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Periprocedural stroke is an uncommon but feared complication in patients undergoing transcatheter aortic valve replacement (TAVR). Typically embolic, it occurs more frequent in the first days (within seven days) after the procedure and it is secondary to procedural factors. It has a wide clinical spectrum and it is associated with increased mortality and a controversial worse impact on cognitive functions. Capture of the debris by different cerebral embolic protection devices (CEPDs) during the TAVR were thought to be a safe and effective preventive strategy to reduce the risk of stroke. A lot of trials were conducted to demonstrate a benefit of CEPDs, but the current evidence is not conclusive on their impact on periprocedural strokes.
Department of Clinical Internal, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
Improta Riccardo
Department of Clinical Internal, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
Marco Tocci
Department of Clinical Internal, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
Lucia Ilaria Birtolo
Department of Clinical Internal, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
Emanuele Bruno
Department of Clinical Internal, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
Colantonio Riccardo
Department of Clinical Internal, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
Massimo Mancone*
Department of Clinical Internal, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
Gennaro Sardella
Department of Clinical Internal, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
*Address all correspondence to: massimo.mancone@uniroma1.it
1. Introduction
Transcatheter aortic valve replacement (TAVR) is a rapidly growing minimally invasive alternative in patients with symptomatic severe aortic stenosis and intermediate or greater pre-operative surgical risk [1, 2, 3]. While TAVR is associated with a lower risk of complications, shorter recovery and overall effectiveness, periprocedural stroke remains a significant concern [4] with a relevant impact on mortality, cognitive decline and quality of life (QoL) [5, 6, 7, 8]. The progressively expanded recommendation of TAVR for younger or low-risk patients [9, 10, 11] makes it necessary to consider preventive strategies to reduce the incidence of this devasting complication for TAVR patients. Over the years, several studies have investigated the safety and effectiveness of different protection devices whose temporary positioning during percutaneous biological valve implantation is still controversial.
2. The risk of stroke in the early phase after TAVR: Why to prevent?
Periprocedural stroke is defined as a neurological dysfunction of at least 24 hours and/or visible on imaging within seven days after TAVR [7, 12, 13, 14, 15]. In particular, less than half of postoperative strokes occur within the first day after the index procedure [16, 17]. The cerebral embolization of debris during manipulation of the catheters, the calcified native valve and the aortic wall is supposed to be the main pathogenetic mechanism. The impact of sedation and anesthesia on cerebral blood flow has a considerable additional impact [18]. The debris types comprised arterial wall tissue, native valve tissue, calcifications and foreign body material detached from percutaneous devices [19, 20]. Neuroimaging in stroke revealed more frequent supratentorial cerebral left-side lesions [21, 22]. The middle cerebral anterior (MCA) is the most commonly involved artery [22].
Over the years, the impact of vascular access on periprocedural stroke during TAVR was not wholly verified. The Transfemoral (TF) approach is the route of choice for TAVR. Initially, it was associated with a higher risk of periprocedural stroke than transapical (TA) one, supposing that TA-TAVR could allow an accessible and direct implantation and avoid the manipulation of catheters and devices in the aortic arch [23, 24, 25]. However, recent studies did not observe worse outcomes in TF-TAVR than in TA-TAVR [26, 27]. Other vascular approaches (trans-carotid, TC; trans-subclavian TS; direct trans-aortic, TAO) were compared to the gold standard. However, neither TC-/TS [28] nor TAO [29] were associated to lower risk of periprocedural stroke.
The choice of a self-expandable valve (SEV) or a balloon-expandable valve (BEV) is another challenging procedural aspect. SEV-related strokes occur during slow stepwise implantation, while BEV-related strokes occur during valve positioning [30]. The CHOICE trial [31], the REPRISE III trial [32] and the randomized SOLVE-TAVI trial [33] were inconclusive because of the cohorts of patients selected, the frequency of the follow-up and the neurological assessment. However, recent stronger evidences registered that patients who underwent BEV implantation have lower rates of strokes or less silent cerebral lesions detected by DWI-MRI [20, 22, 34, 35, 36, 37].
