The unresolved issue of long-term valve durability is probably the key challenge in expanding TAVI to lower risk and younger age patients. Longitudinal echocardiographic evaluation of the PARTNER trials (PARTNER 1A, 1B, and continued access) demonstrated stable hemodynamic results after TAVI over 5 years of follow-up (19). Similar results were reported in other series and for self-expanding transcatheter heart valves (20). Recently results from the Nordic NOTION trial confirmed not only robust hemodynamic data over 5 years of follow-up but also favorable hemodynamics after TAVI compared to SAVR (2). Particularly in patients with smaller aortic annuli, TAVI may yield a lower incidence of patient-prosthesis mismatch, compared to SAVR. However, increased rates of PVL were consistently observed after TAVI compared to SAVR. Due to an adverse effect of significant paravalvular leakage on survival (10), reduction of residual regurgitation will be essential to improve long-term outcomes. Although progress has been made to reduce residual AR after TAVI in recent studies with next-generation devices (21), further improvements will be required to match data from SAVR cohorts.

Additionally, subclinical leaflet thrombosis, its effects on hemodynamic and clinical results need to be evaluated due to a significantly higher incidence after TAVI compared to SAVR (22). Overall, the incidence of structural valve degeneration and aortic valve re-intervention were low but will naturally become an issue as follow-up length and patient numbers increase. Recently published definitions of prosthesis degeneration may aid comprehensive analysis of this important topic (23, 24). To eliminate durability concerns after TAVI, very solid durability data available for surgical bioprostheses over the course of more than a decade will need to be matched (25).

DEDICATE NOTION 2 PARTNER 3 CoreValve low risk

Reference/NCT number Clinicaltrials.gov/NCT03112980 Clinicaltrials.gov/NCT02825134 Clinicaltrials.gov/NCT02675114 Clinicaltrials.gov/NCT02701283

TABLE 2 | Overview of currently active randomized trials on TAVI vs. SAVR in low to intermediate risk patients with severe aortic stenosis.

SAVR, surgical aortic valve replacement; STS-PROM, Society of Thoracic Surgeons predicted risk of operative mortality; TAVI, transcatheter aortic valve intervention; \*Any commercially available or CE marked device. Information up-to-date as available on clinicaltrials.gov on June 10th, 2018.

Nevertheless, degeneration of THV will occur at some point in patient life, leading to either surgical valve replacement or valve-in-valve procedures. Valve-in-valve procedures have demonstrated encouraging results in patients with degenerated surgical aortic bioprostheses (26). Whether these results can be systematically achieved for valve-in-valve procedures in degenerated THV needs to be demonstrated. Different design features of THV may yield variable results after valve-in-valve implantation, for example with regard to coronary access in degenerated supra-annular THV.

While moving towards younger patients, the prevalence of biscuspid aortic valve disease will inevitably increase. Data from retrospective registries demonstrated lower procedural success and higher residual PVL after TAVI in patients with bicuspid compared to tricuspid aortic valve disease (27–30). Implantation of new-generation devices yielded improved outcomes, giving rise to hope that TAVI may become a valid treatment option in bicuspid aortic valve disease in the future (30). Due to the paucity of data, guidelines favor SAVR in these patients at current (13).

### Morbidity and Mortality

After early reports of increased stroke rates after TAVI (6), more recent trials have consistently demonstrated similar outcomes for mortality and stroke after TAVI or SAVR. However, distinct complication patterns have repeatedly been reported for both treatment options (see **Table 1**). These need to be weighed against the individual patient's risk profile when choosing the optimal treatment modality. These include a higher incidences of acute kidney injury, bleeding events, and atrial fibrillation after SAVR. TAVI was associated with faster recovery and shorter index hospitalization but a higher rate of re-interventions or heart failure were documented during follow-up. Long-term results will be essential to gain further insights into these important first observations. While major vascular complications were common after transfemoral TAVI with first-generation devices (31), a significant decrease was observed in recently reported intermediate-risk trials (8– 10). A shift in patients' risk and device refinements with smaller delivery systems and improved vascular closure devices may be responsible for this decline. Permanent pacemaker implantation remains a concern after TAVI, particularly with self-expanding THV. Although data remain ambiguous regarding the association of pacemaker implantation and outcome after TAVI at current (32, 33), this issue requires in-depth evaluation, particularly in the treatment of younger patients.

Although a major advantage of TAVI relates to the less invasive procedure compared to SAVR, the risk for rare but life-threatening complications after TAVI (e.g., annular rupture, valve migration, or coronary obstruction) requiring bail-out emergency cardiac surgery must be taken into account. Recently published data from the European Registry on Emergent Cardiac Surgery during TAVI (EuRECS-TAVI) reported an incidence of emergent cardiac surgery of 0.7% in recent years. Most common causes were left ventricular guidewire perforations (28.3%) and annular ruptures (21.2%). Most of these complications occurred during the procedure and mortality remained high despite emergent cardiac surgery (34). While these serious procedure-related complications were more frequent in the early TAVI era and have become very rare events at this stage (35), expansion of TAVI towards younger and low-risk patients requires an even more critical appraisal and all measures need to be taken to prevent these complications.

### Cost-Effectiveness

With the rapid growth of TAVI volume, its implications on healthcare systems and its cost-effectiveness will become even more important, particularly while expanding TAVI indications to lower risk patients (36). An early analysis from the Netherlands demonstrated higher 1-years costs of TAVI vs. SAVR in intermediate-risk patients (37). This cost difference was mainly driven by the difference in device prices. A recent cost-effectiveness analysis from the Partner 2A and Sapien 3 trials reported lower costs at 2 years after TAVI (3). Higher procedural costs were compensated for by shorter hospitalization and substantially lower costs during follow-up. Regional and national differences in reimbursement and device costs impede

### REFERENCES

generalization of these results. However, health economic analyses will gain importance as the field expands.

### CONCLUSION

TAVI has become the standard treatment in patients at increased surgical risk and is increasingly being performed in patients at intermediate to low risk at current. Non-inferiority has been demonstrated in different intermediate risk cohorts. However, before broad expansion to lower risk and younger patients can be recommended, several challenges—particularly with regard to valve durability—need to be addressed. Several randomized trials are under way to investigate these issues and will determine future guideline recommendations. For now, distinct risks should be weighed into the decision of TAVI vs. SAVR, incorporating each patient's individual risk profile and personal preferences. Shared-decision making will increasingly become a crucial element in this process. Preferences of the informed patient should be discussed, balanced, and weighed into the joint treatment decision of the interdisciplinary heart team to select the appropriate treatment for every individual patient while expanding TAVI to intermediate and low risk operative patients.

### AUTHOR CONTRIBUTIONS

LV: literature research, drafted the manuscript; MS: literature research, critical revision of the manuscript.

patients with severe aortic valve stenosis: one-year results from the all-comers Nordic Aortic Valve Intervention (NOTION) randomized clinical trial. J Am Coll Cardiol. (2015) 65:2184–94. doi: 10.1016/j.jacc.2015.03.014

Registry. J Am Coll Cardiol. (2017) 69:1215–30. doi: 10.1016/j.jacc.2016.1 1.033

disease. J Am Coll Cardiol. (2014) 64:2330–9. doi: 10.1016/j.jacc.2014. 09.039

**Conflict of Interest Statement:** MS received travel compensation from Edwards Lifesciences and lecture fees from Medtronic, serves as coordinating investigator for the DEDICATE-DZHK6 trial.

The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2018 Voigtländer and Seiffert. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

# Access Sites for TAVI: Patient Selection Criteria, Technical Aspects, and Outcomes

Luigi Biasco1 \* † , Enrico Ferrari 2†, Giovanni Pedrazzini 1 , Francesco Faletra1 , Tiziano Moccetti 1 , Francesco Petracca1 and Marco Moccetti 1

*1 Division of Cardiology, Fondazione Cardiocentro Ticino, Lugano, Switzerland, 2 Division of Cardiovascular Surgery, Fondazione Cardiocentro Ticino, Lugano, Switzerland*

During the last ten years, transcatheter aortic valve implantation (TAVI) has become a reliable and valid alternative treatment for elderly patients with severe symptomatic aortic valve stenosis requiring valve replacement and being at high or intermediate surgical risk. While common femoral arteries are the access site of choice in the vast majority of TAVI patients, in up to 15–20% of TAVI candidates this route might be precluded due to the presence of diffuse atherosclerotic disease, tortuosity or small vessel diameter. Therefore, in order to achieve an antegrade or retrograde implant, several alterative access routes have been described, namely trans-axillary, trans-aortic, trans-apical, trans-carotid, trans-septal, and trans-caval. The aim of this paper is to give a concise overview on vascular access sites for TAVI, with a particular focus on patient's selection criteria, imaging, technical aspects, and clinical outcome.

#### Edited by:

*Crochan John O'Sullivan, Triemli Hospital, Switzerland*

### Reviewed by:

*Paolo Denti, San Raffaele Hospital (IRCCS), Italy Moritz Seiffert, University Heart Center Hamburg GmbH, Germany*

> \*Correspondence: *Luigi Biasco<EMAIL_ADDRESS>
*†These authors have contributed equally to this work.*

#### Specialty section:

*This article was submitted to Structural Interventional Cardiology, a section of the journal Frontiers in Cardiovascular Medicine*

> Received: *16 April 2018* Accepted: *19 June 2018* Published: *17 July 2018*

#### Citation:

*Biasco L, Ferrari E, Pedrazzini G, Faletra F, Moccetti T, Petracca F and Moccetti M (2018) Access Sites for TAVI: Patient Selection Criteria, Technical Aspects, and Outcomes. Front. Cardiovasc. Med. 5:88. doi: 10.3389/fcvm.2018.00088* Keywords: TAVI, trans-axillary, trans-aortic, trans-apical, trans-carotid, trans-septal, trans-caval, access

### INTRODUCTION

Transcatheter aortic valve implantation (TAVI) has gained prime time as the preferred treatment for elderly patients suffering from severe symptomatic aortic valve stenosis and at high or intermediate risk for standard surgery (1). During the last decade, cardiac centers have faced a continuously increasing number of TAVI procedures that overtook, in some countries, the number of standard surgical aortic valve replacements (2).

Experience acquired in this setting suggests that procedural success is achieved through an accurate pre-procedural evaluation, a perfect matching between commercially available prostheses and the peculiar anatomical characteristics of TAVI patients, technical implant skills of the TAVI team and a tailored choice of access options, the latter representing one of the most critical points.

The trans-femoral access represents the preferred route in the vast majority of TAVI patients because of its minimal invasiveness and the possibility to perform the procedure under conscious sedation without intubation. Increased expertise and technical advancements lead to a significant reduction of major access site-related vascular complications that occur, nowadays, in <10% of cases.

Due to its wide diffusion and feasibility, the trans-femoral access is the preferred route in the majority of the clinical trials and is recommended as first choice by all guidelines and consensus documents (1–5).

Nonetheless, data from randomized clinical trials (3–7) and registries (8–14) clearly show that the trans-femoral access might be precluded in up to 25–30% of TAVI patients due to the presence of severe arterial disease (**Figure 1**). In particular, obstructive peripheral vascular disease, femoro-iliac tortuosity, aortic atheromas, or the presence of previously implanted arterial grafts can seriously limit the possibility of a transfemoral access (**Figure 2**).

Beside technical aspects, the choice of the access in TAVI seems to be independently associated with an impact on prognosis, in particular in the case of the trans-apical approach, when manipulation of the left ventricular apex is needed (14, 15). This evidence highlights the priority of an appropriate access route selection in TAVI. So far, several alternative options for antegrade or retrograde TAVI procedures have been described, namely the trans-femoral, trans-axyllarian, trans-aortic, transapical, trans-carotid, trans-septal, and trans-caval. Nonetheless, no randomized comparisons are so far available, thus the choice is often based on data derived from retrospective analyses of national registries as well as on local experience.

In this report we give a concise overview on accesses for TAVI, with a particular focus on patient's selection criteria, technical aspects and clinical outcome.

## FEMORAL ACCESS

The common femoral artery represents the preferred access in the vast majority of TAVI procedures. This route allows a fullypercutaneous TAVI under conscious sedation/local anesthesia. Careful procedural planning and accurate choice of the proper site for vascular puncture are keys for procedural success.

### Patient's Selection and Planning

While obtaining the femoral access is technically easy, planning a successful procedure through this route might be demanding and time consuming. Unplanned (or angio-only guided) femoral access should be avoided whenever possible, this representing a potential risk of severe vascular complications. A detailed reconstruction of the arterial route along with precise aortic annular dimensions can be obtained at CT scan analysis, adding invaluable data about the feasibility of different approaches.

As a standard protocol in our center, patients referred for TAVR undergo an angio CT-scan and a 3D reconstruction extending from the aortic annulus to the superficial femoral artery with commercially available software packages (e.g., 3mensio structural Heart, Pie Medical Imaging, Maastricht, The Netherlands). The relationship of the vessels, in particular of the bifurcation, with the femoral head should be carefully evaluated. In selected cases, the angiographic reconstruction will help to perform a fluoro-guided puncture of the artery with no or minimal contrast injection (**Figure 3**).

