Author + information
- Published online January 23, 2017.
- aInterventional Cardiology Unit, San Raffaele Scientific Institute, Milan, Italy
- bInterventional Cardiology Unit, EMO-GVM Centro Cuore Columbus, Milan, Italy
- ↵∗Reprint requests and correspondence:
Dr. Azeem Latib, Interventional Cardiology Unit, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy.
- cerebral embolic protection
- transcatheter aortic valve replacement (TAVR)
Despite the continuous evolution of transcatheter aortic valve replacement (TAVR), cerebral injury is still a major issue. The PARTNER (Placement of Aortic Transcatheter Valves) II cohort A trial reported a 30-day stroke rate of 5.5% after TAVR, thus confirming that procedure-related neurological events are a significant concern even in lower-risk patients and with next-generation transcatheter heart valves (1). Besides the risk of clinically apparent cerebrovascular events, most 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). Long-term consequences of these lesions are not understood, but increasing evidence suggests that they represent silent brain infarctions that could be related to memory loss, cognitive decline, and dementia (3). 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 used as a surrogate endpoint for TAVR-related neurological damage and as the primary endpoint in studies evaluating the efficacy of cerebral embolic protection (CEP) devices.
Small studies suggested efficacy of CEP during TAVR (4–6). The report by Kapadia et al. (7) in this issue of the Journal provides results from a large randomized clinical trial evaluating safety and efficacy of a transcatheter CEP system during TAVR. The SENTINEL (Cerebral Protection in Transcatheter Aortic Valve Replacement) trial enrolled 363 high-risk patients with severe symptomatic aortic stenosis who underwent TAVR with valves approved by the U.S. Food and Drug Administration. Patients 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, the Sentinel system (Claret Medical, Santa Rosa, California), was designed to deliver filters to the brachiocephalic and left common carotid arteries through the right radial or brachial artery and to capture embolic debris traveling to the brain during TAVR. We commend the authors of the report, the study investigators, and the participating patients for this well-conducted and important study. The most relevant findings are as follows:
• The device did not result in a significant reduction of median total new lesion volume in protected territories as detected by DW-MRI at 2 to 7 days after TAVR.
• Despite a small increase in total procedure fluoroscopy times, use of the Sentinel device was safe.
• 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 not significantly different in device versus control arms of the study.
• Debris was found within filters in 99% of patients, a finding confirming the clear embolic risk during TAVR with frequent embolization of nonthrombotic material (arterial wall in 94% of cases) and thus corroborating the fact that more aggressive antithrombotic therapy would not have prevented neurological injury.
• A correlation between new lesion volume and neurocognitive decline was demonstrated.
Logically, a device that captures cerebral embolic material in 99% of cases should prevent ischemic injury of the brain, yet data from this trial do not appear to support routine cerebral protection with the Sentinel device. However, it would be inappropriate and unfair to close the book on cerebral protection after this chapter. While keeping in mind that the study result is negative for the primary endpoint, we should appreciate what we can learn from this trial and the challenges of performing a study of CEP during TAVR:
• Interpretation and standardization of DW-MRI: The 3-T MRI scans are more sensitive (∼30% more lesions) than the 1.5-T scans, but this does not allow pooling of data or comparisons with historical data. 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 the primary endpoint in the device versus control arms of the study.
• Evaluation time points: An MRI window of 2 to 7 days after TAVR is probably too broad and creates too much heterogeneity 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 older 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 cause fatigue in patients and inaccurate results. A simpler and more focused battery of tests repeated at later time points (60 to 90 days) may have been preferable. Furthermore, given the current study design and the patient cohort being treated, it is impractical to evaluate long-term cognitive dysfunction.
• Stratification for device: The inclusion of and lack of stratification for multiple TAVR devices requiring different techniques of implantation were problematic because valve type was an important cause of interaction with the primary efficacy endpoint.
• Incomplete cerebral protection: The current Sentinel device fully protects only 9 of 28 brain regions because of the dual blood supply of the posterior circulation. It is likely that no device can completely protect the brain from embolic material of all sizes, and protection depends on the placement and stability of the device as well as the patient’s underlying anatomic features. Notably, total new lesion volume was not significantly different for the entire brain in the 2 arms of the study.
• Manipulation and positioning of the device: All transcatheter CEP systems require some manipulation in the aortic arch and great vessels, and device positioning 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 study was underpowered. A pre-estimated MRI sample size of 75 patients per group would have implied a high total new lesion volume in control subjects or a large assumed treatment effect, or both. This factor was probably overestimated and significantly affected by patients’ comorbidities, newer TAVR valves, variability in procedural steps and antithrombotic therapy, increasing operator experience, and the high dropout rate that is common in MRI studies (2).
The small imaging sample size is probably the main reason that the results of the SENTINEL study are negative, but this does not equate to saying that CEP has no role in TAVR. If we pool study-level data from the 3 randomized trials investigating the Claret CEP device (4,5,7), this data pool includes a total of 314 patients undergoing TAVR with (n = 165) or without (n = 149) CEP and cerebral DW-MRI before and after the procedure. This meta-analysis suggests that the Sentinel double-filter device significantly reduces total new lesion volume in protected regions by approximately 100 mm3 of damaged brain (Figure 1) (i.e., 8 million neurons and 450 million synapses) (9). This potential benefit cannot be ignored as TAVR shifts to younger and lower-risk patients; in these groups, preventing procedure-related cerebral injury remains a significant unmet clinical need with potentially important long-term sequelae. Furthermore, if we believe that CEP is important, then we should not accept that there are areas of the brain that are unimportant. Iterations of the current device are required, and we need to evaluate more effectively the CEP systems that protect all regions of the brain, such as the TriGuard device (Keystone Heart, Caesarea, Israel) currently 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; NCT02536196) trial. The bar will now be higher for newer devices to be accepted as routine adjuncts to the TAVR procedure. Larger randomized studies showing not only significant reductions in DW-MRI lesions but also evidence of benefit in neurocognitive dysfunction will be required.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
San Raffaele Scientific Institute is or has been involved in clinical studies of cerebral embolic protection devices for transcatheter aortic valve replacement developed by Claret Medical, Keystone Heart, and Innovative Cardiovascular Solutions. Dr. Latib is on the advisory board of Medtronic; is a consultant for Direct Flow Medical; and has conducted research studies with Claret Medical, Keystone Heart, and Innovative Cardiac Solutions. Dr. Pagnesi has reported that he has no relationships relevant to the contents of this paper to disclose.
Deepak L. Bhatt, MD, MPH, served as Guest Editor-in-Chief for this paper.
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