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TAVR fragments were arrested, but strokes were not reduced, is the anti-fragmentation device worth? NEJM

 Last Update: 2022-10-20
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Transcatheter aortic valve replacement (TAVR) has become the mainstay of treatment for
aortic stenosis.
During TAVR, debris from artery walls, blood clots, valve tissue, etc.
can cause stroke
.
To intercept debris and prevent perioperative embolic stroke, the US FDA approved a cerebral embolization protection device (Sentinel CEP)
in 2017.
Although it is highly effective in capturing fragments from TAVR, there are no large-scale randomized controlled trials evaluating whether CEP devices reduce the risk of
stroke.

LAST WEEK, THE NEW ENGLAND JOURNAL OF MEDICINE (NEJM) PUBLISHED THE RESULTS
OF THE PROTECTED TAVR TRIAL THAT EXPLORED THESE QUESTIONS.
In this post-marketing, prospective, multicenter, randomized controlled trial of the Sentinel CEP device, 3000 patients with aortic stenosis who planned to receive TAVR were randomized to either intraoperatively or without CEP, and the results showed that the CEP device failed to significantly reduce the incidence of perioperative stroke (2.
3% vs.
2.
9%), but the authors considered the 95% confidence interval to be -1.
7~0.
5, CEP device benefits
cannot be ruled out.

A NEJM editorial issued at the same time called the findings a "heavy blow" to hopes of definitive evidence that CEP prevented TAVR-related strokes, and although CEP captured TAVR fragments, this surrogate outcome did not translate into a "high-quality stroke prevention" outcome
.
THE EDITORIAL URGED FDA TO CLARIFY ITS POSITION ON APPROVING CEP AND SPECULATED THAT SOME DOCTORS AND HOSPITALS WOULD STOP USING CEP BECAUSE OF A LACK OF CLINICAL EVIDENCE AND HIGH COST, BUT OTHERS MIGHT CONTINUE TO USE
IT BECAUSE PROTECTED TAVR SUGGESTED THAT CEP HAD THE POTENTIAL TO PREVENT DISABLING STROKE AND WAS SAFE.

NEJM Medical Frontiers invited Professor Chen Mao, Director of the Department of Cardiology, West China Hospital of Sichuan University and Head of the Structural Cardiology Group of the Cardiovascular Disease Branch of the Chinese Medical Association, to interpret the study
.
To read the full translation, please visit the NEJM Medical Frontiers official website, APP or click on the WeChat mini program picture
.

PROTECTED TAVR STUDY: FURTHER VALIDATION OF THE SAFETY AND EFFICACY OF TAVR INTRAOPERATIVE BRAIN PROTECTION DEVICES

ZHANG Yi,CHEN Mao*

Department of Cardiology, West China Hospital, Sichuan University

*Corresponding author

With the accumulation of evidence and the iteration of technology, transcatheter aortic valve replacement (TAVR) has become one of
the standard treatment methods recommended by guidelines for patients with high-, intermediate, and low-risk severe aortic stenosis.
However, cerebrovascular adverse events after TAVR are one of its inherently common complications and can be more common than other cardiac interventional procedures
.
Postoperative cerebrovascular adverse events often occur perioperatively with TAVR and have a worse prognosis [1-3].

Calcification/atherosclerotic plaque, damage to the valve/blood vessel tissue itself, or thrombosis on the surface of the implanted instrument and obstruction of cerebral blood vessels during vascular access, balloon dilation, or valve stent release are the main causes of perioperative acute cerebral embolism in TAVR [4]
Cerebral embolization protection (CEP) devices have been used in the surgical treatment of carotid artery stenosis in the past, which may reduce cerebral embolic events and improve clinical outcomes for patients [5,6]
。 This inspired
the use of CEP devices in TAVR to reduce perioperative cerebral embolic events.
With the first intraoperative use of CEP device in TAVR in 2010, a series of clinical validation studies have been conducted on the value of CEP in TAVR [7].

Early studies of PROTAVI-C and DEFLECT I have shown that TAVR intraoperative CEP implantation has a high success rate, good safety, and can effectively reduce the volume of ischemic brain lesions, but there is no significant reduction in new clinical cerebroembolic events overall [8,9].