While analyzing the common femoral and iliac arteries, particular attention should be paid to their caliber (that has to exceed at least 5.5 mm, ideally 6.5 mm for a 18F delivery system) and to the presence and extension of atherosclerotic plaques, calcifications as well as to the degree and extension of tortuosity. When calcifications are concentric, located anywhere from the aorto iliac bifurcation to the femoral bifurcation, even in the presence of vessels of good caliber, this could represent a potential contraindication for the trans-femoral access and the need for alternative accesses should be discussed within the Heart Team. A good estimation of the caliber of the iliac artery is of paramount importance in balloon size selection when transient occlusion is needed in bailout situations.

Beside detailed analysis of the iliiac-femoral arteries, a cautious exploration of the aorta should be performed as well in order to identify potential challenges such as tortuosity, presence of aneurysms, thrombotic appositions, or aortic arch calcifications. All these anatomic features are potential sources of embolization or causes of vascular rupture/dissection when large catheters are inserted and, therefore, can be considered as relative contraindications for a transfemoral approach.

### Technical Aspects

When deemed suitable for transcutaneous access, an optimal puncture site is then identified (**Figures 3A,B**) in the segment of the common femoral artery extending between the inferior epigastric artery and the distal portion of the common femoral artery, ideally 1 cm above the femoral bifurcation (**Figure 3C**). In case of vascular complications, the most common being failure of the vascular closure device; having enough distance from the femoral bifurcation will allow the placement of a covered stent or, in alternative, a safe surgical isolation and repair.

In presence of an anterior calcification of the femoral artery, attention should be paid when percutaneous suturebased vascular closure devices (e.g., Perclose, Prostar, both from Abbot medical) are meant to be used, because their efficacy might be reduced. In those cases, surgical cut down with or without surgical endarterectomy or alternative access, should be considered.

When performing a transcutaneous femoral artery puncture for TAVR, we almost invariably try to roadmap the route. For this purpose a selective angiography with a pigtail inserted by the contralateral access through a cross-over technique is used (**Figures 4A–C**). Then, the needle is directed toward the middle of the pigtail, and the arterial wall is punctured on its anterior aspect (**Figure 4D**). This will minimize the risk of vascular injury and enhance the success rate of percutaneous closure devices as well. While in the first TAVI series the Prostar was widely adopted, nowadays vascular preclosure with two Perclose/Proglide (Abbot Medical) devices inserted on the medial (2 o'clock) and lateral (11 o'clock) aspect of the arterial wall are used in the vast majority of transfemoral cases. When using this technique, attention should be paid in removing the contralateral pigtail before the insertion of the closure devices in order to prevent the entrapment of the catheter, a complication requireing surgical removal (**Figure 4E**). In some centers, omolateral injections using micropuncture needles (3F) are used to identify the optimal site. In obese patients with deep femoral arteries (i.e., >8 cm from the skin) as well as in cases with anterior calcifications, surgical cut down or alternative accesses should be considered. At case completion, when doubting about the efficacy of the preclosure devices implanted, a good tip to keep in mind is to perform a crossover from the contralateral femoral artery before removing the main sheath. This will allow to position a safety wire in the iliac/femoral artery that could be used rapidly for balloon occlusion and, eventually, to deliver a covered stent.

FIGURE 2 | Three dimensional angio CT reconstruction obtained with the 3mensio software in a patient with severe aortic stenosis referred for TAVI (A). Snake view of the aorta and right iliacofemoral arteries (B) clearly shows diffuse calcific atherosclerotic disease precluding trans-femoral route. (C) shows diffuse tortuosity of the iliac arteries, while (D) the incidental finding of an infrarenal abdominal aneurysm. All the above mentioned findings might preclude a transfemoral approach.

## Outcome Data

Increased awareness of operators regarding the intrinsic difficulties of the femoral access in TAVI associated with technological advancements such as the progressive reduction of the caliber of the vascular sheaths and delivery systems has led to a perceivable reduction in the occurrence of major vascular

FIGURE 3 | Three dimensional reconstruction of the arterial system (A) and cross section of the common right femoral artery at the optimal puncture site (B). The artery shows a good caliber (exceeding 6.5 mm as evident from the yellow circle) and no calcifications. Moderate tortuosity of the superficial iliac artery is evident at both 3 D and angio reconstruction (C). In particular, the angio reconstruction allows for the fluoro guided detection of the optimal access site, based on its relationship with the femoral head.

FIGURE 4 | Step by step approach for the transfemoral access. Once the common femoral artery has been deemed suitable for a trans-femoral approach due to the good caliber and the lack of anterior calcifications, the relationships with the femoral head (inferior border of the femoral head is highlighted in red), observed at the angio reconstruction, have to be described (A). Through a contralateral crossover, the pigtail is inserted in the common right femoral artery (B) and its position confirmed by contrast injection (C). Vessel puncture aiming at the anterior aspect of the femoral artery is then performed (D). Particular attention has to be paid in removing the pigtail before inserting the suture based closure devices with the consequent risk of catheter jailing and need for surgical removal (E).

complications, declined from above 10% in early PARTNER trials to about 6% in the more recent SURTAVI, NOTION and COREVALVE high risk trials (3–7). These data are in line with real-life data reported from national registries [(8–14), **Table 1**].

### TRANS-AXILLARY/TRANS-SUBCLAVIAN ACCESS

The subclavian artery is the terminal branch of the brachiocephalic artery. For the purpose of a retrograde TAVI implant, the right axillary/subclavian artery is rarely (if not ever) used due to the anatomy of the vessel leading to an unfavorable implantation angle. The left subclavian artery arises as the third branch of the aortic arch after the left common carotid artery, and exits the thorax from the superior thoracic aperture between the anterior and middle scalene muscles before passing between the first rib and the clavicle. At the lateral border of the first rib it continues as the axillary artery. The proximal third of the axillary artery (i.e., between the lateral border of the first rib and the medial border of the pectoralis minor) represents the ideal target for both surgical and percutaneous approaches (**Figures 5A,B**).

### Patient's Selection and Planning

Trans-axillary approach represents a valid option in 5–10% of patients referred for transarterial retrograde TAVI (32) and, in many centers, is considered the second option when transfemoral TAVI is not feasible. Currently available software for CT-scan analysis allows a semi-automated 3D reconstruction of the axillary and subclavian arteries. As for the femoral approach, caliber (>6.5 mm), calcifications, tortuosity and anatomical relationships with side branches have to be taken into account. Particular attention should be paid to the aortic take-off of the subclavian artery, a typical site of atherosclerotic calcific plaque apposition.

Worth to mention is the different histological structure of the axillary and subclavian arteries when compared to the femoral artery. In fact, the subclavian, and axillary arteries are of the elastic type while the femoral is of the muscular type with a media containing smooth muscle cells instead of elastic fibers and a thicker, and more fibrous, adventitia (33). Those characteristics predispose this access to vascular complications such as ruptures or dissections. For these reasons, in the presence of a patent right internal mammarian artery to left anterior descending artery, the use of this access has been questioned due to the increased risk of vascular complication leading to the potentially lethal acute graft occlusion.

### Technical Aspects

Transaxillarian approach was usually performed through a surgical cut down (**Figure 5C**), but the feasibility of a full percutaneous approach has been demonstrated (33).

When performing a surgical cut down, a 6–7 cm incision 1 cm below and parallel to the clavicle from the mid clavicular line to the axillary line is performed. Then, the pectoralis major muscle is dissected along its fibers, the pectoralis minor is retracted, and vessels are exposed. Attention is required to not damage to the nervous structures of the brachial plexus. Once isolated, a single or double purse string suture is placed on the subclavian artery and access to lumen is achieved by means of a direct puncture. In selected cases, a 10–12 cm Dacron vascular graft can be anastomosed end-to-side to the subclavian artery with and a standard large femoral sheath (>18F), custom modified by cutting the distal portion in order to allow to accommodate the sheath inside the vascular graft without extending its distal edge into the subclavian artery (34) (**Figures 5D,E**). This modified technique avoids extensive manipulation of the artery in case of borderline vascular diameter allowing a safe implantation even in patients with patent left internal mammary artery to the left anterior descending coronary artery.

A fully percutaneuos approach was described by Schäfer et al. in 2012 as the "Hamburg Sankt Georg Approach" (33). The axillary artery was landmarked with a regular J-wire and punctured below the clavicula to allow manual compression and reduce the risk of pneumothorax. Subsequently, the procedure was carried out as for the trans-femoral access. In their report, vascular complications significantly decreased when two Proglide (Abbott Vascular Devices) were used instead of a ProStar (Abbott

‡*Data derived from Partner A, Partner B, Partner II, Notion and SURTAVI trials.* †*Data derived from TVT, Gary, UK TAVI, Observant and France2 registries.*

FIGURE 5 | Anatomy of the subclavian and axillary artery (A) and its relationship with the clavicle, the first rib and the medial border of the pectoralis minor. The first segment of the axillary artery (comprised between the two red lines) is usually the target for both surgical or percutaneous approaches. (B) shows the angiographic anatomy of the subclavian and axillary artery. (C) reports the surgical cut down for axillary artery with the vessel isolated by two yellow rubber bands. (D) shows a "Chimney approach" performed by means of a 15 cm × 8 mm GelwaveTM prosthesis, a gelatin sealed woven polyester peripheral vascular graft and a Check-FloVR PerformerTM 18 F Cook sheath (length 35 cm), routinely used for the transfemoral modified by cutting the distal portion in order to obtain an approximate length of 10–12 cm that could allow to accommodate the sheath inside the vascular graft without extending its distal edge into the axillary artery. (E) shows the navigation of a Medtronic Corevalve delivery system through the left subclavian artery.

Vascular Devices, Redwood City, California). At completion of the case, closure of the axillary artery was achieved with the preimplanted vascular closure devices, while a peripheral balloon was always advanced in the subclavian artery to control possible bleedings.

Self-expandable prostheses are chosen in the vast majority of cases performed through this access, mainly the Medtronic Corevalve, while balloon expandable devices have been used only in selected cases.

### Outcome Data

Trans-axillary approach has shown to be non-inferior to the femoral approach in terms of procedural and medium-term results in a propensity matched comparison derived from the Italian national registry (16). Both groups showed comparable rates of procedural success (subclavian 97.9 vs. femoral 96.5%, p = ns), major vascular complications (5.0 vs. 7.8%, p = ns) and life-threatening bleeding (7.8 vs. 5.7%, p = ns). Freedom from cardiovascular death as well as survival at 2 years was also comparable between the two groups, providing strong support to the use of this approach as a valid alternative to the trans-femoral access.

### DIRECT TRANSAORTIC ACCESS

The direct transaortic TAVI has been originally reported by Bapat in 2012 (17, 18). The new concept behind this first report was the use of the short transapical TAVI delivery system for the retrograde TAVI implant through the ascending aorta. Since its advent, the trans-aortic technique was well accepted by heart teams and it has become a valid option in case of severe vascular disease impeding trans-femoral TAVI (19–24). Both balloon-expandable and self-expandable prostheses are currently used with good results. Some dedicated delivery systems are commercially avaliable, but standard trans-femoral systems can be used, adopting some tricks in room set-up (long delivery systems requiring good support).

### Patient's Selection and Planning

Most of the patients selected for TAVI are in fact eligible for a direct trans-aortic access with few exclusions, basically represented by the presence of thorax deformities, very short ascending aorta, porcelain aorta and the presence of a patent venous coronary artery bypass graft with proximal anastomosis on the ascending aorta at risk of damage. When facing a severely atherosclerotic aortic arch (with a good ascending portion), the direct aortic access might represent a good choice. This will allow to avoid extensive manipulation of an atherosclerotic aortic arch with the consequent risk of hembolization. In case a trans-aortic TAVI is planned, a careful evaluation of the quality of the aortic wall area where the purse string sutures will be placed (free of calcium for at least 1 square cm) is mandatory (**Figures 6A,B**). This is usually performed at CT-scan analysis, and for this purpose, a native contrast-free scan can be enough.

trans-aortic puncture. (C) the distance between the aortic entry site and the aortic valve annulus is of paramount importance for the valve release. A minimal distance of 6 cm is required for small delivery systems. The larger the valve size, the longer will be the length for delivery system retrieval.

Then, the trajectory between the entry site and the aortic valve annulus has to be considered in order to allow a perfect alignment between the delivery system and the native aortic valve. An "horizontal" ascending aorta (i.e., with an angle >70◦ ) requires more banding of the delivery system with the subsequent risk of valve malalignment. Additionally, in order to allow the complete release of the valve, the aortic entry should be at least 6 cm between the above the aortic annulus (**Figure 6C**).

### Technical Aspects

The right antero-lateral mini-thoracotomy at second intercostal space and the direct trans-aortic TAVI through an upper mini-sternotomy requires a different set-up of the cath lab as compared to the traditional trans-femoral access. First, the fluoroscopy arm is placed at patient's left side with cardiac surgeon and cardiologist standing together at the patient's right side. Compared to the mini-sternotomy, the advantage of the right mini-thoracotomy is represented by a lateral entry site into aortic lumen (right side) allowing for a straight trajectory of the delivery system through the stenotic aortic, with a consequent reduced risk of aortic damage.

Trans-aortic TAVI can be successfully performed with the Edwards Sapien balloon-expandable valve, using the dedicated trans-apical delivery system (valve mounted with the tissue skirt toward the tip of the delivery system) as well as with the Corevalve system (19–24). Other devices such as the transfemoral Boston Lotus, the trans-femoral Accurate Neo Symetis and the St Jude Portico valve systems have been rarely used by the trans-apical route.

