Device Selection in Patients with Borderline Size Aortic Valve Annulus Undergoing Transcatheter Aortic Valve Implantation

Transcatheter heart valve (THV) selection for transcatheter aortic valve implantation (TAVI) is crucial to achieve procedural success. Borderline aortic annulus size (BAAS), which allows a choice between two consecutive valve sizes, is a common challenge during device selection. In the present study, we evaluated TAVI outcomes in patients with BAAS according to THV size selection. We performed a retrospective study including patients with severe aortic stenosis (AS) and BAAS, measured by multidetector computed tomography (MDCT), undergoing TAVI with self-expandable (SE) or balloon-expandable (BE) THV from the Israeli multicenter TAVI registry. TAVI outcomes were assessed according to the Valve Academic Research Consortium-2 (VARC-2). Out of 2,352 patients with MDCT measurements, 598 patients with BAAS as dened for at least one THV type were included in the study. In BAAS patients treated with SE-THV, larger THV selection was associated with lower rate of paravalvular leak (PVL), compared to smaller THV (45.3% vs. 64.5%; pv = 0.0038). Regarding BE-THV, larger valve selection was associated with lower post-procedural transvalvular gradients compared to smaller THV (mean gradient: 9.9 ± 3.7mmHg vs. 12.5 ± 7.2mmHg; p = 0.019). Of note, rates of mortality, left bundle branch block, permanent pacemaker implantation, stroke, annular rupture and/or coronary occlusion did not differ between groups. BAAS is common among patients undergoing TAVI. Selection of a larger THV in these patients is associated with lower rates of PVL and better hemodynamic prole in patients implanted with SE and BE-THV, respectively, with no effect on procedural complications.


Introduction
Aortic valve stenosis (AS) is the most common valvular heart disease among elderly 1 . Transcatheter aortic valve implantation (TAVI) has become an established and effective therapeutic procedure for symptomatic patients with severe AS regardless of procedural risk 2, 3 , and recently is offered to a younger and lower risk population. These changes in TAVI candidates emphasize the need for optimal transcatheter heart valve (THV) implantation to achieve procedural success and prolonged durability. The selection of an appropriately sized THV is a crucial component of the TAVI procedure. Valve undersizing may lead to paravalvular leak (PVL), valve embolization and poor hemodynamics. Oversizing may result in coronary occlusion, atrioventricular block, mitral valve injury, septal or annular rupture and periaortic hematoma 4 .
Multidetector computed tomography (MDCT) is the gold standard method for pre-procedural planning and annular sizing of both balloon-expandable (BE) and self-expanding (SE) THV 5 . THVs are currently available in a limited number of sizes and the manufacturer's sizing guidelines allow for a gray area with considerable overlap, where patients with borderline aortic annulus size (BAAS) may be candidates for either of the two suitable THV sizes (smaller or larger). Meanwhile, BAAS remains a common challenge during device size selection and the most effective THV selection strategy for these patients remains unclear.
Herein, we aim to evaluate the outcomes of TAVI in patients with BAAS according to THV size selection (smaller vs larger), as well as the bene t of shifting between THV types to avoid gray-zone size selection.

Study design and methodology
We performed a retrospective analysis from the Israeli multicenter TAVI registry, including patients with severe symptomatic AS and BAAS, measured by MDCT, undergoing TAVI with SE-THV (CoreValve, Evolut R and Evolut PRO) or BE-THV (Sapien XT, Sapien 3) during the years 2015-2019, at 1 of 4 tertiary centers in Israel. The study was approved by the institutional review board of the Rabin Medical Center, Tel-Aviv Sourasky Medical Center, Chaim Sheba Medical Center and Hadassah Medical Center. All methods were carried out in accordance with relevant guidelines and regulations. The Israeli Multicenter TAVI registry depends upon the Israeli Heart Society and includes anonymized data from 4 tertiary hospital in Israel. Informed consent was waived by the Helsinki Committee of the Tel-Aviv Sourasky Medical center; the Rabin Medical Center institutional review board -Helsinki Committee; the Helsinki Committee of the Chaim Sheba Medical Center and the Helsinki Committee of the Hadassah Medical Center Eligibility for TAVI was established after a multidisciplinary approach as indicated by the current recommendations. The preoperative workout included MDCT scan to plan the most appropriate route of intervention and to establish the aortic size and dimensions. Aortic sizing and valve measurements were performed by the local team in each center. All centers adopted a transfemoral-rst approach policy; other vascular accesses (trans-apical, trans-subclavian, etc.) were considered in cases in which the transfemoral access was not feasible. According to the local policy, TAVIs were performed under local or general anesthesia. The selection of prosthesis type and size was at the discretion of the treating physicians at each center.
Prespeci ed clinical and laboratory data were collected for all patients at baseline before the procedure, immediately after the procedure, during the index hospitalization, and during long-term follow-up. Collected data included medical history, electrocardiogram, echocardiography studies, MDCT measurements, laboratory tests, and clinical outcomes. Outcomes were collected according to the Valve Academic Research Consortium (VARC) 2 consensus document 6 .