There are also inconsistent findings on whether CEP devices improve new-onset clinical stroke in patients with TAVR [10,11].

Therefore, there has been controversy
over whether the use of intraoperative CEP devices confers a definite benefit in the TAVR population.

The Sentinel Brain Protector is the first intraoperative CEP device
for TAVR approved by the U.
S.
Food and Drug Administration.
The device includes two filters that can be placed through the radial artery in the brachiocephalic trunk and the left common carotid artery
.
Embolic fragments from the TAVR procedure are retained by the device's filter and removed
from the patient along with the device.

Previous single-center, small-sample randomized clinical trials such as CLEAN-TAVI and MISTRAL-C have shown that Sentinel can effectively reduce the incidence of cerebral ischemic lesions, reduce the volume of cerebral ischemic lesions, and protect the neurocognitive function of patients with TAVR [12,13].

Subsequently, the large-sample, multicenter randomized clinical trial SENTINEL showed that Sentinel brain protection devices effectively captured embolized fragments and protected neurocognitive function in 99 percent of patients, but brain magnetic resonance evaluation in patients implanted by Sentinel did not significantly reduce new brain injury [14].

Based on this, the need for multicenter randomized clinical trials with larger sample sizes has become more urgent to further determine the effectiveness
of Sentinel in TAVR patient populations.

ON OCTOBER 6, 2022, THE NEW ENGLAND JOURNAL OF MEDICINE (NEJM) PUBLISHED THE RESULTS OF THE PROTECTED TAVR STUDY
.
This is a prospective, post-marketing, multicenter randomized controlled trial in patients
with severe aortic stenosis across all surgical risk classes.
Enrolled patients were randomized in a 1:1 ratio to receive transfemoral TAVR with CEP (CEP group) or without CEP (control group).

The final data collection was completed in 2970 patients (including 1483 in the CEP group and 1487 in the control group), and the proportion of surgical risk (high, medium and low) was uniform between the two groups (30.
4%, 33.
2%, 36.
3% vs.
30.
4%, 34.
2%, 35.
4% in the control group).

THE RESULTS OF THE PROTECTED TAVR STUDY FOUND THAT THE SUCCESS RATE OF CEP PLACEMENT WAS HIGH DURING TAVR SURGERY (94.
4%, 1406/1489), AND THE INCIDENCE OF CLINICAL STROKE WITHIN 72 HOURS OF TAVR OR BEFORE DISCHARGE WAS NOT SIGNIFICANTLY DIFFERENT BETWEEN CEP AND CONTROL GROUPS (2.
3% VS.
2.
9%; P = 0.
30), but the incidence of disabling stroke was significantly lower in the CEP group than in the control group (0.
5% vs.
1.
3%; 95% CI，-1.
5~-0.
1）
。 In addition, there were no significant differences
between the CEP and control outcomes in mortality (0.
5% vs.
0.
3%), combined endpoints of stroke/transient ischemic attack/delirium (3.
1% vs.
3.
7%), and acute kidney injury (0.
5% vs.
0.
5%).

Figure 1 Clinical stroke incidence within 72 hours of TAVR or before hospital discharge

Figure 2 Clinical and neurological outcomes within 72 hours of TAVR or before hospital discharge

Based on this, the conclusion of the PROTECTED TAVR study suggests that the use of Sentinel in TAVR patients is safe and effective
.
Although Sentinel did not reduce the perioperative incidence of clinical stroke (including stroke in all subgroups) of TAVR, the incidence of disabling stroke, particularly ischaemic stroke, was lower
in patients.

The PROTECTED TAVR study is the largest post-marketing randomized controlled clinical trial of Sentinel in the field of structural heart disease intervention, and its results further validate the safety
of the Sentinel device in the TAVR population 。 Although the results of the study suggest that the use of CEP devices is not effective in reducing perioperative clinical stroke events in patients, it may also be related
to the reduced neuroprotective effectiveness of the device due to the aperture of the Sentinel device being larger than the embolic fragment or the device not effectively covering the left vertebral artery.
In addition, the study has conclusively demonstrated that the use of the Sentinel device is effective in reducing the incidence of disabling stroke, especially ischemic stroke, and reducing the risk
of this catastrophic adverse event in patients.