Due to the invasiveness of the approach, procedures are invariably performed under general anesthesia and the mechanical ventilation is obtained with a single or a double lumen endotracheal tube.

In the case the right antero-lateral mini-thoracotomy is choosen, a 5–8 cm long incision is usually performed at the right second intercostal space, parallel to the right clavicle, and muscles are gently dissected. If possible, mammary vessels should not be damaged. The pleural space is opened and the lung is either deflated (with a double-lumen tube) or displaced in order to identify the pericardium at the level of the ascending aorta. Ribs are retracted, the pericardium is opened and stay sutures are placed to expand the surgical field and pull the ascending aorta toward the operators. To identify the entry site, the ascending aorta is gently manipulated for calcium detection or a Doppler probe is used for the same purpose. The distance between the entry site and the aortic annulus is confirmed with a graduated pigtail catheter placed against the non-coronary aortic cusps under fluoroscopy. Two 3-0 or 4-0 polypropylene purse-string sutures reinforced by pledgets are placed at the entry site on the lateral wall of the ascending aorta. The ascending aorta is then punctured within the purse-string sutures and a soft guidewire is advanced toward the aortic valve, allowing for a standard valve implant. In case the trans-aortic TAVI is performed through an upper mini-sternotomy, the incision (5–8 cm) is carried out along the mid line of the thorax and the upper part of the sternum is sawed to reach the cranial portion of the ascending aorta. Once a sternal spreader is in place and the pericardium is opened, placement of the purse string sutures follows the same rules of the mini-thoracotomy but entry site is at a more more anterior. The advantage of an upper mini-sternotomy is that pleural spaces are not open. Full sternotomy is usually performed in highrisk patients requiring combined procedures such as off-pump coronary artery bypass grafting and/or tricuspid valve repair on cardiopulmonary bypass and beating heart can be considered in selected cases (35–37). The device insertion is similar to the upper mini-sternotomy.

FIGURE 7 | Procedural steps in trans-apical approach. (A) surgical incision at the left fifth intercostal space and, after placement of a rib retractor and opening pericardium the apex is exposed. (B) Purse-string sutures reinforced by pledgets are placed at the apex and stabilized with a Tourniquet. (C) after apex is punctured within the purse-string sutures and a soft guidewire is advanced with an antegrade approach toward the aortic valve and positioned in the ascending aorta. Then, a conventional 18F sheath is advanced in the left ventricular cavity.

### Clinical Results

While trans-apical can be at risk of apical bleeding and major access related complications in frail elderly patients (38, 39), the transaortic TAVI can be a valid alternative in preventing apical manipulations and peripheral vascular injuries, with satisfactory clinical results. Procedural success rates of above 90% have been reported in the vast majority of series, with a 30 days mortality ranging from 6.1 to 13%. In a recently published review comparing trans-aortic vs. trans-apical TAVI procedures, Dunne et al. (40) reported similar 30-day outcomes: mortality of 7.9% (TAO) and 9.7% (TA); procedural success of 95% for both; rate of conversion to surgical aortic valve replacement of 2.1% (TAO) and 1.1% (TA); rate of new pacemaker implantation of 5.5% (TAO) and 5.9% (TA). A trend toward a lower rate of stroke in the trans-aortic TAVI group was also evident (0.9% in TAO vs 2.1% in TA).

Compared to the transapical TAVI, avoidance of apical incision with the related myocardial scar reduces the risk of apical aneurysm formation, ventricular rupture and late arrhythmias (35).

## TRANSAPICAL ACCESS

The transapical access represents the historical alternative to the trans-femoral TAVI and can be performed in all patients with contraindications to the transfemoral TAVI (13, 25–28).

### Patient's Selection and Planning

The approach requires a left mini-thoracotomy andgeneral anesthesia. Contraindications to the transapical access route are a few, basically represented by a severely reduced left ventricular function and the presence of apical thrombus. Preoperative CTscan images, can be useful in identifying the ventricular apex and its relationship with the thorax wall while transthoracic echocardiogram right before the procedure helps in identifying the apex and guiding the mini-thoracotomy. With regards to the commercially available transcatheter aortic valves and delivery systems, the transapical TAVI requires short dedicated delivery catheters. So far only the Edwards Sapien balloonexpandable valve and the self-expandable Symetis valve provide such possibility.

### Technical Aspects

A left antero-lateral mini-thoracotomy at the fifth intercostal space requires a different set-up of the cath lab as compared to the trans-femoral and the transaortic accesses. The fluoroscopy arm is placed at patient's right side with cardiac surgeon and cardiologist standing together at the patient's left side. Due to the invasiveness of the approach, the transapical TAVI is performed under general anesthesia and the mechanical ventilation is obtained with a single lumen endotracheal tube. A 5–8 cm long incision is performed at left fifth intercostal space and muscles are gently dissected (**Figure 7A**). The pleura space is opened. After the placement of a rib retractor the pericardium is opened and stay sutures are placed to expand the surgical field and pull apex toward the operators. Two concentric 3-0 or 4-0 polypropylene purse-string sutures reinforced by pledgets are placed at the apex (**Figure 7B**). Then, the apex is punctured within the pursestring sutures and a soft guidewire is advanced toward the aortic valve and the ascending aorta (**Figure 7C**). The valve is placed and delivered following standard techniques. Once implant is achieved, the delivery system and the sheath are gently removed and sutures are secured. In order to lower the intraventricular pressure during this phase, a short period of rapid pacing can be useful.

### Clinical Results

The transapical TAVI can be an alternative to the transfemoral TAVI in case of severe vascular disease. Also in this case, reported procedural success rate are above 90% with 30 days mortality rate ranging from 4 to 14%.

According to data derived from the German GARY registry, trans-apical access is an independent predictor of 1 year mortality in TAVI patients. While this effect is related to the impact of apical manipulation or associated to the increased co-morbidities of those patients is still widely debated (14, 15).

## OTHER ACCESSES

Starting from the original description of the first in human case of a percutaneous transcatheter implantation of an aortic valve prosthesis performed by Alain Cribier in April 2002 (41), access's choice seems to represent an intrinsic challenge of this technique. In their ground-breaking report, the procedure was performed through an antegrade approach from the right femoral vein. Access to the left atrium was obtained by transseptal puncture, then the stenotic aortic valve was crossed on an antegrade fashion creating a venous arterial loop to allow the advancement and the stability of the percutaneous valve. Apart from this pioneering description, the antegrade transeptal approach is nowadays not considered as an option in patients unsuitable for other conventional accesses.

Rarely, the trans-carotid approach can be considered as an alternative option in patients unsuitable for trans-femoral, transsubclavian or surgical trans-aortic/apical approaches.

While pro's are represented by avoidance of chest opening and the possibility to perform the procedure under local anesthesia, cons are mainly related to the necessity of a complex pre procedural planning with carotid and vertebral doppler to exclude significant atheromatosis, and cerebral MRI to confirm patency of the circle of Willis that could limit the cerebral perfusion during the carotid occlusion. While both common carotid arteries can be chosen, usually the left one is preferred given the straight pathway to the aortic valve. From a practical perspective, a 2 cm incision above the left clavicle allows the surgical exposure of the common carotid artery. Attention to avoid injury to the vagus nerve has to be paid. The arterial lumen is then accessed by direct puncture and surgical closure is performed at case completion. To the best of our knowledge, percutaneous access was not reported in this setting due to the complex management of potential bleedings and vascular damage. Mylotte et al. reported the feasibility and the safety of this trans-carotid approach in 96 patients enrolled in 3 different French sites (42). In their series, no major bleedings nor vascular complications related to the access site occurred, while only three transient ischemic attacks and no strokes were reported. No direct or propensity matched comparisons to trans-femoral TAVI are available so far.

The trans-caval approach, described by Greenbaum et al. in 2014 (29) is considered as the last resort in patients not qualifying for any other vascular access. Procedural planning requires a baseline CT-scan to identify a calcium free target on the right abdominal aortic wall allowing for a safe passage from the inferior vena cava to the aortic lumen of the large bore sheath. After having obtained a femoral venous access, the inferior vena cava is punctured by means of a stiff CTO wire (usually a Confianza PRO 12) mounted over a microcatheter and a standard RCA or IMA guiding catheter. The caval and aortic walls are perforated by using electrocautery applied at the distal end of the wire. Once obtained access to the aortic lumen, the wire is snared and both the microcatheter and the guiding catether are advanced into the abdominal aorta. This allows for the placement of a stiff "0.035" wire and the advancement of a large introducer sheath from the femoral vein into the aortic lumen for conventional retrograde aortic valve replacement. At case completion, heparin is reversed, and the aortic perforation is closed using a conventional vascular, duct or ventricular septal defect occluder device. The authors recently reported the 30-day outcomes of the first 100 patients from the prospective multicentre study (30). Device success, defined as successful trans-caval access and deployment of a closure device without death or emergent surgery was obtained in 98% of cases. Nonetheless, VARC-2 major or life threatening bleedings were evident in 12 patients, retroperitoneal hematomas were found at post procedural CT-scans in 24% of patients, while in 8 cases implant of an aortic covered stent was deemed necessary during the index procedure or in the early post procedural phase. Thus, so far, based on the above mentioned data, this approach should be considered as a proof of concept rather than as an effective alternative option to standard TAVI access routes and should only be considered in patients without alternative treatment options.

### CONCLUSIONS

Retrograde trans-femoral TAVI is the access of choice in the vast majority of patients with severe aortic stenosis deemed at intermediate or high operative risk for traditional surgical aortic valve replacement, and current guidelines highlight that the feasibility of a transfemoral approach should be considered as a determinant aspect favoring TAVI in the decision making process when choosing between percutaneous or surgical procedures. In line with current recommendations, also in our clinical experience, the transfemoral access is always considered as the first option. Nonetheless, in a discrete percentage of cases, this access might be precluded. This implies that several different options have been proposed as alternatives, each of them with unique features, pros and cons. The availability of different, mainly surgical accesses, should be seen as a possibility for

the patients to be treated with a trans-catheter approach and for the involved heart team as a concrete opportunity to increase even more the collaboration between cardiac experts with interventional or surgical skills. So far, no randomized head to head comparisons between different access options are available, and if ever obtainable, several local factors and patient's characteristics should be considered when choosing an alternative approach. Future extension of TAVI to lower risk patients will probably result in a relative increase of transfemoral procedures. Nonetheless, in those higher risk patients in which the femoral approach is precluded, alternative routes, either percutaneously or surgically achieved might represent a concrete opportunity. When willing to avoid either general anesthesia and/or sternum/rib opening with pulmonary deflation, an option that could result as a game changer in the post op management of elderly patients allowing early mobilization

### REFERENCES

and discharge, the axillary (either surgically or percutaneously performed) and trans-carotid access can be considered as a second option. On the other hand, local expertise might favor trans-aortic or trans-apical approaches due to their wide availability.

Surely, while no clear indications are still available, TAVI operators are called to a tailored decision making. Comprehensive patient's evaluation as well as extensive discussion within the heart team will represent the key points to achieve good procedural and long term outcomes.

### AUTHOR CONTRIBUTIONS

LB conceived, drafted and finalized the manuscript. EF wrote the sections regarding transapical and transaortic access. GP, FF, TM, FP, and MM critically reviewed the manuscript.

Cardiovascular Outcomes Research. Transcatheter aortic valve implantation in the United Kingdom: temporal trends, predictors of outcome, and 6- year follow- up: a report from the UK transcatheter aortic valve implantation (TAVI) registry, 2007 to 2012. Circulation (2015) 131:1181–90. doi: 10.1161/CIRCULATIONAHA.114.013947

**Conflict of Interest Statement:** EF is proctor and consultant for Edwards Lifesciences.

The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2018 Biasco, Ferrari, Pedrazzini, Faletra, Moccetti, Petracca and Moccetti. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

# TAVI: Simplification Is the Ultimate Sophistication

#### Mariama Akodad1,2 and Thierry Lefèvre1 \*

1 Ramsay Générale de Santé, Institut Cardiovasculaire Paris Sud, Massy, France, 2 Centre Hospitalier Universitaire Arnaud de Villeneuve, Montpellier, France

Since its introduction in 2002, TAVI has evolved dramatically and is now standard of care for intermediate risk patients when the femoral approach can be implemented safely. The development of innovative transcatheter heart valves (THVs) and refinement of technical skills have contributed to the decrease in complication rates associated with TAVI4 . Increased experience, smaller sheaths, rigorous pre-procedural planning and improved vascular closing techniques have resulted in markedly lower rates of vascular complications. The next step is the simplification of the procedure, which should contribute to a further decrease in complications, and also reduce procedural time, hospital stay as well as staff workload and costs. Moving to conscious sedation, no predilatation, no temporary pace maker and use of the radial approach as the contralateral approach are all instrumental in achieving this ultimate refinement.

Keywords: TAVI, simplification, minimalist, vascular complications, temporary pace maker, hospital stay duration

### INTRODUCTION

Since the first successful procedure was carried out in 2002 (1), transcatheter aortic valve implantation (TAVI) has gradually been established as an alternative to conventional surgery in patients with severe aortic stenosis contra-indicated to surgery or at high surgical risk (2). In 2017, during the last ESC meeting, TAVI indications were extended to intermediate risk patients when the transfemoral approach (TFA) is feasible (3).

