Transcatheter Aortic Valve Replacement in Patients With a Small Annulus　― From the Japanese Nationwide Registry (J-TVT) ―

Abstract

Background: The details and consequences of a small aortic annulus among transcatheter aortic valve replacement (TAVR) patients remain uncertain. This study investigated the short-term outcomes in patients with small annular size and compared the 30-day outcome between intra- and supra-annular devices, with similar outer casing diameter in this subgroup.

Methods and Results: Cases registered in the Japanese national TAVR registry between August 2013 and December 2017 were analyzed. Among a total of 5,870 registered patients, 647 (11.0%) had small annulus (area ≤314 mm²) measured by multi-detector computed tomography. Patients with a small annulus had a significantly smaller indexed effective orifice area (iEOA, 1.10 cm²/m² [0.92–1.35] vs. 1.16 cm²/m² [0.96–1.39], P<0.001) and higher mean pressure gradient (mPG, 10.0 mmHg [6.9–14.2] vs. 8.5 mmHg [6.0–11.5], P<0.001) compared with a normal-sized annulus. Among patients with a small annulus, those receiving a 20 mm intra-annular device had a smaller iEOA (0.94 cm²/m² [0.78–1.06] vs. 1.07 cm²/m² [0.8–1.24], P=0.001) and higher mPG (14.0 mmHg [10.0–18.5] vs. 11.0 [7.0–14.0], P<0.001) compared with those receiving a 23-mm supra-annular device, although the incidence of paravalvular leakage (≥moderate) was similar (14.4% vs. 16.5%, P=0.69).

Conclusions: Patients with a small annulus were associated with less hemodynamic improvement. A supra-annular device is associated with better echocardiographic improvement in patients with a small annulus, without increasing paravalvular leakage.

Transcatheter aortic valve replacement (TAVR) has become a widely accepted strategy for the treatment of aortic stenosis, regardless of risk profile based on randomized trials.^1–6 Compared with Western people, Asian people have lower body height and weight. Despite the relatively slow adoption of TAVR technology in Asia and the relatively lower number of cases performed in many Asian countries, results of TAVR procedures performed in Asia have been comparable to those from high-volume Western countries.^7,8 Previous reports have demonstrated that the Asian people who underwent TAVR had a smaller aortic annulus size with a smaller implanted valve size.^8,9 Small valve size, particularly with the use of surgical aortic valve replacements (SAVR), has been linked to a higher risk of patient-prosthesis mismatch (PPM), resulting in a residual post-procedural pressure gradient.^10,11 A recent study revealed that a PPM was associated with higher mortality and heart failure rehospitalization after TAVR.¹² However, the effect of PPM in those patients with a small valve who underwent TAVR has not been as well documented as that for SAVR patients.^13–15 In addition, it is not clear whether the supra-annular transcatheter heart valve (THV), designed to work in the supra-annular position to optimize the effective orifice area (EOA) and flow, would have a favorable hemodynamic profile compared to the intra-annular THV in these patients. It was reported that the EOA in the supra-annular THV became larger over a long period of time, compared with that in surgical valves,^3,16 whereas the EOA for the intra-annular THV has been reported to be similar to that of the surgical valves.¹⁷ The Japan Transcatheter Valve Therapies (J-TVT) registry is the national TAVR registry in Japan that is linked to institutional and operator qualifications and contains baseline patient information, as well as the short-term outcomes of all the procedures performed in the nation. Compared to the European or the Society of Thoracic Surgeons/the American College of Cardiology (STS/ACC) TVT registries, the body size of the J-TVT registry is expected to be smaller. We conducted an analysis to clarify: (1) the short-term outcome of TAVR in patients with a small annulus, including PPM rate; and (2) the differences of intra-annular and supra-annular THVs in a small annulus, using the J-TVT registry.