The study still has some limitations, such as the simple observation of endpoint indicators, the lack of blinding of neurology assessment, etc.
, but the current trial results do not negate the potential advantages
of using Sentinel in TAVR.
Perhaps in the future, more definite clinical benefits
can be achieved by fully identifying and screening patients with TAVR at high risk of perioperative acute cerebral embolism for the use of CEP.
In the context of the current controversy over the use of CEP devices in TAVR patients, the publication of this study results further solidifies the safety and effectiveness of the use of CEP devices in TAVR patients, and will also promote the further development of more application research of different types of CEP devices in TAVR
.

References

1.
Tay EL, Gurvitch R, Wijesinghe N, et al.
A high-risk period for cerebrovascular events exists after transcatheter aortic valve implantation.
JACC Cardiovasc Interv 2011; 4:1290-1297.

2.
Vlastra W, Jimenez-Quevedo P, Tchétché D, et al.
Predictors, incidence, and outcomes of patients undergoing transfemoral transcatheter aortic valve implantation complicated by stroke.
Circ Cardiovasc Interv 2019; 12:e007546.

3.
Huded CP, Tuzcu EM, Krishnaswamy A, et al.
Association between transcatheter aortic valve replacement and early postprocedural stroke.
JAMA 2019; 321:2306-2315.

4.
Van Mieghem NM, Schipper ME, Ladich E, et al.
Histopathology of embolic debris captured during transcatheter aortic valve replacement.
Circulation 2013; 127:2194-2201.

5.
Garg N, Karagiorgos N, Pisimisis GT, et al.
Cerebral protection devices reduce periprocedural strokes during carotid angioplasty and stenting: A systematic review of the current literature.
J Endovasc Ther 2009; 16:412-427.

6.
Barbato JE, Dillavou E, Horowitz MB, et al.
A randomized trial of carotid artery stenting with and without cerebral protection.
J Vasc Surg 2008; 47:760-765.

7.
Naber CK, Ghanem A, Abizaid AA, et al.
First-in-man use of a novel embolic protection device for patients undergoing transcatheter aortic valve implantation.
EuroIntervention 2012; 8:43-50.

8.
Rodés-Cabau J, Kahlert P, Neumann FJ, 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.
JACC Cardiovasc Interv 2014; 7:1146-1155.

9.
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.

10.
Butala NM, Makkar R, Secemsky EA, et al.
Cerebral embolic protection and outcomes of transcatheter aortic valve replacement: Results from the Transcatheter Valve Therapy Registry.
Circulation 2021; 143:2229-2240.

11.
Seeger J, Gonska B, Otto M, et al.
Cerebral embolic protection during transcatheter aortic valve replacement significantly reduces death and stroke compared with unprotected procedures.
JACC Cardiovasc Interv 2017; 10:2297-2303.

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; 316:592-601.

13.
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; 12:499-507.

14.
Kapadia SR, Kodali S, Makkar R, et al.
Protection against cerebral embolism during transcatheter aortic valve replacement.
J Am Coll Cardiol 2017; 69:367-377.

About the author

Chen Mao, chief physician, professor, doctoral supervisor
.
Director of the Department of Cardiology, West China Hospital, Sichuan University, and Director of
the Research Office of Valvular Heart Disease.
The fourth batch of national "10,000 people plan" scientific and technological innovation leading talents, standing committee member of the Cardiovascular Medicine Branch of the Chinese Medical Doctor Association, standing committee member of the Cardiovascular Disease Branch of the Chinese Medical Association, and leader of
the structural cardiology group.
The research results have been published in international high-level academic journals such as European Heart Journal and Nature Reviews Cardiology, and more than 170 SCI papers have been published as the first or corresponding author
.
He has presided over a number of national projects
such as the 13th Five-Year Plan and the Natural Science Foundation of China.
He has won 4 provincial and ministerial awards such as the first prize of Sichuan Science and Technology Progress Award
.
It is the first in the country to carry out interventional treatment of transcatheter valvular heart disease, and the number of completed cases ranks first
in the country.
His main research interests are the basic, applied and clinical research
of transcatheter interventional treatment of valvular heart disease, interventional treatment of coronary heart disease and cardiomyopathy.

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.
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.
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.
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