Improvements in technique, devices, operator's experience, and patient selection have contributed to a dramatic decrease in procedural complications, thus allowing further technical simplification at every step of the procedure (4–9). In this paper, our aim is to describe how to simplify the technique at each stage of the procedure in order to turn it into a "PCI-like" procedure and to discuss how this may improve TAVI outcomes.

### PRE-PROCEDURAL EVALUATION AND PROCEDURAL SETTING

Patient clinical and anatomical criteria may influence per- and post- procedural outcomes. Therefore, a truly minimalist approach should be considered only when femoral access is possible. Recently, Barbalios et al. compared minimalist TAVI performed in the catheterization laboratory to standard TAVI performed in the hybrid room demonstrating shorter procedure and intensive care unit time, as well as reduced hospitalization duration and costs in the minimalist approach group without differences in terms of short- and long-term survival (10).

#### Edited by:

Darren Mylotte, National University of Ireland Galway, Ireland

#### Reviewed by:

Marco Barbanti, Università degli Studi di Catania, Italy Andrew Roy, Mater Private Hospital, Ireland, Ireland Alexander Lauten, Charité Universitätsmedizin Berlin, Germany Gidon Yehuda Perlman, Hadassah Medical Center, Israel

> \*Correspondence: Thierry Lefèvre<EMAIL_ADDRESS>
#### Specialty section:

This article was submitted to Structural Interventional Cardiology, a section of the journal Frontiers in Cardiovascular Medicine

> Received: 10 March 2018 Accepted: 29 June 2018 Published: 18 July 2018

#### Citation:

Akodad M and Lefèvre T (2018) TAVI: Simplification Is the Ultimate Sophistication. Front. Cardiovasc. Med. 5:96. doi: 10.3389/fcvm.2018.00096

**62**

Multislice CT (MSCT) is instrumental in procedural simplification. Image quality and optimal analysis are therefore crucial for anticipating the potential difficulty of the procedure as well as for optimal valve selection and working view. The role of MSCT has also been central in allowing a shift from general anesthesia to conscious sedation by obviating the need for transesophageal echocardiography (TOE) during the procedure. MSCT became the gold standard for evaluation of the aortic root in our center in 2009.

The use of the TRA for preprocedural evaluation of the coronary arteries is also part of the simplification process. It helps not only to reduce the risk of vascular complications related to the screening phase, but also to assess femoral access by performing a selective bilateral iliac injection using a long multipurpose catheter. Recently, screening of coronary artery disease and ad hoc percutaneous coronary intervention (PCI) during TAVI has been described by Barbanti et al. showing to be feasible without increased periprocedural complications (11).

A minimalist approach can be performed in routine practice with two operators, two nurses and an anesthesiologist (**Figure 1**). A cardiac surgeon and an echocardiographist are not mandatory in the room but should be available.

### FROM GENERAL ANESTHESIA TO CONSCIOUS SEDATION

Although the first in-man TAVI cases in Rouen were initially performed on conscious sedation (1), the procedure was commonly carried out under general anesthesia between 2002 and 2008 in Europe. It remains standard practice in the majority of cases in North America (12). However, it was Alain Cribier's idea that TAVI should be a "PCI- like" procedure. Potential advantages of general anesthesia are patient's procedural comfort, possibility of using TOE and rapid conversion to surgery when complications occur (13–15). Conversely, many issues are related to general anesthesia such as hemodynamic instability, higher need for inotropic drugs, higher risk of bleeding, increased risk of pulmonary infection, extubation difficulty or delay in patients with chronic pulmonary disease, late complication identification such as stroke or aortic complications and finally, longer procedural duration, hospital stay, higher staff workload, and global costs (16–18). In the France 2 and the France TAVI registries, the adoption of local anesthesia with conscious sedation has progressively increased from 30% in 2010 to 70% in 2017 (15, 19). In a recent meta-analysis, outcomes of both approaches were similar with respect to in-hospital mortality, conversion to open-heart surgery, major vascular complications, acute kidney failure and stroke (17). Cross-over to general anesthesia was observed in only 6%. Conversely, catecholamine requirement and transfusion were less frequent in patients on conscious sedation, and duration of intensive care unit and global hospital stay was also shorter (17, 20, 21). No difference concerning neurocognitive outcomes was highlighted between both approaches (21).

Data from registries demonstrated the feasibility, safety, and cost-effectiveness of local anesthesia with conscious sedation in comparison to general anesthesia, with potential advantages in terms of bleeding and hospitalization length. It has been adopted as the default approach in our center since April 2009.

### FROM SURGICAL CUT DOWN TO PERCUTANEOUS ACCESS

Initially, TAVI procedures were performed exclusively via surgical cut down (1). Over the past decade, sheath diameter has been gradually reduced to 14–16 French with the last generation percutaneous heart valves (**Figure 2**). TFA is currently the default access route, with superior outcomes than transapical route and other transvascular approaches as carotid, aortic, axillary, and caval-aortic. Alternative transvascular routes may be considered anly in case of unsuitable femoral access (22).

Percutaneous closure has been progressively adopted in routine practice in most centers for TF TAVI procedures (23). Indeed, even though the surgical approach has been reported to be associated with a low rate of vascular complications and to provide a more direct control of haemostasis (24), percutaneous closure is a less invasive technique and may result in shorter hospital stay (25). With the refinement of the TAVI procedure, better patient preprocedural screening, increased operator experience, and device improvement, the percutaneous approach has become more simple, less time consuming, thus allowing a reduction in staff workload. The Prostar technique was introduced in our center in 2009 and we moved progressively to Proglide (Abbott Vascular Devices, Redwood City, CA, United States) preclosing in 2015-2016 (26) because this technique was simpler and less costly. In 2016, a lower risk of vascular complications was reported with the use of 2 Proglide devices in comparison with Prostar (27). New collagen-based closure devices were recently described in TAVI procedure as the MANTA closure device with similar results than suture based closure devices (28).

In addition to the selection of the most appropriate percutaneous device, the percutaneous technique should be rigorous in order to limit access site complications. Indeed, the common femoral artery puncture site should be carefully selected on the CT-scan or angiography before the procedure. During the procedure, puncture should be performed under angiographic or ultra-sound guidance at the center of the anterior arterial wall (29). Percutaneous closure devices should be subsequently deployed as previously described (30).

Thus, percutaneous transfemoral access is as safe as the surgical approach and feasible in the majority of cases with a very high rate of success after the learning phase. Most vascular complications can be managed percutaneously. It is an essential component of TAVI's simplification process allowing early discharge.

**Abbreviations:** BAV, balloon aortic valvuloplasty; CCU, conventional cardiology unit; ICU, intensive care unit; LV, left ventricle; MP, multipurpose; MSCT, multislice CT; PCI, percutaneous coronary intervention; TAVI, transcatheter aortic valve implantation; TFA, transfemoral approach; TOE, transesophagal echocardiography; TRA, transradial approach.

## FROM CONTRALATERAL FEMORAL ACCESS TO RADIAL ACCESS

Although vascular complications dramatically decreased in parallel with enhanced operator experience, availability of low profile sheaths and better patient selection, 25–30% of these complications occurred at the contralateral femoral access site, (9). Therefore, using the TRA as a secondary access appears to be very promising (29–31). We have been using this approach since 2016 and have observed a 50% reduction in vascular complications. The radial artery (right or left) is punctured and a 40 cm 6 Fr hydrophilic sheath with a side port for blood pressure measurement is subsequently inserted through the radial artery. A 125 4 or 5 Fr multipurpose (MP) catheter is advanced over a standard 0.35 guide wire to the common iliac artery in order to obtain a reference image and guide the puncture. After the puncture, the MP catheter is retrieved and a pig-tail is advanced in the ascending aorta via the 0.35 guide wire to perform aortography before and after TAVI. At the end of the procedure, prior to access closure, the MP catheter is re-advanced to the common femoral artery in order to check the final result of the closure (29). In cases of vascular complication, a long 120 cm 5 Fr catheter (Optimed, Germany) can be positioned in the common femoral artery to perform femoral artery balloon inflation or stent implantation. In rare cases where a covered stent is needed, a larger balloon can be used through the Optimed catheter in order to close temporarily the iliac or femoral artery, while a cross-over femoral approach is implemented (29). Indeed, in our practice, even if the radial secondary access is our default approach, the controlateral femoral access should be available immediately in case of failure or emergent need of cross-over.

Therefore, by reducing contralateral vascular complications and simplifying the procedure, TRA will probably follow the predominant tendency observed in other interventional cardiology settings and become the gold standard contralateral approach for TAVI.

### FROM VENOUS STIMULATION TO LV GUIDE WIRE PACING

During balloon valvuloplasty (BAV) or balloon expandable TAVI procedures, rapid ventricular pacing is mandatory. Traditionally, rapid pacing is performed through a venous access with temporary pacemaker implantation (1). However, this technique may be challenging in anatomic variations and may lead to increased X-ray exposure and complications (32) such as hematoma, arterio-venous fistula, thrombosis or right ventricle perforation. Recently, rapid ventricular pacing through the left ventricle guide wire has been described as a way of simplifying the procedure by eliminating the need for additional vascular access during TAVI (33). This approach was adopted in 2016 in our center. Briefly, a 22 G needle is inserted subcutaneously near the femoral sheath. Alligator clips are then connected to the left ventricle guide wire (negative clip) and to the needle (positive clip) following insertion of the delivery system close to the aortic valve. The rapid pacing is then tested using maximal output and minimal sensitivity (**Figure 3**). Valve implantation is then carried out under rapid pacing. In the presence of high-degree conduction disturbance, stimulation can be performed with this technique while a temporary pacemaker is inserted through a venous access, more frequently through brachial vein access to limit femoral vascular complications.

This new technique has been shown to be feasible and safe, allowing stable stimulation with a low rate of complications and a potential reduction in procedural time. A randomized trial comparing left ventricle guide wire rapid pacing to conventional pacing (Easy TAVI) is ongoing in France (NCT02781896).

### VALVE IMPLANTATION WITHOUT PREDILATION

In the early days of TAVI, BAV was considered a mandatory step. However BAV have been shown to be associated with a higher risk of cerebral embolization, and severe acute aortic regurgitation may occur after predilatation in up to 3% of cases. TAVI without BAV was evaluated for the first time in 2011 by Grübe et al. (34) and was shown to be feasible in non-randomized studies (35, 36). Currently, improvements in new generation devices including paravalvular skirts, the ability of repositioning of the valve, lower profile of delivery system, and of the prosthesis provide more favorable outcomes (22). Therefore, BAV seems no longer essential during TAVI procedures, and consequently, TAVI without predilation is routinely implemented in many centers.

We moved progressively to this approach between 2012 and 2015 in our center. Today, more than 90% of cases are performed without predilatation. Only very complex anatomies or highly calcified valves are predilated before valve deployment (5–10%). Post dilatation is performed mainly after self-expandable valve deployment in the presence of significant paravalvular leak or transvalvular gradient (10–15%).

Thus, avoiding balloon predilatation may reduce complication rates, decrease the need for permanent pacemaker and reduce procedural time. A large randomized trial (37) with the Sapien 3 valve is on-going in France (NCT02729519).

FIGURE 3 | From left to right and up to down: Alligator clips with negative clip (black) and positive clip (red). After insertion of Sheath, a 22G needle is inserted subcutaneously through the skin, close to the femoral sheath and the positive clip is connected to the needle while the negative clip is connected to the guidewire. Setting of the temporary pacemaker with maximal output and minimal sensitivity. Pacing efficacy at 180 beats per minute with the LV wire and drop in blood pressure.

#### TABLE 1 | Current outcomes of early discharge after TAVI.

### POST-PROCEDURE MANAGEMENT:

### From Intensive Care Unit (ICU) to Conventional Cardiology Unit (CCU)

After TAVI, systematic close monitoring with special attention to hemodynamic and cardiac rhythm is mandatory to allow early detection of periprocedural complications. In many centers, monitoring is performed for at least 12 to 24 h in the ICU before transferring the patient to a CCU after clinical and paraclinical status re-assessment. Recently, TAVI without subsequent ICU admission has been evaluated and has been shown to be feasible and safe in selected patients after rigorous preprocedural and postprocedural evaluation (38). Indeed, this new strategy adopted in our center in 2017 may obviate ICU admission in up to one third of cases and should be considered a part of the "minimalist" approach.

### Short Hospitalization

Early discharge was evaluated in the literature demonstrating safety in patients with hospitalization duration shorter than 48 h (39). Indeed, the median length of hospitalization was 1 day in the early discharge group with no differences between early discharge and discharge after 48 h in terms of 1-month mortality, stroke and readmission. A "minimalistic" TAVI procedure with local anesthesia, no predilatation, urinary catheter avoidance

### REFERENCES

and early removal of temporary pacemaker was predictive of early discharge in this study. Current outcomes of early discharge after TAVI are summarized in **Table 1.** Shortening hospital stay is also an essential component of the TAVI simplification process with a potential reduction in procedural costs and need for rehabilitation but may be studied in large studies to ensure safety without increased risk of outcomes or readmission.

## CONCLUSION

TAVI simplification has already been adopted in routine practice in experienced centers, resulting in a low rate of complications, shorter procedural time, improved patient comfort, as well as decreased costs and staff workload. However, rigorous patient selection, and risk stratification are key factors in ensuring successful "PCI-like" procedures. On-going randomized trials may confirm preliminary results, thus leading to a "simple" but not "simpler" procedure in the near future with lower profile devices.