Editorial p 977

Methods

Database

The J-TVT registry was developed by 4 Japanese academic societies (The Japanese Circulation Society, the Society of Japanese Cardiovascular Surgery, the Japanese Association for Thoracic Surgery, and the Japanese Association of Cardiovascular Intervention and Therapeutics). Registration of all TAVR cases in the registry is mandatory for the facilities and operators for certification, which is currently a requirement for receiving the device supply from the manufacturers. Details about the J-TVT registry have been described previously.⁷

At each participating site, the institutional review board or director of the institution approved the registration of patient information into the database with an opt-out process according to the ethical human subject guidelines, published by the Ministry of Education, Culture, Sports, Science and Technology, and the Ministry of Health, Labor and Welfare of Japan (2005). The current study was approved by Kitasato University Hospital institutional review board.

Study Patients and Design

We enrolled patients undergoing TAVR between August 2013 and December 2017 in Japan and who were registered in the J-TVT registry. We included only the first TAVR intervention case for each patient. We excluded those patients who did not have data on their annulus area measured by multi-detector computed tomography (MDCT) before the TAVR procedure and those without an EOA measured by echocardiography within 30 days after the TAVR procedure. Patients were stratified into 2 groups based on MDCT-measured annulus size: patients with a small annulus (annulus area ≤314 mm², small annulus) and those without (annulus area >314 mm², normal-sized annulus).^11,18 During the assessment, we found that a limited number of patients in our small anulus group had received a 29-mm THVs (n=25) and a 20-mm THV was received in the normal anulus group (n=68). Although this is clinically possible, we also conducted an additional analysis that excluded these patients from either of the groups, to evaluate the robustness of our findings. We further selected the patients in the small annulus group for comparison of intra-annular THVs and supra-annular THVs; patients who used the smallest currently available THVs in each THV type; that is, an intra-annular THV with a 20-mm diameter and a supra-annular THV with a 23-mm diameter, were selected for the comparison.

THV Types

During the study period, 4 types of THV, including SAPIEN XT, SAPIEN 3 (Edwards Lifesciences, Irvine, CA, USA), CoreValve, and Evolut R (Medtronic, Minneapolis, MN, USA), were approved and used in Japan; SAPIEN XT was approved for clinical use in August 2013. The SAPIEN XT 20-mm valve started to be used in May 2015. SAPIEN 3 was approved for only the transfemoral approach in May 2015. For the self-expanding valve, CoreValve was approved in January 2016, and Evolut R was introduced in December 2016.

Outcomes

The primary outcome of interest was patients’ first available post-implant echocardiographic data within 30 days after their procedure. We also studied post-procedural events, including death, conduction disturbance requiring a new permanent pacemaker, and stroke that occurred within 30 days. We used the first available post-procedural echocardiographic data to calculate the aortic valve EOA and mean pressure gradient (mPG). We defined severe PPM as an indexed EOA (iEOA) of <0.65 cm²/m² and moderate PPM as an iEOA of ≥0.65 and <0.85 cm²/m².^15,19 We also calculated the cover index, which shows the relation of annulus area to prosthesis area, and is an indicator of good sealing of the annulus by the prosthesis valve, calculated as (100 × [Prosthesis Valve Area in cm² − Annulus Area in cm²] / Prosthesis Area in cm²), as previously described.^20,21

Statistical Analysis

We first compared the baseline patient and procedural characteristics between the small annulus and the normal-sized annulus groups. We also compared the outcomes between the 2 groups and tested the difference, using the chi-squared test or Fisher’s exact test, as appropriate for categorical factors, and the Wilcoxon rank sum test for continuous variables. Continuous variables are expressed as medians with the interquartile range (IQR). Among these patients, we modeled the occurrence of PPM by a stepwise logistic regression (P value for entry=0.3, P value for exit=0.35) and identified baseline characteristics that were associated statistically and significantly with PPM from all baseline characteristics. We then compared the baseline characteristics as well as the outcome of the procedure between procedures, by using the 20-mm diameter intra-annular THV vs. the 23-mm diameter supra-annular THV. All statistical analyses were performed using SAS, version 9.4 (SAS Institute, Cary, NC, USA).