During the biological valve implantation, the role of pre- (BAV) and post- (BPD) dilatation is also crucial. Pre-dilatation was initially thought mandatory to cross the stenosed valve, to prepare the prosthesis, and to decrease the radial counterforces. However, the DIRECT and DIRECTAVI trials demonstrated the feasibility of direct-TAVI approaches without increasing rates of periprocedural strokes [38, 39]. Instead, post-dilatation guarantees an optimal frame expansion, reduces paravalvular leak (PVL) and avoids the patient-prosthesis mismatch (PPM). This aspect is not irrelevant, considering that small aortic valvular areas (AVA) after TAVR or malposition predispose to ischemic cerebral embolism due to subclinical leaflet thrombus [40]. Despite this, in several studies, BPD seems to double the risk of periprocedural strokes [41, 42, 43, 44] and nowadays it is considered an independent risk factor of early stroke after TAVR [45]. In conclusion, BAV has no apparent impact on stroke rates, but reduced pre-dilatation is not justified if BPD increases in a direct-TAVR approach. On the contrary, BPD should be minimized more and more, improving the sizing of the annulus by cardiac tomography (CT).
The “intrinsic” thromboembolic risk of the patient should also be considered. Several factors, including age, female sex, prior stroke or TIA, obesity, diabetes, chronic renal failure, and atrial fibrillation, are independent predictors of TAVR post-operative stroke [17]. Recent data showed that carotid artery disease is not associated with increased rates of early stroke [46].
The incidence of periprocedural stroke is still debated (Figure 1). Initially, in the high-risk patients-PARTNER 1 trial [7], neurological events were higher in TAVR-group compared to the open-surgery standard of care at one year (8.3% vs. 4.3%, p = 0.04). The cross-clamping of the aorta was supposed to allow the debris removal. However, the selection bias of the high risk group eligible for TAVR seems to be related to these results. Conversely, the PARTNER trial 2 [3] and the SURTAVI [47] selected non-high risk patients showing a significant lower rate of strokes in the TAVR-group. Nevertheless, observational registries are frequently based on self-reporting events without a strict neurological assessment or monitoring and a central adjudication of events. The ADVANCE trial [48] first tried to evaluate the neurological outcomes after TAVR thanks to an Independent Clinical Events Committee. It showed an incidence of about 1.4% from zero to one postoperative day. Additionally, the CoreValve US Extreme Risk and High Pivotal Trials were studied by Kleiman et al. with a particular issue about cerebrovascular events (CVEs) [14]. The paper was drawn from trials (and not registries or prospective studies) that involved a rigorous method of neurological assessment of patients after TAVR. In the early phase (0–10 days after the procedure), the incidence of stroke was found to be at 4%, higher compared to previous registries.
Figure 1.
Thromboembolic incidence in larger studies about TAVR.
However, the real world rate of periprocedural cerebral events (CVEs) may be underestimated. The phenomenon of silent cerebral embolism (SCE) may be a partial explanation. Silent brain lesions were detected in at least 70% of patients underwent DWI-MRI after TAVR [22, 49, 50], but only 27% of lesions evolved into gliotic scars at the follow-up [22]. Other reasons for under-reporting are: (a) sedating drugs and anesthesia; (b) lack of understanding of symptoms; (c) formation of thrombus after depositing of embolus.
In 2020, an STS/ACC TVT Registry analysis [51] included over 276,316 patients undergoing TAVR between 2011 and 2019. The authors found that the incidence of in-hospital stroke or transient ischemic attack (TIA) has decreased from 2011 (2.1%) to 2019 (1.6%), as well as 30-day stroke rates (2.75% vs. 2.3%). It could be partly influenced by the operator experience improved over time. Salemi et al. high-lightened that procedures performed by more experienced operators are associated with significantly lower risks for post-procedural stroke [52].