### AUTHOR CONTRIBUTIONS

All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.

with aortic stenosis. Eur Heart J. (2016) 37:2252–62. doi: 10.1093/eurheartj/ ehw112

for vascular access management in transcatheter aortic valve implantation: the Milan experience. Catheter Cardiovasc Interv. (2014) 83:156–61. doi: 10.1002/ccd.24913

**Conflict of Interest Statement:** TL is proctor for edwards and Abbott vascular MA received research grants from Edwards Lifescience and Medtronic.

Copyright © 2018 Akodad and Lefèvre. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

# Transcatheter Treatment of Bicuspid Aortic Valve Disease: Imaging and Interventional Considerations

#### Rajiv Das 1 \* and Rishi Puri 2 \*

1 Freeman Hospital, Newcastle upon Tyne, United Kingdom, 2 Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH, United States

Patients with bicuspid aortic valve disease have systematically been excluded from large randomized clinical trials investigating transcatheter aortic valve implantation (TAVI) due to their younger age, lower surgical risk and complex aortic anatomy. The asymmetric nature of the bicuspid valve orifice often accompanied by heavy regional calcification has led to concerns regarding valve positioning and expansion. Bicuspid aortic valve disease patients are at heightened risk of TAVI-related complications including coronary occlusion, aortic dissection and annular rupture, as well as the known risks of progressive aortopathy in these patients. These unique anatomical characteristics pose challenges for TAVI operators. However, with recent and ongoing refinements in implantation technique, improvements in pre-procedural imaging and iterations in device design, TAVI is emerging as a safe and feasible treatment option in this population. Paravalvular aortic regurgitation and high pacemaker rates have been the Achilles Heel for TAVI in bicuspid valve patients, yet newer generation devices are yielding promising results. Further studies are required before TAVI ultimately emerges as a viable option in low and intermediate surgical-risk patients with bicuspid valve disease. This review comprehensively summarizes the epidemiology, pathology and current evidence for TAVI in patients with bicuspid aortic valve disease. We also outline some practical tips for performing TAVI in these patients.

Keywords: TAVI, bicuspid valve disease, CT, treatment, bicuspid aortic valve

### INTRODUCTION

The transcatheter aortic valve implantation (TAVI) revolution for severe tricuspid aortic valve stenosis (AS) is well-recognized as an alternative to surgical aortic valve replacement (SAVR) for severe aortic stenosis. This has been established in the randomized clinical trials for balloon-expandable and self-expanding valves (1–4). TAVI is now regarded as the standard of care for patients with severe symptomatic AS that are considered inoperable or in patients at high surgical risk. More recently randomized clinical trials have shown non-inferiority when TAVI has been compared with SAVR in patients at intermediate or low surgical risk (5–7). Bicuspid aortic valve (BAV) has largely been excluded from seminal randomized clinical trials involving TAVI. This was due to concerns about (i) valve positioning and expansion due to the asymmetrical nature of the leaflets and heavy calcification leading to severe paravalvular leak (PVL), (ii) aortic annulus rupture and risk of coronary occlusion, (iii) concomitant aortopathy associated with BAV increasing

#### Edited by:

Crochan John O'Sullivan, Triemli Hospital, Switzerland

### Reviewed by:

Augusto D'Onofrio, Università degli Studi di Padova, Italy Ozan Demir, San Raffaele Hospital (IRCCS), Italy

#### \*Correspondence:

Rajiv Das<EMAIL_ADDRESS>Rishi Puri<EMAIL_ADDRESS>
#### Specialty section:

This article was submitted to Structural Interventional Cardiology, a section of the journal Frontiers in Cardiovascular Medicine

> Received: 28 March 2018 Accepted: 25 June 2018 Published: 19 July 2018

#### Citation:

Das R and Puri R (2018) Transcatheter Treatment of Bicuspid Aortic Valve Disease: Imaging and Interventional Considerations. Front. Cardiovasc. Med. 5:91. doi: 10.3389/fcvm.2018.00091 the risk of spontaneous and iatrogenic aortic dissection and rupture, and (iv) concerns regarding the long-term durability of Transcatheter Heart Valves (THV), particularly in a younger BAV population. There is clear data on the safety and efficacy of TAVI in patients with tricuspid valve severe AS (1–10), and despite encouraging data from registries including BAV disease patients (11–14), TAVI has yet to establish itself in this patient cohort.

This review summarizes the evidence for TAVI in bicuspid aortic valve disease, the role of multi-slice computed tomography (MSCT) to aid procedural planning, and technical considerations to undertake when performing TAVI in BAV.

### EPIDEMIOLOGY

BAV disease is a common congenital cardiac abnormality seen in adults and is frequently associated with AS (15). The estimated incidence of bicuspid aortic valves is 0.4–2.25% in the general population. The most frequent complication of BAV is AS, often requiring aortic valve replacement surgery. BAV is commonly associated with aortopathy leading to asymptomatic dilatation of the ascending aorta in the initial stages followed by aneurysm formation of the aorta and the potential lifethreatening complication of aortic dissection (16–20). In a large population based study involving nearly 200 patients with a mean follow-up of 15 years, 13% developed severe AS requiring SAVR. In this cohort of patients, the main indication for surgery was severe AS; performed at a younger age group compared with the general population (21).

Registry data has shown that 37% of BAV patients have moderate-to-severe AS at the time of their initial echocardiogram (22). The prevalence of bicuspid aortic valve disease in patients undergoing surgical aortic valve replacement has been reported to be as high as 50% in some surgical series, 27.5% amongst octogenarians, and up to 41.7% of septuagenarians (23). In an Asian transcatheter aortic valve implantation (TAVI) population, BAV has been reported in upto 50%, potentially posing unique challenges for percutaneous treatment options in the Asian landscape (24).

## PATHOLOGY

BAV disease is frequently associated with valvular stenosis, valvular regurgitation, aortic coarctation, aortic dilatation, aneurysms, and dissection. It is essential that pre-procedural imaging assesses the thoracic aorta in BAV patients. Aortic root dilatation occurs in 50–60% of patients with a normally functioning bicuspid valve, increasing the risk of aortic dissection nine-fold (25). The etiology of ascending aortic dilatation may be due to genetic and hemodynamic factors that affect the aortic wall elasticity and strength. Genetic mutations in smooth muscle cells α actin (ACTA2) and transforming growth factor β receptor (TGFBR1 and TGFBR2) have been linked with aortopathy in BAV disease (26). A genetic link between aortic dilatation and BAV can be substantiated by the fact there is greater incidence of aortopathy in first degree relatives with BAV disease, and not infrequently we see progressive aortic root dilatation in patients post SAVR with BAV disease (27).

Abnormalities in wall shear stress can arise due to the asymmetrical nature of the orifice in BAV patients. Studies using flow-sensitive MRI and four-dimensional (4D) cardiovascular MRI have looked at abnormalities in wall shear stress and flow patterns in the aortic wall for different BAV fusion patterns, which in turn has been linked with adverse remodeling within the aortic root wall (28, 29). The right and left cusp fusion variant of BAV is associated with asymmetrically elevated wall shear stress in the ascending aorta (30, 31). Phenotypic variations in BAV fusion patterns may need to be considered when assessing patients, especially if TAVI is to be extended to low-risk patients. As highlighted certain BAV fusion patterns are predictors of increased wall shear stress and aortic root dilatation (**Figure 1**).

## CLASSIFICATION SYSTEMS FOR BICUSPID AORTIC VALVE DISEASE

Different classification systems exist for the varying BAV morphologies; based on the presence and characteristics of the raphe, commissural position, description of the cusp and its size and the aortic sinus characteristics (15, 21). The most widely used classification is by Sievers and Schmidtke; due to its simplicity and user friendliness (33). Valve morphology is classified according to the number of cusps and the presence of raphes, as well as the position and symmetry of the cusps. Type 0 has 2 symmetric leaflet/cusps and 1 commissure without evidence of a raphe, Type 1 has a single raphe due to fusion of the left coronary cusp with either the right or non-coronary cusp, and Type 2 arises when 2 raphes are present with fusion of both the right and non-coronary cusps (**Figure 2**). A functional (bicuspid) valve are classified as tricuspid valves with no raphe present, but there is fixation of the commissure between 2 cusps due to degenerative processes. Mylotte et al. used a modified Sievers classification system and observed higher rates of PVL in Sievers type 1 morphology (34.2%) than in Sievers type 0 (13.3%), possibly due to incomplete THV expansion due to calcified raphe and leaflet asymmetry (14).

Jilaihawi et al. proposed a classification system for BAV and described 3 subtypes, tricommissural, bicommisural raphe type, and bicommisural non-raphe type (11). The classification enabled a greater understanding of the interaction of the valve with the aortic-valvular complex at both the basal leaflet plane (presence or absence of a raphe) and at the commissural level (presence of 2 or 3 commissures). It was noted that the presence of a calcified raphe may impact on TAVI expansion and device apposition at the annulus. Tricommisural BAV type was not found to be associated with aortopathy and has widely been termed functional or acquired BAV disease. Tricommisural BAV arises from rheumatic, fibrotic, or calcific processes leading to focal commissural fusion (11). Tricommisural BAV disease is different from tricuspid valve aortic stenosis and may account for the higher incidence of PPM after TAVI. Interestingly, there were marked geographical differences between the subtypes of BAV. Non-raphe type bicommisural bicuspid AS was more

common in Asia, but not in North America or Europe. The classification system did not predict the rates of moderate or severe PVL (tricommisural 19%, bicommisural raphe type 19.5%, and bicommisural non-raphe subtype 15%). Thirty-day mortality rates according to the BAV subtypes were not found to be statistically different (tricommisural 4.2%, bicommissural raphe subtype 2.7%, and bicommisural non-raphe subtype 9.5%). There was also no difference in new permanent pacemaker implantation rates between the BAV subtypes.

### CURRENT REGISTRY DATA ON BICUSPID AORTIC VALVE DISEASE

Our current understanding of the safety and efficacy of treating BAV patients with TAVI is largely based on small registries, most of which used older generation THVs (14, 34, 35). A multi-center study raised concerns regarding an excess of bioprosthetic PVL in bicuspid aortic valve disease patients undergoing TAVI (14). This was a retrospective registry of 139 patients across 12 centers collecting clinical, procedural, and follow-up data. Procedural mortality was 3.6%, with THV embolization occurring in 2.2% with a 1-year mortality of 17.5%. MSCT-based TAVI sizing was used in 63.5% of patients. AR grade 2+ post-TAVI was not infrequent at 28.4% which decreased to 17.4% when CT-sizing and planning algorithms were used. This series demonstrated that pre-procedural MSCT imaging can minimize PVL in TAVI for BAV disease by more accurately sizing the annulus. In a registry using a newer generation SAPIEN 3 valve, 51 patients with BAV disease from 8 centers were evaluated (13). The incidence of trivial and no AR post-TAVI was 63% and mild AR was 37%. The 30-day mortality rate was reported at 3.9%.

In a study of 130 patients with severe AS and BAV from 14 centers undergoing TAVI (11), the 30-day outcomes were comparable with those reported in patients with tricuspid valve stenosis (1, 2, 7, 36, 37). There was however an excess of new pacemaker implantation which was similar for balloon expandable and self-expanding valves (**Table 1**). An increase in significant PVL was not observed in this study as compared with tricuspid valve stenosis patients undergoing TAVI. Once again, PVL rates were lower in this study if MSCT data was used for sizing.

The Bicuspid AS TAVI multicentre registry is the largest study to date evaluating 546 patients with either bicuspid or tricuspid AS who were propensity scored matched (12). Patients were recruited from Europe, North America and the Asia specific region. The patients with bicuspid severe AS had lower STS scores and represented an intermediate risk profile population, and furthermore the use of a large prostheses was more commonly associated with bicuspid AS patients. The major findings of this study were bicuspid severe AS patients had more frequent conversion to open surgery and a significantly lower device success rate as compared with propensity matched tricuspid AS patients. There were no significant betweengroup differences in procedural complications such aortic root injury and moderate-to-severe PVL when new generation devices were used. All-cause mortality at 2-year followup was comparable between the bicuspid and tricuspid groups.

ME\*, mechanical expanding valve LOTUS valve; NA, not available; CVE, cerebrovascular event, stroke, or transient ischemic attack.

### PROSTHESIS CHOICE IN BICUSPID VALVE DISEASE

Operators need to be cognisant of the potential advantages and disadvantages of balloon-expandable and self-expanding devices in the BAV space. Balloon-expandable valves exert greater radial force as compared with self-expanding devices and may circularize the native annulus minimizing potential sites for paravalvular leaks. Mylotte et al. (14) reported outcomes on both balloon-expandable and self-expanding devices observing a greater incidence of PVL ≥2 with selfexpanding valves (19.6% with Sapien XT and 32.2% with CoreValve). This may be attributable to the reduced radial strength in self-expanding devices increasing the likelihood of residual PVL. Conversely, when comparisons are made using newer generation balloon-expandable and self-expanding devices which feature an external sealing skirt there were no significant differences between the two general valve designs (38).

