Accepted Manuscript. Cerebral Embolic Protection During Transcatheter Aortic Valve Replacement: A Disconnect Between Logic and Data?

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1 Accepted Manuscript Cerebral Embolic Protection During Transcatheter Aortic Valve Replacement: A Disconnect Between Logic and Data? Azeem Latib, MD, Matteo Pagnesi, MD PII: S (16) DOI: /j.jacc Reference: JAC To appear in: Journal of the American College of Cardiology Received Date: 26 October 2016 Accepted Date: 27 October 2016 Please cite this article as: Latib A, Pagnesi M, Cerebral Embolic Protection During Transcatheter Aortic Valve Replacement: A Disconnect Between Logic and Data?, Journal of the American College of Cardiology (2016), doi: /j.jacc This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

2 Cerebral Embolic Protection During Transcatheter Aortic Valve Replacement: A Disconnect Between Logic and Data? Azeem Latib, MD a,b, and Matteo Pagnesi, MD a a Interventional Cardiology Unit, San Raffaele Scientific Institute, Milan, Italy b Interventional Cardiology Unit, EMO-GVM Centro Cuore Columbus, Milan, Italy Short Title: TAVR and Cerebral Embolic Protection Cover Title: A Disconnect Between Logic and Data? Disclosures: San Raffaele Hospital is or has been involved in clinical studies of cerebral embolic protection devices for TAVR developed by Claret Medical, Keystone Heart, and Innovative Cardiovascular Solutions. Address for correspondence and reprints: Azeem Latib, MD Interventional Cardiology Unit San Raffaele Scientific Institute Via Olgettina Milan, Italy Telephone: Fax: alatib@gmail.com 1

3 Despite the continuous evolution of transcatheter aortic valve replacement (TAVR), cerebral injury is still a major issue of this procedure. The PARTNER IIA trial reported a 30-day stroke rate of 5.5% after TAVR, confirming that procedure-related neurological events remain a significant concern even in lower-risk patients and with next-generation transcatheter heart valves (1). Besides the risk of clinically apparent cerebrovascular events, the vast majority of patients undergoing TAVR (77.5% in a recent pooled analysis) have new silent cerebral lesions detected by post-procedural diffusion-weighted magnetic resonance imaging (DW-MRI) (2). The long-term clinical and neurocognitive consequences of these lesions are not completely understood, but there is increasing evidence that these DW-MRI lesions represent silent brain infarctions that could be related to memory loss, cognitive decline, and dementia (3). However, given the relatively low rate of clinical neurological events at short-term follow-up and the high frequency of new DW-MRI lesions after TAVR, total new lesion volume on DW-MRI has been utilized as a surrogate endpoint for TAVRrelated neurological damage and as the primary endpoint to limit sample size in designing studies to evaluate the efficacy of cerebral embolic protection (CEP) devices. In the wake of smaller studies suggesting the efficacy of CEP during TAVR (4-6), Kapadia and Kodali et al report in this issue of the Journal (7) the results of the largest randomized clinical trial evaluating the safety and efficacy of a transcatheter CEP system during TAVR. The SENTINEL trial enrolled 363 high-risk patients with severe symptomatic aortic stenosis undergoing TAVR with FDA-approved valves, who were randomized 1:1:1 into a safety arm (n = 123), an imaging device arm (n = 121), and an imaging control arm (n = 119). The device under investigation was the Sentinel system (Claret Medical, Santa Rosa, California) that was designed to deliver filters to the brachiocephalic and left common carotid arteries via the right radial or brachial artery, in order to capture embolic debris travelling to the brain during TAVR. The authors, investigators and patients need to be commended for 2