Results

Patient Population

Between August 2013 and December 2017, a total of 10,761 patients underwent TAVR at 103 sites in Japan and were entered in the J-TVT registry. We excluded patients who did not have data for the annulus area registered, measured by MDCT before the TAVR procedure (n=1,732) and EOA measured by echocardiography within 30 days after the TAVR procedure (n=3,159), as shown in Figure 1. A total of 5,870 patients were available for this study, with a median (IQR) age of 85 (81–88) years; 31.6% were male.

Figure 1.

Study diagram. The study population analyzed is shown. Patients without registration of an annulus size detected by MDCT or an EOA within 30 days of TAVI were excluded from this study. MDCT, multi-detector computed tomography; EOA, effective orifice area; TAVI, transcatheter aortic valve implantation.

Comparisons Between Patients With Small and Normal-Sized Annulus

The baseline and procedural characteristics of the study population, stratified by annulus size measured by MDCT, are shown in Table 1. Six hundred and forty-seven patients (11.0%) had a small annulus measured by MDCT. Compared to patients without a small annulus, patients with a small annulus were more likely to be women (93.2% vs. 65.3%, P<0.001), have a smaller body surface area (1.34 m² [IQR: 1.24–1.42] vs. 1.42 m² [IQR: 1.31–1.55], P<0.001), were less likely to have coronary artery disease (28.0% vs. 32.9%, P=0.01), but more likely to have had a prior stroke (12.7% vs. 7.6%, P<0.001), to have a pacemaker implantation (8.5% vs. 5.7%, P=0.01), and to have a higher STS Predicted Risk of Operative Mortality score (6.7% [IQR: 4.9–9.3] vs. 6.2% [IQR: 4.5–8.8], P<0.001). The cover index in each THV was significantly larger in patients with a small annulus. In terms of a small annulus, a majority of patients (74.0%) received small 20- or 23-mm THVs. In contrast, a THV of 29 mm is larger for patients with a small annulus and a THV of 20 mm is smaller for patients with a normal-sized annulus. Therefore, we also analyzed our cohort excluding those patients with a small annulus who received a 29-mm THV (n=25) and the patients in the normal-sized group (n=68) who received a 20-mm THV, as described in Supplementary Table 1.

