groups. Subsequently, a multicenter trial containing 240 patients failed to reproduce the improved neurological imaging findings seen during the initial study.19 Interesting, this study found that there was a significant outcome interaction between TAVR valve type (balloon expandable vs. self-expanding) and number of embolic lesions. The PROTECT-TAVI (Prospective Randomized Outcome Study in TAVI Patients Undergoing Periprocedural Embolic Cerebral Protection With the Claret Sentinel™ Device) multicenter trial is currently enrolling European patients and evaluating the efficacy of the Sentinel device when used with self-expanding and balloon expandable valves. A meta-analysis of all randomized Sentinel studies has been performed, containing 314 patients. This meta-analysis found a signification reduction in the total new lesion volume in areas protected by the Sentinel device.29 Of note, a limitation of the Sentinel device is that it does not cover the left vertebral artery, which supplies blood to the basilar artery and the circle of Willis. The use of the WIRION (Allium Medical; Caesarea, Israel) single filter in addition to the Sentinel device has been studied in 11 patients. When used, the filter captured equal amounts of debris compared with the two Sentinel filters. Thus, the Sentinel device may decrease embolic events in the protected cerebral territories, but there are still concerns about the unprotected circulation.30 Additional randomized clinical trial data are required to understand the clinical benefit of this device.

The use of embolic protection devices has been studied mostly in small clinical trials. A meta-analysis was performed in order to determine whether using embolic protection devices during TAVR reduced the rates of silent ischemic and clinically evident strokes. A total of 16 studies containing a total of 1,170 patients was included in the analysis. This study did not find any differences in the rate of clinically evident stroke.31 Although there was no difference in the number of lesions, the use of protection devices was associated with smaller ischemic volume per lesion and smaller total volume of lesions. This is an important meta-analysis, but it is limited by the small number of patients included in each study and the high rates of loss to follow-up in most of the studies. Furthermore, it is unclear whether a "class effect" of embolic protection devices can be assumed in these analyses given the different designs of each device. Additional studies and analyses will be required in the future to elucidate the impact of these devices on clinical outcomes.

Future Directions

In order to better understand the rates of strokes as well as the clinical relevance of seemingly silent cerebral ischemic events, systematic and rigorous neurological evaluations performed after TAVR are crucial. Variability in reported outcome rates in prior studies is partly the result of differences in event definitions and ascertainment methods. As such, the Neurologic Academic Research Consortium proposed standardized definitions and assessments of neurological endpoints for TAVR as well as other cardiac interventions.32 By standardizing definitions and methodologies of ascertaining neurological events, clinicians will be better able to interpret studies and compare studies of different devices over time. Furthermore, this will improve our ability to perform additional analyses that pool data to determine which patients are at highest risk for cerebrovascular events and who would benefit the most from cerebral embolic protection devices.

Moreover, additional studies are required to understand which patients are at highest risk for cerebrovascular events. Factors such as aortic atheromas, porcelain aorta, and carotid disease may impact the risk of events during TAVR and the selection of embolic protection device utilized.

In conclusion, TAVR is now a mainstay therapy in the treatment of AS in select patient populations. As the technology continues to advance, additional designs should take into consideration methods to reduce stroke rates, such has continuing to develop smaller delivery systems. Early data on embolic protection devices suggest that they are feasible and safe; however, the devices' efficacy in preventing clinically relevant embolic events remains to be determined.

References

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Clinical Topics: Arrhythmias and Clinical EP, Cardiac Surgery, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Valvular Heart Disease, Atrial Fibrillation/Supraventricular Arrhythmias, Aortic Surgery, Cardiac Surgery and Arrhythmias, Cardiac Surgery and VHD, Interventions and Imaging, Interventions and Structural Heart Disease, Interventions and Vascular Medicine, Magnetic Resonance Imaging

Keywords: Heart Valve Diseases, Allium, Aortic Valve, Aortic Valve Stenosis, Transcatheter Aortic Valve Replacement, Aorta, Thoracic, Atrial Fibrillation, Basilar Artery, Cerebrovascular Circulation, Calcinosis, Cerebrum, Carotid Artery, Common, Constriction, Circle of Willis, Dilatation, Embolism, Embolic Protection Devices, Follow-Up Studies, Heart Valve Prosthesis, Intracranial Embolism, Magnetic Resonance Imaging, Outcome Assessment (Health Care), Prospective Studies, Quality of Life, Radial Artery, Sternotomy, Risk Factors, Vertebral Artery, Stroke


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