Study Devices
The Evolut R SE valve is constituted by a nitinol frame mounting 3 porcine pericardial lea ets. The valve is repositionable, partially recapturable, and it is deliverable using a dedicated delivery system 14/16-Fr compatible depending on valve size. The Evolut PRO device represents an evolution of its predecessor and features a porcine pericardial outer wrap that contributes to reduce the risk of residual PVL. Evolut R covers a wide range of sizes and is available in 23, 26, 29, and 34 mm sizes 8 ; the PRO valve is available in 23, 26, and 29 mm sizes 9 .
The Sapien XT/3 BE valve incorporates a cobalt chromium stent that mounts bovine pericardial lea ets. Sapien 3, has both an inner and an outer polyethylene terephthalate fabric seal to minimize the risk of PVL. The delivery system has an active 3-dimensional coaxial positioning catheter and a 16-Fr expandable sheath 10 .

Statistical methods
Continuous variables were expressed as mean ± standard deviation and compared using Mann-Whitney test. Categorical variables were compared using Chi-square or Fisher's exact tests as needed. All analyses were conducted using Python version 3.5, p value < 0.05 was considered statistically signi cant.

Results
Out of 2,352 patients following implantation of SE-THV (CoreValve, Evolut R and Evolut PRO) or BE-THV (Sapien XT, Sapien 3) with pre-procedural MDCT measurements, 124 were excluded due to valve in valve, valve in ring or mitral valve interventions. Additional thirty-eight patients with BAAS and an annulus area of 330-350mm 2 who were implanted with BE-THV were excluded from the analysis since the smaller valve size of 20mm was not implanted. Eventually, 598 patients with BAAS as de ned for at least one THV type, 309 for SE-THV, 248 for BE-THV and forty-one patients for both devices were included in the analysis. Of them, 367 (61.4%) patients were implanted with borderline valves, while all others were implanted with non-borderline valves due to shift from SE-THV to BE-THV, or vice versa. The SE-THV group included 93 patients implanted with smaller valves, and 150 patients implanted with larger valves. In the BE-THV group, 22 patients were implanted with smaller valves, and 102 patients with larger valves.
In BAAS patients implanted with SE-THV, the baseline clinical characteristics of both groups (smaller and larger valves) did not differ, except for the New York Heart Association (NYHA) functional class (Table  1A). In addition, no signi cant differences were observed in imaging (echocardiography and MDCT) measurements (Table 2A). In BAAS patients implanted with BE-THV, differences were noted in left ventricular function (Table 2B). Other measured baseline clinical and imaging characteristics did not differ between smaller and larger valves implantation (Table 1B and Table 2B).
Baseline clinical and imaging characteristics of patients with borderline annulus for SE devices implanted with borderline large SE-THV or non-borderline BE-THV did not differ, except for aortic valve mean pressure gradient (Table 2A). Comparison between non-borderline SE-THV implantation to large BE-borderline valves implantation in patients with borderline annulus for BE devices showed more females and higher Society of Thoracic Surgeons (STS) score in patients implanted with non-borderline SE-THV compared to large BE-borderline valves (Table 1B). In addition, in patients implanted with non-borderline SE-THV the left main (LM) and right coronary artery (RCA) heights were shorter compared with patients implanted with larger BE-borderline valves (Table 2B).