Rates of annular rupture have been reported to be as high as 5.3% in some series using the balloon-expandable Sapien XT valve (38). This may have been largely driven by a degree of oversizing required for device anchoring to prevent significant PVL. With improvements in design of the newer-generation balloon expandable valves there is sufficient anchoring with less oversizing which has led to acceptable rates of PVL and annular rupture (39, 40). When sizing is guided by CT annular measurements a degree of oversizing (7–13% for the S3 THV design) appears to be safe with newer generation valves, leading to a reduction in AR in patients with bicuspid valve disease.

In a series of 51 patients who underwent TAVI in bicuspid AS using the new generation balloon expandable S3 valve, device success rate was reported to be 98% with no cases of moderate to severe aortic regurgitation (13). Improvements in design of the newer generation S3 THVs have resulted in a lower profile device with more accurate positioning, and improved sealing with its polyethylene terephthalate outer skirt. The Lotus mechanical expanding valve has an outer adaptive seal with the ability to be repositioned and retrieved. Promising results were also demonstrated with regards device success when this device was used to treat bicuspid AS patients (38).

### NEW PERMANENT PACEMAKER IMPLANTATION RATES FOR TAVI IN BICUSPID VALVE DISEASE

One of the main limitations of TAVI in tricuspid valve severe AS compared with SAVR is the high incidence of conduction abnormalities. New permanent pacemaker implantation has emerged to be an important short-term complication; reported to be around 6.0% for balloon expandable valves and up to 28.0% for self-expanding valves (41, 42). There are no specific design advances that have been incorporated in the newer generation THVs to reduce the risk of permanent pacemaker implantation. Moreover, there has been a reported increase in conduction abnormalities with newer generation devices (43). Mauri et al. identified technical and anatomical factors predisposing to new permanent pacemaker implantation (44). In this study using the new generation SAPIEN 3 THV, 33 of 229 patients received a pacemaker following TAVI. Pre-existing RBBB, left ventricular outflow tract calcification and an implantation depth defined as >25.5% of the stent frame below the annulus were each found to be important predictors of new permanent pacemaker implantation. This study highlighted important technical factors such as reducing the depth of the valve implant by a mere 3 mm reduced the need for permanent pacemaker implantation by 52%. TAVI operators will need to consider such technical aspects to reduce pacing rates, yet balance these with the risk of THV embolization with higher implants (45).

For bicuspid valve severe AS, pacemaker implantation rates were similar for balloon expandable (BE) and self-expanding (SE) THVs (11, 14). Jilaihawi et al. reported pacing rates of 25.5% for balloon expanding valves and 26.9% for self-expanding valves (11). Mylotte et al. also reported higher than expected pacing rates (16.7% for balloon expanding and 26.7% for self-expanding valves) in TAVI patients (14).

It has been postulated that the higher incidence of PPM implantation rates in BAV patients is related to asymmetric THV expansion due to resistant calcified raphe and leaflet fusion. There may be preferential expansion posteriorly to the noncoronary cusp which lies adjacent to the atrioventricular node. In tricuspid valve disease or incomplete raphe type BAV, there may be a more symmetrical expansion of THVs, thus diverting tissue away from the AV node (11). The presence of bulky calcification in the Sievers L-R Type 1 BAV may cause protrusion toward the membranous part of the interventricular septum leading to atrioventricular and intraventricular conduction block (46). The higher pacemaker rates may thus be associated with difficulty in valve positioning due to irregular leaflet shape and inability to achieve a coaxial position during valve deployment. This can often lead to lower implantation depths, known to be associated with higher pacing rates. Patients with BAV disease also tend to be younger, and as TAVI moves to intermediate and the low-risk, complications such as pacemaker implantations will be important. Understanding the factors contributing to new permanent pacemaker implantation need to be addressed with particular focus on implantation depth and important calcification in the left ventricular outflow tract.

### CORONARY OCCLUSION AND ANNULAR RUPTURE

The data on acute coronary occlusion during TAVI stems from isolated case reports and case series. The incidence is reported to be <1% and is a rare yet potentially life-threatening (4, 47– 52). Randomized control trials of patients with tricuspid severe AS; report an acute coronary obstruction incidence of 0.1–1.2%. Data from bicuspid TAVI registry data report a similar 0–1.5% incidence of acute coronary obstruction (11–14, 38). Certain factors may increase the risk of coronary obstruction post-TAVI such as female sex, coronary ostia height of <10 mm, sinus of Valsalva dimensions and the presence of severe valve calcification (53). Most reported cases of coronary obstruction post-TAVI received a balloon-expandable THV.

Recent reports have arisen of the development of delayed coronary obstruction (DCO) occurring hours or days following TAVI. In a recently published international registry of 17,092 patients undergoing TAVI, the reported incidence of delayed coronary obstruction was 0.22% (54). DCO can be divided into early (0–7 days) and late (>7 days) post-TAVI. The etiology of DCO relates to a number factors such as a narrow sinuses of Valsalva, low coronary heights, excessive calcification, valvein-valve TAVI and pharmacological factors such as antiplatelet and anticoagulation (54). Aortic root injury and annulus rupture likewise is a rare complication in BAV undergoing TAVI; reported to have an incidence ranging from 0 to 2% in the reported literature (11–14, 38).

### COMPARISON OF OUTCOMES BETWEEN OLD AND NEWER GENERATION THVS IN BAV

THV device iteration significantly addressed the shortcomings of earlier generation THVs which were limited by PVL. Significant PVL post-TAVI has been shown to correlate with increased mortality (37, 55–57). PVL rates have improved significantly with newer-generation devices for patients with tricuspid AS patients, and has also been seen when newer-generation THVs are used in BAV patients (13). In a recently reported BAV registry comparing older versus newer generation THVs in BAV, moderate or severe paravalvular leak was significantly less frequent with newgeneration devices compared to early generation devices (0.0 vs. 8.5%; p = 0.002), which resulted in a higher device success rate (92.2 vs. 80.9%; p = 0.01) (38). When compared with TAVI in tricuspid valve stenosis, there were no differences in procedural related complications with new generation devices. This was true for cumulative mortality at 2 years which were similar for tricuspid and bicuspid valves with newer generation devices (12). This has also been seen in several other registries using the SAPIEN 3 valve in tricuspid AS (58–61). Improvements in PVL have largely been made by developing a poly-ethylene terephthalate sealing skirt along with more accurate positioning. With the Lotus valve, the incidence of moderate to severe PVL has been reported to be as low as 2.0%, largely due to the adaptive seal and optimal positioning due to device retrievability and repositionability (62).

### TECHNICAL CONSIDERATIONS FOR TAVI IN BAV

BAV disease poses many technical challenges for TAVI operators. Selection of the optimal angiographic projection and visualization of the aortic annulus can be difficult due to the asymmetric shape of the cusps and sinus of Valsalva. Calcium distribution throughout the aorto-annular complex is frequently asymmetric, along with raphe resistant to pre-dilatation and aortic root dilatation. These variations may promote poor valve expansion and thus adversely affect valve hemodynamics and durability which in turn can lead to high transvalvular gradients, PVL, device malpositioning, and higher permanent pacemaker rates post-TAVI (11, 12, 14, 63). The aortic annulus is often elliptical in shape, larger in size, and associated with a dilated and horizontal aorta, (64) further giving rise to difficulties in device positioning and expansion. The native valve leaflets can be capacious due to leaflet fusion resulting in longer leaflets increasing the risk of coronary obstruction (34, 65).

Himbert et al. reported on the use of self-expanding devices in 15 patients with BAV disease (66). The device was associated with non-circular expansion at the annular level which was less frequent when the device was implanted lower in the left ventricular outflow tract. In another series of 21 patients who had post-procedural MSCT imaging, non-circular expansion of the valve was seen more commonly with self-expanding valves due to the asymmetrical nature of the bicuspid valve orifice and resistant raphe (67). With balloon-expandable valves there have been reports of asymmetric longitudinal valve expansion, however further assessment is required for both self-expanding and balloon-expandable valves to ascertain if this ultimately affects leaflet motion and durability (13).

### Imaging for TAVI in Bicuspid-Aortic Valve Disease

Sizing of THVs can be difficult due to multiple anatomical considerations including a large and eccentric annulus, calcified raphe, horizontal aorta, complex calcification, and aortic root dilatation. Each of these variables can interplay and make TAVI implantation technically challenging. MSCT has enabled operators to have a better understanding of the anatomy of BAV disease, critical for procedural planning pre-TAVI to minimize complications (68).

Due to the percutaneous nature of TAVI, operators lack the ability to expose the surgical field and directly visualize the aortic valve, annulus and structures around it. MSCT is used to provide a comprehensive 3-dimensional data-set of the aortic valve anatomy and identification of concomitant aortopathy. MSCT provides anatomical measurements of the aortic annulus, detail of the aortic valve, calcium burden, aortic root ("sinus of Valsalva"), coronary ostia and access site, all of which are essential to minimize complications and improve procedural outcomes. In BAV, MSCT is key to providing information on leaflet morphology, symmetry of the valve leaflets, presence of raphe and the location of calcification all of which can influence the type and size of THV selected (**Figure 3**) (69).

In a study using MSCT which looked at the shape and size of the annulus in bicuspid (n = 200) and tricuspid valves (n = 200), the aortic annulus was found to be less elliptical in bicuspid than tricuspid valves (ellipticity index 1.24 vs. 1.29, respectively). This study also highlighted that biscuspid valve patients had large annular areas compared with tricuspid valves (5.21 vs. 4.63 cm2 ) (27). Reports from recent large series of bicuspid patients indicate that annular dimensions still fall within the valve sizing recommendations for current commercially available THVs (13, 14, 67).

THV oversizing can lead to distortion and poor expansion of the valve prosthesis leading to PVL. This can be improved with intra-procedural post-dilatation, however there is a risk of annular rupture, aortic root haematoma and heart block with subsequent post-dilatations. A self-expanding THV may minimize the risk of annular rupture, however when compared with balloon expandable THVs, there is a greater incidence of PVL and heart block in BAV disease patients (38, 70).

### Balloon Sizing

Other techniques can be used to help with valve sizing such as fluoroscopic balloon sizing of the aortic valve annulus pre-TAVI (71). Balloon sizing can complement MSCT especially when there is ambiguity regarding valve sizing and when measurements fall in the "gray zone" between two valve sizes. In the presence of bulky cusps or long leaflets, balloon sizing can mimic valve implantation and also identify patients at risk of coronary obstruction. It provides additional information that is not available from MSCT or transoesphageal echocardiography (TEE) and can help predict how situations such as severe, eccentric calcification may behave and the complications that can arise from it.

Commonly in BAV disease the abnormal geometry at the annular level and unequal-sized leaflets makes alignment of the two or three hinge points (depending on BAV type) difficult. MSCT is useful in tricuspid valve disease to find the optimal implantation projection of the aortic root and an orthogonal alignment of the native annulus. This however, is often found to be unhelpful in BAV disease. Techniques have been described using the pigtail catheter and altering the fluoroscopic projection to find an optimal view for implantation; "follow the right cusp rule" (72) and the "Right cusp rule, Part II" (73).

### Valve Crossing

Crossing the stenotic BAV may be challenging and time-consuming, increasing the risk of embolic cerebral complications. Careful interrogation of the MSCT can identify the fused cusps in BAV disease and may help with predicting the location of valve opening and maximize the chance of the wire to cross. Frangieh et al. (68) have described a step by step approach to crossing a stenotic BAV. Wire movement should start from the non-fused leaflet ("single cusp") which has no raphe and then with careful rotation direct the wire in small steps toward the fused cusps. If starting in the NCC rotate clockwise, or anticlockwise if starting in the LCC. In BAV with no raphe, there are only two anatomical cusps and the guide wire should be slowly manipulated between each cusp carefully interrogating the opening between the leaflets. In more angulated aortic roots, catheters with a bigger curve such as an Amplatz-2 (AL-2) may help with retrograde crossing, and/or softer hydrophilic coated wires such as the Glidewire. In extreme circumstances when conventional retrograde wire crossing of the BAV is not possible, ad hoc trans-septal puncture followed

leaflets indicate a risk of coronary occlusion during TAVI.

by wire delivery into the left ventricular apex, anterograde aortic valve crossing, wire externalization and subsequent aorto-venous loop creation can be undertaken. A catheter of choice (i.e., AL) can then be placed retrogradely across the stenotic BAV thus facilitating regular fully percutaneous transfemoral TAVI (**Figure 4**) (74, 75).

## HOW TO PERFORM TAVI IN BICUSPID AORTIC VALVE DISEASE

Historically, patients with BAV disease with severe AS were referred for SAVR. However, there is an increasing tendency for some younger patients to opt for a less invasive percutaneous

FIGURE 4 | (A) Transeptal puncture and positioning of hydrophilic wire and Judkins Right in the left ventricle. (B) Anterograde crossing of the aortic valve and wire changed for exchange wire. (C) Amplatz Goose Neck Snare used to snare the exchange wire. (D) Exchange wire then externalized via the left femoral artery [Adapted with permission from the Rodríguez-Olivares et al. (75)].