4 performing and participating in a well-conducted and important study. The most relevant findings are as follows: - The study did not meet its primary efficacy endpoint; i.e., the device did not result in a significant reduction of median total new lesion volume in protected territories (102.8 mm 3, interquartile range [IQR] mm 3 in the device arm vs mm 3, IQR mm 3 in the control arm; p = 0.33), as detected by DW-MRI at 2-7 days after TAVR. - Despite a small increase in the total procedure time and a very small increase in the fluoroscopy time, the use of the Sentinel device during TAVR was safe. - Secondary efficacy endpoints, such as total new lesion volume in all cerebral territories, new lesion number in both protected and all territories, and neurocognitive function at 30 and 90 days, were also not significantly different in device vs. control arms. - Histopathological debris was found within filters in 99% of patients, confirming the clear embolic risk during TAVR with frequent embolization of non-thrombotic material (arterial wall in 94% of cases), thus corroborating the fact that more aggressive antithrombotic therapy would not have prevented neurological injury. - The authors were able to demonstrate for the first time that there is a correlation between new lesion volume and neurocognitive decline. From a logical standpoint, a device that captures cerebral embolic material in 99% of cases should prevent ischemic injury of the brain, yet the data from this randomized trial does not appear to support routine cerebral protection with the Sentinel device. However, in our opinion, it would be inappropriate and unfair to close the book on cerebral protection after this chapter. Akin to standing too close to Maurits Cornelis Escher s Relativity and staring at a single staircase, we might lose perspective unless we took a step back to look at the 3

5 bigger picture. So while keeping in mind that the study is negative for the primary endpoint, let s try to take a step back and appreciate the bigger picture, starting with what we can learn from this trial and the challenges of performing a study on CEP during TAVR: - Difficulties in interpretation and standardization of DW-MRI: The 3-Tesla MRI scans used in this study are more sensitive (~30% more lesions) than 1.5-Tesla scans, but this does not allow pooling of data or comparisons with historical data. It appears that baseline MRI may be essential to detect previous neurological damage and its impact on new cerebral injuries, as a post hoc adjustment for baseline lesion volume resulted in a significant reduction of primary endpoint in the device vs. control arms. - Time points of evaluation: a MRI window of 2-7 days after TAVR is probably too broad and creates too much heterogeneity in terms of detected volumes of ischemic lesions, given the time-dependent sensitivity of DW-MRI in this context. - Evaluation of cognitive dysfunction: Neurocognitive assessment can be challenging in elderly patients in the first few days after TAVR and is dependent on the time of day and alertness of the patient; moreover, a large battery of tests can result in patient fatigue and inaccurate results. It may have been better to have simpler and more focused battery of tests, which were also repeated at later time-points (60-90 days). Furthermore, due to the design of current studies and the patient cohort being treated, it is impractical to evaluate long-term cognitive dysfunction. - The inclusion of and lack of stratification for the multiple TAVR devices requiring different techniques of implantation, as regards pre- and post-dilation. Indeed, valve type was an important cause of interaction with the primary efficacy endpoint. - Incomplete cerebral protection: The current Sentinel device fully protects only 9 out of 28 brain regions, because of the dual blood supply of the posterior circulation. Furthermore, it is likely that no device can completely protect the brain from embolic 4

6 material of all sizes and the protection offered is dependent on the placement and stability of the device as well as the underlying anatomy. It is worth noting that total new lesion volume was not significantly different for the entire brain in the two arms. - Manipulation and positioning of the device: all transcatheter CEP systems require some degree of manipulation in the aortic arch and great vessels and purely positioning the device can result in cerebral embolization (8). - Insufficient sample size: Although the CEP device resulted in a 42% reduction in total new lesion volume that exceeded the pre-specified success criterion (30% reduction), the sample size was inadequate and the study underpowered. A pre-estimated MRI sample size of 75 patients per group would have implied either a high total new lesion volume in controls or a large assumed treatment effect or both. This factor was probably overestimated and significantly impacted by patient comorbidities, newer TAVR valves, variability in procedural steps and antithrombotic therapy, increasing operator experience, and the high drop-out rate that is common in MRI studies (2). In considering all these potential pitfalls of a performing a randomized study of CEP during TAVR, the small imaging sample size is probably the main reason the SENTINEL study is negative, but this does not equate to saying that there is no role for CEP. Indeed, if we pool study-level data from the 3 randomized trials investigating the Claret CEP device (4,5,7), it would result in a total of 314 patients undergoing TAVR with (n = 165) or without (n = 149) CEP. This pooled analysis suggests that the Sentinel double-filter significantly reduces total new lesion volume in protected regions by approximately 100 mm 3 of damaged brain (Figure 1), i.e., 8 million neurons and 450 million synapses.(9) We are dealing with a potential benefit that cannot be ignored as TAVR shifts to younger and lower-risk patients, where preventing procedure-related cerebral injury remains a significant unmet clinical need with potentially important long-term sequelae. Furthermore, if we believe that CEP is 5