Discussion
BAAS is common among patients undergoing TAVI, however, the most effective THV selection strategy for these patients remains unclear. The present study of 598 patients with severe symptomatic AS undergoing TAVI based on the ISRAELI-TAVI registry is the largest observational study to date comparing clinical outcomes according to size selection of SE-THV and BE-THV in patients with BAAS. The main ndings of our study (Figure 1) are as follows: Selection of a larger valve in BAAS patients did not increase adverse clinical outcomes such as new LBBB, rate of new pacemaker implantation, stroke or TIA, annular rupture, coronary occlusion or mortality.
Favorable outcomes were observed while using larger versus smaller valves in BAAS patients. For SE-THV, selection of a larger valve was accompanied by signi cantly lower rates of PVL and a trend toward lower gradients across the THV; for BE-THV, selection of a larger valve resulted in better hemodynamics with lower gradients across the THV.
Shift from borderline SE-THV to non-borderline BE-THV was associated with lower post-dilatation rates, but with higher THV gradients. Shift from borderline BE-THV to non-borderline SE-THV led to lower gradients, but resulted in increased post-dilatation rates; In addition, in a subgroup of patients in whom post-dilatation was not performed, increased PVL rates were observed.
Large size THV implantation was previously shown to be associated with favorable hemodynamics and lower PVL rate, both associated with better outcomes 4,11 . In fact, evidence shows deleterious prognostic effects even with mild residual PVL after TAVI, including increased mortality 12,13 . In addition, higher post-TAVI transaortic gradients are associated with decreased THV long-term durability 14 . The advantages of implanting larger, over smaller, devices were indeed re ected in our cohort of BAAS patients by lower gradients across BE-THV and lower rates of PVL with SE-THV. These ndings are particularly important in the current era, in which younger and relatively healthier patients are being treated with TAVI and in whom the durability of the device is extremely important to minimize the need for future reintervention. Importantly, the use of a larger THV in BAAS patients was not associated with increased adverse outcomes commonly encountered with large prostheses, such as conduction disturbances, annular rupture and coronary occlusion 15,16 . Given the above results, the present study advocates the selection of a large THV for BAAS patients undergoing TAVI with either SE or BE prostheses.
In our cohort of BAAS patients, 93% of cases were de ned as BAAS for one device only (i.e. either BE or SE). In these patients, it is thus conceivable to apply a strategy of selecting the non-borderline device whenever possible. In fact, non-borderline devices were selected over borderline devices in 38.6% of patients in our cohort. We found that selection of non-borderline SE-THV over borderline BE-THV led to lower gradients, but at the cost of increased rates of post-dilatation or PVL. On the other hand, selection of non-borderline BE-THV over borderline SE-THV was associated with lower rates of post-dilatation, but at the cost of increased gradients. This trade-off between PVL and higher gradients was repeatedly described in comparative studies between BE and SE devices both in tricuspid and bicuspid AS patients 17,18 . These changes were mainly attributed to THV mechanical characteristics, such as annular/supra-annular valve position, radial forces, and the presence of outer skirt 14 . Therefore, our ndings point out that similar considerations taken while selecting THV type for non-BAAS patients (including calci cations, coronary height, sinus of valsalva dimensions), should be applied also in BAAS patients.
We acknowledge several limitations of our study. The main limitation is the observational nature of the study. Therefore, undocumented factors, such as sinus of valsalva diameter or calcium score, may have affected device selection. In addition, potential impact of unknown or unmeasured confounding factors on study outcomes cannot be excluded. The low number of patients implanted with smaller BE-valve may affect the signi cance of the results and even necessitated the exclusion of patients with annulus measurements of 330-350mm 2 from the analysis. BE-TVH over or under-sizing by over or under-in ation of the valve balloon in order to ne tune the valve dimensions was not registered and might have affected in-situ valve size. Nevertheless, the practice of over/under-in ation in the four centers was according to a known algorithm proposed by the company.
The results of the present study support, for both devices (BE and SE), the selection of larger valves for TAVI candidates with BAAS. Shifting from borderline devices to non-borderline devices resulted in signi cant changes in post-dilatation, PVL and gradients across the THV. Therefore, our ndings point out that the same consideration taken while selecting THV type for non-BAAS patients, should be applied in BAAS patients, and whenever a borderline device is selected the larger valve device should be recommended.       Severe (< 29%) 6 (6.5) 4 (2.7) 0 (0)   Severe (< 29%) 2 (9.5) 2 (2) 0 (0)   Figure 1 Central Illustration -Algorithm for valve selection in BAAS patients. BE = balloon-expandable; SE = selfexpandable; THV = transcatheter heart valve; BAAS = borderline aortic annulus size; PVL = paravalvular leak.