FIGURE 5 | MSCT imaging of bicuspid aortic valve. (A) Annulus measurement with minimum diameter of 17 mm and maximum diameter of 24 mm and area of 325 mm2 . (B) Cross-sectional view taken 4 mm above the level of the annulus. The valve is a Type 0 Sievers BAV with no raphe. (C) Distance to coronary ostia >10 mm. (D) The distance from the aortic annulus to the mitral valve ring measures 10.1 mm acceptable for TAVI implantation.

procedure, particularly in the presence of significant comorbidity or prior cardiac surgery. The selection of the type and size of the valve can be challenging due to the anatomical reasons outlined above, with MSCT playing an important role in THV device selection and implantation technique. Sizing and implantation technique is key to success in TAVI in bicuspid valve disease. Due the asymmetric nature of the aortic annulus, eccentric heavy calcification and raphe resistant to dilation, THV valves are implanted higher and anchored at the tightest part of the commissural. This has in part led to sizing of valves at +4 mm above the annulus at the intercommisural space. The final implantation depth are often higher due to the anchoring effect of the calcification at the level of the commisures with <4 m for CoreValve, <3 mm for CoreValve Evolute R (Medtronic, Minneapolis, Minnesota) and atrio-ventricular ratio of 60/40 for Sapien XT/S3 (Edwards Lifesciences, Minnesota). Here we present 2 illustrative cases of how to perform TAVI in BAV.

### Case 1

A 67-year old female with acute respiratory failure due to severe AS was referred for consideration of TAVI. She underwent ventricular septal defect repair at the age of 10. At the age of 57 she presented with progressive breathlessness secondary to severe mitral regurgitation and underwent a mitral valve replacement with a 27 mm Carpentier Edwards Magna Valve. Six years later she developed further progressive dyspnoea and underwent an urgent redo mitral valve replacement for a stenotic prosthetic mitral valve. A 33 mm Carbomedics Valve was inserted into the mitral position. She has end-stage renal disease requiring haemodialysis.

Transthoracic echocardiography showed a degenerated bicuspid aortic valve with a peak velocity of 5.2 m/s (peak gradient 108 mmHg; mean gradient 68 mmHg, area of 0.43 cm2 ). The mitral valve prosthesis was functioning normally. Invasive coronary angiography revealed normal coronary arteries. Following a Heart team discussion, it was decided to perform TAVI due to her previous mitral and redo mitral valve replacement. The aortic valve was a Sievers Type 0 bicuspid valve. The aortic annulus minimum diameter was 17 mm, maximum diameter 24 mm, perimeter 69 mm, and an area of 355 mm2 (**Figure 5**). The common femoral arteries measured 6 mm bilaterally. A technical concern regarding TAVI in this lady was the interaction of the TAVI valve with the mitral valve prosthesis and the risk of valve embolization

FIGURE 6 | Implantation of SAPIEN 3 in patient with bicuspid aortic valve with previous mitral valve replacement. (A) Aortogram for root alignment with pigtail catheter in the right coronary cusp. (B) Balloon sizing with 20 mm balloon touching hinge points with simultaneous aortogram showing filling of coronary arteries. (C) Successful deployment of 23 mm SAPIEN 3 valve with no paravalvular leakage.

FIGURE 7 | MSCT imaging of the aortic annulus post TAVI implantation with 23 mm Edwards Sapien Valve. (A) shows circular deployment of the transcatheter heart valve. (B) Left ventricular outflow tract view showing bi-leaflet mitral valve prosthesis and TAVI valve post deployment. (C) Volume rendered imaging confirming there is no interaction between the base of the TAVI valve and mitral valve prosthesis.

during deployment. The MSCT identified the rim between the mitral valve prosthesis and the aortic annulus to measure 10 mm, which was felt to provide an adequate landing zone for the THV, with the risk of valve embolization deemed to be small.

The right femoral artery was cannulated and a 14 French Esheath was introduced. The annulus area was felt to be between two valve sizes (23and 26 mm Sapien S3 valves). The valve was crossed retrogradely using an Amplatz Left1 diagnostic catheter and a "straight" standard wire. The wire was then exchanged with a pre-shaped small Safari wire (Boston Scientific, Natick, MA, USA). A balloon aortic valvuloplasty was performed and simultaneous aortogram was performed. An aortogram confirmed that during inflation the 20 mm balloon adequately filled the aortic annulus and was in contact with the hinge points (**Figure 6**). Coronary filling was also visualized. It was therefore decided to implant a 23 mm Edwards Sapien S3 Valve. Careful attention was given during valve positioning ensuring the valve skirt was positioned just below the hinge points. The valve was confirmed to be well positioned with good hemodynamics without paravalvular regurgitation. Following valve deployment, MSCT was performed confirming circular expansion of the valve and no infringement on the mitral valve prosthesis (**Figure 7**).

In cases of BAV, large aortic annuli pose a challenge for the TAVI operator as large annular dimensions fall outside the recommended sizing ranges for currently available THVs. There are concerns regarding significant paravalvular leakage post TAVI deployment in this group of patients. In certain cases with large annuli the inter-commisural space can be used for the landing zone with good effect. Improvements in THV design (in particular the sealing skirt) and technical considerations such as landing the valve in the inter-commisural space means that these patients can be treated with good outcomes. This forms the rationale of some TAVI operators who suggest to size and land the THV 4 mm above the measured annulus.

### Case 2

A 58 year-old male with end stage renal disease due to IgA nephropathy who had previously undergone a renal transplant which had failed was declined for redo renal transplantation. He had progressive dyspnoea and a history of syncope on exertion. The transthoracic echocardiogram confirmed severe stenosis of a BAV with a peak velocity of 3.9 m/s (peak gradient 61 mmHg, mean gradient of 39 mmHg and area of 0.89 cm2 ). There was also the presence of moderate aortic regurgitation. Coronary angiography revealed non-flow limiting coronary artery disease. MSCT confirmed a Sievers Type 1 bicuspid valve with a partial raphe between the right and left cusps. The aortic annulus was large with a perimeter measuring 98 mm, mean Sinus of Valsalva diameter of 40 mm and an inter-commisural distance of 29 mm (**Figure 8**). Both common femoral arteries were of large caliber and measured 8 mm on the left and 9 mm on the right. Following discussion by the Heart team and careful analysis of the MSCT it was felt that TAVI was technically possible if deployed at the inter-commisural space.

TAVI was performed under local anesthetic and the right femoral artery was cannulated and a 20 Fr sheath was inserted. The left femoral artery was cannulated and a 7 Fr sheath was inserted. The left femoral vein was used for insertion of a temporary pacemaker lead. The bicuspid aortic valve was crossed retrogradely using a Amplatz Left 1 diagnostic catheter and a hydrophilic coated straight tipped Glidewire. This was exchanged for a pre-shaped Safari wire and placed in the left ventricular apex. A balloon valvuloplasty was performed using a 25 mm balloon and a simultaneous aortogram was performed. The aortogram revealed a leak of contrast into the left ventricular cavity during balloon aortic valvuloplasty and felt to be an inadequate seal. A 34 mm Evolut CoreValve was deployed at the level of the leaflet tips, with hemodynamics and echocardiography confirming a good result with no significant PVL. The peak velocity across the TAVI valve was 1.8 m/s, peak gradient of 14 mmHg and area of 1.11 cm2 .

### CONCLUSIONS

Despite encouraging data, especially with newer generation THVs for BAV disease, caution needs to be taken as patients with bicuspid AS are more likely to be younger (12, 38, 76) and therefore concerns regarding significant PVL and high permanent pacemaker implantation rates need to be

addressed before offering it to younger and lower operative risk patients. With improvements in the design of the sealing skirts of THVs, PVL rates have reduced and the ability to reposition and retrieve the devices have led to more technical success with TAVI in selected patients with BAV disease. Procedural success is high and the survival rates are similar to those in patients with tricuspid valve AS undergoing TAVI. However, complications such as moderate or severe PVL and aortic root dissection are more common in BAV disease compared to tricuspid aortic valve patients. As the indications for TAVI expands with data supporting its use in the younger and intermediate risk group patients, the proportion of patients with BAV is expected rise. Specifically designed prospective studies are required to provide further evidence on durability, anatomical selection criteria and long-term

### REFERENCES

success before it becomes a viable option for patients with BAV.

### AUTHOR CONTRIBUTIONS

RD and RP wrote the manuscript and provided substantial contribution to the discussion and content. All the authors researched data for the article, and reviewed and/or edited the manuscript before submission.

### ACKNOWLEDGMENTS

The authors can confirm that full written informed consent was obtained from the patients for publication of the case reports included in this review.

versus tricuspid aortic valve stenosis. J Am Coll Cardiol. (2017) 69:2579–89. doi: 10.1016/j.jacc.2017.03.017

balloon-expandable transcatheter heart valve: a single-center experience. JACC Cardiovasc Interv. (2015) 8:1809–16. doi: 10.1016/j.jcin.2015.08.014

**Conflict of Interest Statement:** The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2018 Das and Puri. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

# Cerebrovascular Events After Transcatheter Aortic Valve Implantation

### German Armijo, Luis Nombela-Franco\* and Gabriela Tirado-Conte

Interventional Cardiology Department, Cardiovascular Institute, Hospital Clinico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), Madrid, Spain

Transcatheter aortic valve implantation (TAVI) has emerged as an alternative less invasive treatment for patients with symptomatic severe aortic stenosis. Despite the technological development and knowledge improvement in recent years, neurological complications remain a concern, especially with the expansion of the technique toward younger and lower risk patients. Clinical cerebrovascular events have an important impact on patients' morbidity and mortality with a multifactorial origin. While cerebral microembolizations during TAVI is a universal phenomenon and embolic protection devices have been developed in an attempt to reduce them, their clinical utility remains unclear. We review the current evidence on cerebrovascular events associated with TAVI and potential preventive strategies.

### Edited by:

Crochan John O'Sullivan, Triemli Hospital, Switzerland

### Reviewed by:

Masahiko Asami, Inselspital, Switzerland David Chistian Reineke, Inselspital, Switzerland

\*Correspondence: Luis Nombela-Franco<EMAIL_ADDRESS>
### Specialty section:

This article was submitted to Structural Interventional Cardiology, a section of the journal Frontiers in Cardiovascular Medicine

> Received: 04 May 2018 Accepted: 12 July 2018 Published: 31 July 2018

#### Citation:

Armijo G, Nombela-Franco L and Tirado-Conte G (2018) Cerebrovascular Events After Transcatheter Aortic Valve Implantation. Front. Cardiovasc. Med. 5:104. doi: 10.3389/fcvm.2018.00104 Keywords: TAVI, cerebrovascular event, stroke, aortic valve stenosis, transcatheter aortic valve implantation, transcatheter aortic vave replacement

### INTRODUCTION

Transcatheter aortic valve implantation (TAVI) has been established as the therapy of choice in patients with severe aortic stenosis of high or prohibitive risk, and in the last years as a valid alternative to surgery (SAVR) in patients with intermediate risk (1–4). Despite the great technological advances, cerebrovascular events (CVE) remain one of the most feared complications, increasing the risk of morbidity and mortality at short and long term (5, 6). The incidence of CVE following TAVI varies according to definition ranging from 1 to 11% (7) and with a similar frequency compared to SAVR in randomized clinical trials (4, 8). However, it exceeds any other daily percutaneous cardiac intervention especially in the acute period to decrease later in the following months (6, 9).  Furthermore, the real impact of these micro emboli on patients' cognitive function and development of future cerebral complications remain unclear. We present a review of the current knowledge about CVE following TAVI and insights about potential preventive strategies and future implications.

### CLASSIFICATION AND DEFINITION OF CEREBROVASCULAR EVENTS

In an effort to unify the discrepancies in the stroke definition used across the studies, the Valve Academic Research Consortium (VARC-I) in 2012 recommended to use the definitions of transient ischemic attack (TIA) and stroke (10). TIA was defined as a neurological deficit that resolves

### TABLE 1 | The modified Rankin Scale for classification of stroke severity.

Adapted from Sacco et al. (11).

rapidly, in <24 h, without evidence of tissue injury in neuroimaging study. Stroke was defined as a new focal or global neurological deficit that persisted more than 24 h, or <24 h associated with cerebral injury in neuroimaging study, or if the neurological deficit resulted in death. The severity of stroke is usually categorized according to the modified Rankin Scale (mRS), classifying it into disabiling (major stroke mRS ≥2) and non-disabiling (minor stroke mRS <2) (**Table 1**). This criteria have been recently complemented by the Neurologic Academic Research Consortium in 2017 after the preparation of a consensus document where they established a new classification and also defined the endpoints applicable to clinical trials (12) (**Table 2**).

### INCIDENCE OF CLINICAL CEREBROVASCULAR EVENTS

Cerebrovascular complications related to TAVI showed a significant variability between centers and studies, ranging from 1 to 11% (7). Rates of 30-day CVE in randomized trials and national registries are shown in **Figure 1**. This variability might be explained depending on the definition used, study design, diagnostic methods, patient risk-profile, site-specific factors, and systematic evaluation by a neurologist (13–15). The stroke incidence reported in most studies was generally a combination of non-disabling (minor) and disabling (major) stroke, while TIA is less frequently reported. The studies that categorized the stroke severity, suggested that disabling stroke had a higher incidence (58%) than non-disabling (26%) and transient ischemic attack (16%) (16). However, this data could be influenced by a lack of adequate and systematic neurological assessment to detect minor stroke or TIA in observational and randomized studies.