The occurrence of significant strokes after TAVR has a meaningful clinical impact on mortality and neurocognition. The PARTNER trial [13] was the first to demonstrate that patients with stroke after TAVR had a higher mortality rate at 30 days and one year than those without. Subsequently, either Huded et al. [16] or Kleiman et al. [14] confirmed these results. In addition, in 2023, Castelo et al. affirmed more precisely that patients with stroke after TAVR have longer intensive unit care (ICU) stay (12 vs. 4 days) and higher rates of intra-hospital mortality (21.1% vs. 4.3%) especially cardiovascular 30-days mortality (15,8% vs. 4,1%) [45].
A large body of evidence indicated adverse cognitive consequences of cerebral brain lesions (clinically silent or overt), either in atrial fibrillation [53] or after cardiac surgery [54]. The impact of SCE on cognitive decline has been debated for a long time because several studies were controversial. In 2010, Khalert et al. reported that cerebral lesions are not associated with the deterioration of cognitive functions [55]. On the contrary, in the subsequent Neuro-TAVI trial, Lansky et al. confirmed that one in three patients after TAVI had a cognitive decline assessed by the Montreal Cognitive Assessment score (MoCA) [49]. In the SENTINEL trial, Kapadia reported a correlation between changes in cognition and median silent cerebral lesions volume (p < 0.002, 21]. Similarly, De Carlo et al. observed that patients developing SCILs had a significant worsening in neurocognitive function at discharge with incomplete recovery at the follow-up [22]. However, the small numbers enrolled, the attrition rate, the shorter time of reassessment after discharge and the modest magnitude change in Mini-Mental State Examination (MMSE) or MOCA at the follow-up do not allow a robust conclusion on neurocognitive effects of the early phase stroke after TAVR. More extended studies with longer reassessment are needed for conclusive findings.
TAVR is nowadays going to address even low-risk and younger population [56]: widespread and frequent use of embolic protection devices (EPDs) is necessary to improve outcomes (such as in-hospital mortality and stroke).
EPDs have been projected to hinder the embolization of different kinds of material, released during valve implantation to the brain; the two main classes of EPDs allow to deflect or to filter potential debris thus avoiding cerebrovascular events (Table 1). They are usually positioned along the aortic arch or into the anonymous branch and left common carotid before the valve advancement and release from different peripheric vascular access (both femoral and radial routes are viable alternatives, depending on the device) with dedicated catheters; finally, they are retrieved at the end of the procedure before vascular closure.
Device
Fr – Access – protected vessels
Latest evidence
TriGUARD Deflector
8 Fr Femoral Contralateral 3 Vessels
REFLECT II (2021) No difference with unprotected procedures for:
All-cause mortality or any stroke at 30 days
Worsening NIHSS score at 2 to 5 days
Freedom from any cerebral ischemic lesions detected on DW MRI at 2 to 5 days.
Total volume of cerebral ischemic lesions detected on DW MRI at 2 to 5 days
Embrella Deflector
6 Fr Right Brachial or Radial 2 Vessels
PROTAVI C (2014) No difference with unprotected procedures for:
Stroke, TIA Major vascular complications life-threatening bleeding, AKI, Mortality at 30 days
Increased high-intensity transient signals (HITS) at each step of the transcatheter aortic valve replacement procedure
Point Guard Deflector Filter
10 Fr Femoral 3 Vessels
Point Guard CENTER Trial (2018) Ongoing
ProtEmbo Deflector
6 Fr Left Radial 3 Vessels
PROTEMBO SF Trial (2022) New DW-MRI lesion volumes with ProtEmbo were smaller than in historical data.
Sentinel Filter
6 Fr Right Radial 2 Vessels
PROTECTED TAVR (2022) No difference with unprotected procedures for:
The overall major adverse cardiac and cerebrovascular rate was 6.5% for the Embroliner device, a 46% reduction compared with the historical performance goal
One hundred percent of subjects resulted m debris captured in the Emboliner filter.
Embolk Filter
11 Fr Femoral Access 3 Vessels and subdiaphragmatic vessels
First-in-Man Study Evaluating the Emblok Embolic Protection System During TAVR or 20 patients (2020)
The Emblok embolic protection system appears to be feasible and safe during TAVR.
The device was successfully placed and retrieved in all cases and no neurological events were observed
Table 1.