7 important, then we should not accept that there are areas of the brain that are unimportant. Thus, iterations of the current device are required and we need to better evaluate CEP systems that protect all regions of the brain, such as the TriGuard device (Keystone Heart, Caesarea, Israel) that is under evaluation in the REFLECT (A Randomized Evaluation of the TriGuard Embolic Deflection Device to Reduce the Impact of Cerebral Embolic Lesions After Transcatheter Aortic Valve Implantation) (NCT ) trial. However, the bar will now be higher for newer devices to be accepted as a routine adjunct to the TAVR procedure. Therefore, in order to reconnect what logically makes sense with supportive clinical data, larger randomized studies showing not only significant reductions in DW-MRI lesions, but also evidence of benefit as regards to neurocognitive dysfunction, will be required. 6

8 REFERENCES 1. Leon MB, Smith CR, Mack MJ, et al. Transcatheter or surgical aortic-valve replacement in intermediate-risk patients. N Engl J Med 2016;374: Pagnesi M, Martino EA, Chiarito M, et al. Silent cerebral injury after transcatheter aortic valve implantation and the preventive role of embolic protection devices: A systematic review and meta-analysis. Int J Cardiol 2016;221: Gress DR. The problem with asymptomatic cerebral embolic complications in vascular procedures: what if they are not asymptomatic? J Am Coll Cardiol 2012;60: Van Mieghem NM, van Gils L, Ahmad H, et al. Filter-based cerebral embolic protection with transcatheter aortic valve implantation: the randomised MISTRAL-C trial. EuroIntervention 2016;12: Haussig S, Mangner N, Dwyer MG, et al. Effect of a cerebral protection device on brain lesions following transcatheter aortic valve implantation in patients with severe aortic stenosis: the CLEAN-TAVI randomized clinical trial. JAMA 2016;316: Lansky AJ, Schofer J, Tchetche D, et al. A prospective randomized evaluation of the TriGuardTM HDH embolic DEFLECTion device during transcatheter aortic valve implantation: results from the DEFLECT III trial. Eur Heart J 2015;36: Kapadia SR, Kodali S, Makkar RR, et al. Cerebral embolic protection during transcatheter aortic valve replacement. J Am Coll Cardiol 2016; Rodés-Cabau J, Kahlert P, Neumann F-J, et al. Feasibility and exploratory efficacy evaluation of the Embrella Embolic Deflector system for the prevention of cerebral emboli in patients undergoing transcatheter aortic valve replacement: the PROTAVI- C pilot study. J Am Coll Cardiol Intv 2014;7:

9 9. Insel TR, Landis SC, Collins FS. Research priorities. The NIH BRAIN Initiative. Science 2013;340:

10 Figure 1: Meta-analysis of randomized controlled trials investigating the Claret cerebral protection filters. Forest plot shows results for new total lesion volume in patients undergoing TAVR with vs. without cerebral embolic protection (CEP) filters. The weighted mean difference (WMD) among groups equals to mm 3 (95% confidence interval [CI], mm 3 to mm 3 ), confirming a significant reduction in the analyzed endpoint (p-value 0.031). 9

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