Initially, the results from PARTNER I trial (both cohorts A and B) showed greater stroke incidence in the group undergoing TAVI (1, 3, 17). Later, in the Corevalve trial with high-risk patient, patients undergoing TAVI had a numerically lower stroke rate at 30-day and 1-year compared to SAVR (2). In the recent randomized trials with intermediate risk patients, the results of the NOTION I, PARTNER-2, and SURTAVI trials showed a 1.4,

CNS, central nervous system. Adapted from Lansky et al. (12).

5.5, 3.4% 30-day stroke rate in the TAVI arm, compared to 3.0% (p = 0.37), 6.1% (p = 0.57), and 5.6% (95%CI −4.2 to 0.3) in the surgical arm, respectively. In addition, in the propensity matched comparison of the surgical arm from PARTNER 2 with the observational cohort of Sapien 3 study, the 30-day stroke rate was lower in the TAVI group (−3.5, 95% CI: −5.9 to −1.1, p = 0.004) (18). Thus, the initial fear of higher CVE rates in the TAVI arm has changed over time and now there is enough evidence to support that clinical CVE incidence is at least similar to the surgical arm (4, 8, 19).

Several meta-analyses, including mostly observational studies, have determined the incidence of stroke following TAVI (6, 7, 20). Eggebrecht et al. (with 10,037 patients from 53 studies) reported a 30-day stroke rate of 3.3 ± 1.8%, with the majority being major strokes (2.9 ± 1.8%). More recently, Muralidharan et al. (with 29,043 patients from 34 studies) and Auffret et al. (with 72,318 patients from 64 studies) reported a median 30-day stroke rate of 3.1 and 3.3%, respectively (9, 18).

### TEMPORAL PRESENTATION AND PATHOPHYSIOLOGY OF CEREBROVASCULAR EVENTS

Cerebrovascular events have been also classified according to the temporal pattern in acute (≤24 h), sub-acute (1–30 days), and late (>1 month) events. Several studies have shown that stroke incidence following TAVI has a peak in the immediate period after the procedure (24–48 h), reaching in some studies, half of the total events within 1 month (5, 21). Patients remain vulnerable for a period of up to 2 months after the procedure to subsequently decrease and stay stable over time. Temporal distribution of the CVE is closely related to their mechanism (**Figure 2**) (5).

### Acute Cerebrovascular Events

Most Acute CVE after TAVI are related to an ischemic origin, with <5% reported as hemorrhagic stroke (16). Most of this ischemic CVE are related to an embolic source. Due

to the constitution of the calcified aortic valve and the walls of the aorta, its manipulation with rigid and large delivery catheters, balloon valvuloplasty or the interaction of the stent valve during the positioning or valve release will inevitably generate embolic material (22). This fact is supported by several different findings (**Figure 3**): Firstly, studies with diffusionweighted magnetic resonance imaging (DW-MRI) demonstrated that between 60 and 90% of patients had new silent cerebral lesions after TAVI, independently of the vascular access or device type (22, 25, 26). These lesions were generally multiple, diffuse, distributed in both cerebral hemispheres and from both cerebral vascular territories (anterior and posterior) in most patients, suggesting an embolic nature. Secondly, procedural transcranial doppler studies confirmed that there were high intensity signals (HITS) in the middle cerebral artery in almost all the phases of the procedures, but especially during valve positioning and implantation (24). Interestingly, it has been suggested that valve design and implantation process could be associated with different temporal pattern of the HITS. While balloon expandable valve produces more emboli during valve positioning, self-expandable valve has greater amount of HITS during valve deployment (24). Thirdly, Van Mieghen et al., extensively examined the incidence and the histopathology of embolic debris retained in an embolic protection device during TAVI (27) (**Figure 3**). In the majority of cases (>85%), debris was obtained after the procedure, with a median size of 1 mm (IQR 0.6–1.6 mm). The nature of these emboli was varied. The most frequent was fibrin and thrombotic material (74% of the patients) (**Figure 4**) that were found in similar proportion in balloon and self-expanding valve. The wires and catheters used are known to be prothrombotic, associated with suboptimal anticoagulation during the procedure could be a potential source of thrombus formation. Additionally, damage to endothelium secondary to catheters manipulation, may cause platelet activation and the coagulation cascade, resulting in thrombus generation. Tissuederived debris was present in 63% of the patients, with higher proportion in patients with balloon-expandable valve and higher degree of oversizing. This proportion of debris and its histopathology nature has been confirmed in more recent studies (27–31) (**Figure 4**). In this line, another study reported that total atheroma volume in the aorta was associated with higher risk of acute CVE (32). Another possible source of CVE during the procedure was air embolisms, especially associated with large delivery catheters and contrast injection. However, air disease.

embolisms are usually considered temporary and are difficult to detect.

Systemic hypotension could also develop cerebral hypoperfusion, especially in the border territories supplied by different cerebral arteries, causing a watershed infarct. At least, one ventricular rapid pacing is mandatory in almost every TAVI, either with the valvuloplasty or balloon postdilation (more frequently performed with self-expandable valves) or during valve implantation (with balloon-expandable valves). Rapid pacing causes an impairment of cerebral perfusion but it is usually transitory and well tolerated with a prompt recovery. Patients with very low ejection fraction, especially after a long ventricular rapid pacing, may have a prolonged period of hypotension that requires inotropic support. Additionally, permanent cerebral injury could be caused by maintained systemic hypotension in the setting of hemodynamic instability during any procedural complication (bleeding, cardiac tamponade, severe acute aortic regurgitation. . . ), even when inotropic and mechanical circulatory support are provided. Fortunately, the incidence of such complications has clearly decreased in the later years.

### Subacute/Late Cerebrovascular Events

Cerebrovascular events occurring more than 48 h after TAVI are unlikely to be related to the procedure per se. The etiology of delayed CVE is less understood and has a multifactorial origin. In the immediate period after valve implantation, several theoretical phenomena may be thrombogenic. Disruption of the calcified native valve with denudation of the endothelium, the stent of the valve before endothelization, and the paravalvular space with the native valve compressed against the aortic wall, are some examples of potential sources of thrombus. Intraartrial thrombus formation related to atrial arrhythmias could be another source of thromboembolism. Intracardiac thrombus, usually detected in left atrial appendage, and spontaneous echo contrast were frequent findings in patients with aortic stenosis (10 and 24%, respectively) (33).

### PREDICTORS OF CEREBROVASCULAR EVENTS AFTER TAVI

Based on their mechanism, predictors of CVE following TAVI can be divided in procedural and patient factors related (**Figure 2**). Several studies reported predictors of developing neurological events after TAVI (5, 7, 34). Initially, the PARTNER trial showed that patients with lower aortic valve area had a higher risk of CVE in the early period after TAVI (16). This was related to a more calcified valve, with a plausible mechanism of higher risk of embolization. In this line, Nombela-Franco et al. reported that patients with a higher degree of valve calcification underwent more frequently balloon post-dilation (BPD) to treat paravalvular regurgitation (35). These patients also had a higher rate of acute CVE. However, it was not possible to determine if the independent factor for the acute CVE was the amount of calcium or BPD. Later, other studies highlighted the impact on acute CVE of mechanical procedural factors, such as number of implantation attempts, valve embolization, second valve implantation, or BPD (5, 14, 21).

Attempts have been made to find other risk factors related to CVE following TAVI, such as the presence of porcelain aorta, which in cardiac surgery is a well-established factor with a

higher risk of stroke (36). Although porcelain aorta is associated with a greater burden of cardiovascular risk factors (37), and therefore could lead to a higher incidence of late CVE, the currently available evidence have not found a higher incidence of stroke in this group of patients undergoing TAVI compared to patients without porcelain aorta (1.6 vs. 2.5% respectively, p = 1.0) (37–39). It would appear reasonable that operator, and center experience may also be predictors of stroke post TAVI. Carroll et al. evaluated the association of hospital TAVI volume and patient outcomes by using data from 42,988 procedures conducted at 395 hospitals from the TVT Registry from 2011 through 2015. High-volume centers had significantly lower inhospital events, but no difference was found in the stroke rate (p = 0.14) (40). However, a greater center experience was associated with lower stroke rates (2.03 vs. 1.66%, p = 0.01), similar findings described by Auffret et al. showing 1.55 fold more

risk of CVE after TAVI during the first half of enrollment (95%CI, 1.16–2.08, p = 0.003) (7).

Regarding the access site, no differences were found in MRI studies comparing transfemoral vs. transapical approaches (41). Also, some meta-analysis have revealed that a non-transfemoral approach did not carry a higher stroke risk (RR 1.03, 95%CI 0.83– 1.27, p = 0.81) (7). Transcarotid approach in terms of stroke risk is more controversial. Non-randomized trials found similar neurological outcomes (3.8% 30-day CVE) compared to an historically transfemoral cohort (42). However, recent evidence with a small number of patients (n = 22) showed more than twice the number and total volume of new ischemic lesions evaluated by diffusion-weighted magnetic resonance imaging within the left hemisphere (p < 0.01 for both) when performing TAVI through the left carotid artery (43). Therefore, more information is needed to clarify this issue.

In the sub-acute phase after TAVI, the strongest predictor for 30-day CVE found in several studies was NOAF, which usually occurs in an average of 15% of the patients. In a recent meta-analysis NOAF had a 1.85-fold increased 30-day hazard for CVE after TAVI. Although the incidence and definition of NOAF has varied across the studies, some studies reported that even short and transient periods of NOAF may have a significant influence in CVE, especially because some of these patients had a suboptimal anticoagulation regimen (44, 45). The stroke rate of patients with optimal anticoagulation was 2.9% compared to 40% in non-anticoagulated patients (45). Also Nuis et al. found a temporal relation between NOAF and CVE, where NOAF preceded the first signs of neurological impairment in all patients with an ischemic stroke (44). Auffret et al., also found that chronic kidney disease (CKD) defined by an estimated glomerular filtration rate <60 ml/min. 1.73 m2 , was an additional factor associated with an increased risk of 30-day CVE (7). Renal disease facilitates chronic inflammation, oxidative stress and atherosclerotic process with an increase in vascular calcification and endothelial dysfunction (46). In general, patients with renal impairment usually have an excess risk of stroke after adjusting for age and other cardiovascular risk factor (47).

### PROGNOSIS VALUE ON MORTALITY, MORBIDITY AND NEUROCOGNITIVE FUNCTION OF CEREBROVASCULAR EVENTS AFTER TAVI

Patients with an early CVE (within 30-day) after TAVI had significantly higher mortality at 30-day and 1-year as compared to those without CVE, as shown in several studies (5, 9, 20, 21, 48–50). Eggebrecht et al. also reported a 3.5 times higher 30-day mortality after stroke in a large meta-analysis. Onemonth mortality was as high as 25% in patients with CVE compared to 7% in patients without CVE. Similarly, in a more recent meta-analysis of 29,034 patients, mortality was sixfold higher in patients with stroke (20). Short and long term mortality risk is incremental according to the severity of the CVE, being significantly higher with major stroke (OR 7.43; 95% CI, 2.45–22.53; p = 0.001, and HR 1.75; 95% CI, 1.01–3.04; p = 0.043 respectively) (**Figure 5**).

In addition, stroke is probably the most feared complication (even more than death) reported by patients (51). Coylewright et al. described that the majority of patients undergoing TAVI wanted to maintain independence and be able to participate in daily hobbies, and only 7% of the patients stated that their main goal was to stay alive after the procedure. Importantly, the total proportion of patients with a permanent disability (modified Rankin scale of 2–5) at 30-day is around 50% of patients with CVE (5, 48). This highlights the impact of major stroke, not only in mortality, but also in patients' quality of life.

### Cognitive Function and Cerebral Lesions

As previously commented, new cerebral silent lesions are found in a high (∼75%) percentage of patients undergoing TAVI, and cerebral embolization is almost ubiquitous in studies with filters embolic protection devices. The Rotterdam Scan Study evaluated the presence of silent cerebral infarction in a group of healthy elderly patients, demonstrating 3 times higher risk of stroke, greater decline in cognitive functions and 2 times more risk of dementia after a follow-up of almost 4 years (52, 53). In addition, in SAVR patients, it has been found an association between new cerebral lesions in DWI-MRI studies and cognitive deterioration during follow-up (54). However, the impact of these silent cerebral emboli and its relationship with cognitive deterioration after TAVI is under debate. In one study (n = 111), neurocognitive function declined in 5.4% of patients after TAVI (55) but new cerebral lesions were not associated with cognitive impairment. In a study of 44 consecutive patients with systematic baseline and serial neurologic and cognitive assessments combined with postprocedure DWI-MRI imaging, brain lesions were detected in 94% of the patients (56). Neurologic impairment, assessed by a worsening in the National Institutes of Health Stroke Scale (NIHSS), was detected in 21 and 11% of patients, at discharge and 30-day, respectively, and it was slightly higher in patients with cerebral lesions (23 vs. 15%). In addition, cognitive decline evaluated by the Montreal Cognitive Assessment was identified in 33 and 41% of patients at discharge and 30-day, respectively. However, many studies, failed to find an association between new cerebral lesions post-TAVI and cognitive impairment (57, 58). In more recent studies the volume of these new cerebral lesions had a weak, although statistical significant, correlation with neurocognitive changes (31). These discrepancies across studies could be explained due to the lack of validated models to assess neurocognitive function in TAVI candidates, a certain degree of cognitive dysfunction pre-procedural in some patients and the high prevalence of inter and intra-observer variability for these tests.