Main EPDs, technical features and supporting evidences.
3.1 Deflectors
The first type of devices consists of large porous webs on top of the aortic arch and/or descending aorta, enabling embolic material to be deflected down in the thoracic descending aorta thus protecting the brain from ischemic injury. Some devices cover just the first two collateral vessels from the arch, whereas others are also developed for the left subclavian artery.
3.1.1 TriGUARD
TriGUARD (Keystone Heart) is one of the most studied EPDs and the first deflector device to receive a CE mark. At the moment, the newest technology available is the TriGUARD 3 that guarantees an improved device visualization and more precise positioning and stability. Through an On The Wire, 8 French delivery system the device is introduced in the contralateral femoral artery and accommodates a 5 Fr pigtail catheter into the lumen; it does not require an additional access site. The deflection filter consists of a nitinol frame (74 mm x 98 mm) with a dome-shaped web designed to allow adequate blood flow to the brain. It enables the covering of all three aortic arch branches ostia.
The older generation devices (TriGUARD and TriGUARD HDH) safety and efficacy (defined as decreased lesion volume as compared to unprotected TAVR) were explored through two randomized controlled trials, the DEFLECT I and DEFLECT II [57, 58].
The DEFLECT III trial was a multicentre, randomized controlled trial testing TriGUARD HDH device against unprotected TAVR in a group of 85 patients. In this exploratory study, subjects undergoing protected TAVI had significantly more freedom from ischaemic brain lesions, numerically reduced single and maximum lesion volumes and better cognitive function in some domains [36]. No statistically significant difference was observed for what concerns rates of stroke.
These results were partially confirmed from the prospective, multicentre, single-blind randomized REFLECT II trial [59] that compared TriGUARD 3 protected procedures with unprotected procedures (for a total of 220 patients), finding no significant differences between treatment and control arm regarding rates of stroke, brain lesions volume and neurological impairment at discharge.
3.1.2 Embrella
This device from Edwards Lifescience is designed to cover all three cerebral vessels and it has the advantage of being delivered from a right radial or brachial access through a 6 Fr sheath. However, the main study (PROTAVI-C) [60] comparing unprotected and device-protected TAVR failed to show a reduction in cerebral ischemic events in EPD treated population, reporting, on the contrary, an increased rate of micro-embolization to the brain.
On the other side, the use of the Embrella system was associated with lower lesion volume than the control group. Furthermore, every new cerebral lesion disappeared on the MRI performed 30 days after TAVR.
3.1.3 Other devices
There are a large number of EPDs that are undergoing testing and safety/efficacy studies. We herein mention:
The Point-Guard (Transverse Medical) provides complete cerebral protection by covering all supra-aortic arteries via an embolic material deflection, capture and removal. Like similar devices, it consists of a flexible nitinol frame with a filter web covering the aortic arch, positioned by a femoral route. It also has a supporting extension basket at the distal end: by sealing and conforming the arch anatomy, it addresses the challenge of devices with non-sealing edges. The Point Guard CENTER trial started in 2018 and will be the main multicentre trial across the EU evaluating the safety and efficacy of the device.
ProtEmbo (Protembi) is delivered via a 6 Fr sheath through left radial/brachial artery; it provides protection for all three cerebral vessels and has the smallest pores between the EPDs. Safety and efficacy were assessed through the PROTEMBO C trial showing encouraging results: fewer MACEs and smaller volume brain MRI lesions were observed in comparison to pre-specified performance goals [61].
3.2 Filters
The second class gathers systems of different sizes, positions and access; the entrapment of the embolic material and its removal represents the common denominator between the different devices.
3.2.1 Sentinel
Sentinel was the first capture system to obtain the CE mark and FDA approval, respectively in 2013 and 2017. Two sequential mesh develop on a single 6 Fr catheter and are positioned into the left common carotid artery (the distal one) and into the brachiocephalic artery (the proximal one) from right radial access. The webs are connected by an articulating positioning sheath that allows good manipulation and rapid delivery (less than 10 minutes) during the procedure. The device comes in only one size, thus may not be adequate for some particular aortic and arterial anatomies; moreover, the vertebral artery is not protected.
The three main randomized controlled trials evaluating the efficacy of the Sentinel system highlighted different and controversial results. In almost every patient in the treatment group, embolic debris was captured by the filter.
The MISTRAL-C [37] showed statistically significant reduction in neurocognitive deterioration in the EPD group. The CLEAN-TAVI [62] trial randomized 100 patients to protected vs. unprotected procedures and demonstrated that the EPD group had a decrement in the new-onset brain lesions and reduced volume lesions. The SENTINEL [20] trial failed to demonstrate a significant reduction in stroke rates and lesion volume.
The last and largest randomized trial about Sentinel efficacy is the PROTECTED TAVR [63] study: 3000 patients were randomized in 1:1 fashion to unprotected and protected procedure. The rate of disabling stroke was significantly lower in the Sentinel group with a relative risk reduction of 60%, although this trial was not powered to assess disabling stroke.
3.2.2 Emboliner
Emboliner (Emboline) consist of a cylindrical nitinol mesh filter that circumferentially conforms to the aortic anatomy, covering all three cerebral vessels and, through a downstream filter end captures embolic debris directed to kidneys, abdomen and lower body. Plus, the Emboliner shares the transfemoral access site used for the pigtail catheter, so no additional access or closure is required. After valve advancement and deployement (passing the downstream filter with the prosthesis delivery device), the EPD and the materials entrapped between the mesh are removed. The SAFEPASS 2 [64] study analyzed the safety and efficacy of the device between 31 patients undergoing TAVR compared with an historical performance goal, demonstrating encouraging results. A larger ongoing study will evaluate if the benefit in terms of reduction of stroke and systemic embolism rates is consistent when a protected procedure is compared to an unprotected one.
3.2.3 Emblok
The Emblok (Innovative Medical Solutions) is the only capture device including a radiopaque 4 Fr pigtail catheter, that aids in identifying the non-coronary cusp and favoring correct alignment and positioning of the valve. It is deployed in a single 11 Fr femoral route and covers the ascending aorta and aortic arch [65]. The first 20 patients that underwent TAVR protected procedure with the device were totally free from MACCE at 30 days even if post-procedural MRI showed that 95% of the group developed new silent ischemic brain lesions.
The safety of embolic protection devices in TAVR has been extensively demonstrated in many trials and studies. However, CEPDs’ efficacy and impact on hard clinical outcomes remains a controversial argument of debate. Some of the most recent meta-analyses showed indeed conflictual results. Woldendrop et al. on the European Heart Journal stated that using CEPDs did not result in a significant decrease in the occurrence of silent brain infarcts [50]. In two reviews and meta-analyses [66, 67] reporting results from randomized controlled trials (RCTs) and observational studies, the use of EPDs was effectively associated to fewer short-term stroke events. In contrast, other ones [68, 69, 70] (predominantly based on RCTs) did not show any difference on clinical outcomes or neuroimaging parameters. One of the most recent and updated summaries of evidence by Baloch et al. [71] comprehended 128,471 patients from RCTs and observational studies and highlighted the benefit of CEPD in reducing incidence of 30 day disabling stroke in patients undergoing TAVR; the majority of studies was based on TriGUARD and Sentinel devices.
Stroke is a major concern in patients undergoing TAVR that can affect mortality and morbidity. TAVR expanding indication to low risk young patients raises issues on prevent or reduce the incidence of cerebrovascular ischaemic events that could be pursued through embolic protection devices. Clear univocal evidence does not support the routine use of cerebral embolic protection devices during TAVR to prevent stroke and improve outcomes. However, it may be useful in patients judged at high risk of neurological events; further studies about the ideal patient selection are warranted.
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Written By
Gianluca Di Pietro, Improta Riccardo, Marco Tocci, Lucia Ilaria Birtolo, Emanuele Bruno, Colantonio Riccardo, Massimo Mancone and Gennaro Sardella
Submitted: 30 May 2023Reviewed: 06 June 2023Published: 09 August 2023
Open access peer-reviewed chapter