Table 1. Baseline and Procedural Characteristics of the Study Population

	Small annulus (n=647)	Normal-sized annulus (n=5,223)	P value
Baseline characteristics
Age (years)	85 (82–88)	85 (81–88)	<0.001
Female	603 (93.2)	3,413 (65.3)	<0.001
Height (cm)	145 (140–149)	150 (144–157)	<0.001
Weight (kg)	45 (39–51)	49 (43–57)	<0.001
BMI (kg/m2)	21.6 (18.9–24.2)	21.9 (19.7–24.3)	0.04
BSA (m2)	1.34 (1.24–1.42)	1.42 (1.31–1.55)	<0.001
NYHA functional class III or IV	164 (25.3)	1,356 (26.0)	0.76
Hypertension	506 (78.2)	4,174 (79.9)	0.31
Hyperlipidemia	317 (49.0)	2,480 (47.5)	0.48
Diabetes mellitus	162 (25.0)	1,310 (25.1)	1.00
End-stage renal disease	4 (0.6)	31 (0.6)	0.79
COPD	45 (7.0)	440 (8.4)	0.20
Coronary artery disease	181 (28.0)	1,719 (32.9)	0.01
Prior PCI	137 (21.2)	1,258 (24.1)	0.10
Prior CABG	27 (4.2)	346 (6.6)	0.02
Prior cardiac surgery	69 (10.7)	595 (11.4)	0.58
Prior stroke	82 (12.7)	395 (7.6)	<0.001
Pacemaker	55 (8.5)	300 (5.7)	0.01
Atrial fibrillation or flutter	89 (13.8)	868 (16.6)	0.06
STS score (%)	6.7 (4.9–9.3)	6.2 (4.5–8.8)	<0.001
Logistic EuroSCORE (%)	12.8 (9.3–21.6)	12.8 (8.4–19.9)	0.07
Blood test
Creatinine (mg/dL)	0.8 (0.7–1.1)	0.9 (0.7–1.2)	<0.001
Hemoglobin (g/dL)	11.1 (10.1–12.1)	11.2 (10.1–12.4)	0.42
Albumin	3.7 (3.4–4.1)	3.8 (3.4–4.1)	0.76
Imaging characteristics
Left ventricular ejection fraction (%)	66 (60–72)	63 (55–69)	<0.001
Aortic valve area (cm2)	0.6 (0.5–0.7)	0.6 (0.5–0.7)	<0.001
Mean pressure gradient (mmHg)	47.0 (38.6–62.0)	47.8 (38.7–61.0)	0.74
Aortic insufficiency grade ≥3	41 (6.3)	440 (8.4)	0.07
Mitral insufficiency grade ≥3	41 (6.3)	396 (7.6)	0.26
Bicuspid valve	9 (1.4)	134 (2.6)	0.07
Annulus area (cm2)	2.9 (2.6–3.1)	4.0 (3.6–4.5)	<0.001
Annulus perimeter (mm)	61.3 (24.5–63.6)	71.4 (67.0–76.2)	<0.001
Procedural characteristics
Valve type			<0.001
SAPIEN XT	261 (40.3)	2,533 (48.5)
SAPIEN 3	145 (22.4)	1,152 (22.1)
CoreValve	63 (9.7)	537 (10.3)
Evolut R	175 (27.0)	991 (19.0)
Valve size (mm)			<0.001
20	166 (25.7)	68 (1.3)
23	313 (48.4)	2,075 (39.7)
26	140 (21.6)	2,120 (40.6)
29	25 (3.9)	950 (18.2)
No use	3 (0.5)	10 (0.2)
Cover index
SAPIEN XT	26.0 (21.0–30.1)	13.5 (8.0–19.2)	<0.001
SAPIEN 3	17.7 (8.5–43.6)	6.7 (0.2–13.3)	<0.001
CoreValve	58.9 (43.5–62.3)	31.4 (26.8–35.9)	<0.001
Evolut R	38.1 (30.6–42.2)	31.6 (26.4–36.0)	<0.001
Procedural time (min)	90 (68–120)	97 (72–127)	<0.001
Transfemoral approach	530 (81.9)	4,164 (79.7)	0.19
Device success	608 (94.0)	4,976 (95.3)	0.15
Annulus rupture	2 (0.3)	20 (0.4)	1.00
Coronary obstruction	2 (0.3)	9 (0.2)	0.35
Conversion to open heart surgery	10 (1.5)	67 (1.3)	0.61

BMI, body mass index; BSA, body surface area; CABG, coronary artery bypass grafting; COPD, chronic obstructive pulmonary disease; NHYA, New York Heart Association; PCI, percutaneous coronary intervention; STS score, Society of Thoracic Surgeons score. Data are presented as n (%) and continuous variables are presented as median (interquartile range).

30-Day Outcomes

Clinical and echocardiographic outcomes within 30 days for patients with or without a small annulus are shown in Table 2. Thirty-day mortality, new pacemaker implantation rate, and stroke rate were comparable between the 2 groups. Those patients with a small annulus were more likely to have a smaller EOA (1.5 cm² [IQR: 1.2–1.8] vs. 1.7 cm² [IQR: 1.4–2.0], P<0.001), iEOA (1.10 cm²/m² [IQR: 0.92–1.35] vs. 1.16 cm²/m² [IQR: 0.96–1.39], P<0.001), and higher mPG (10.0 mmHg [IQR 6.9–14.2] vs. 8.5 mmHg [6.0–11.5], P<0.001), and were less likely to have paravalvular leakage (PVL) ≥moderate (17.3% vs. 24.4%, P<0.001). The frequency of PPM was higher in patients with a small annulus (P=0.002). Significant predictors of PPM after TAVR after multivariate analysis are shown in Table 3. The small annulus measured by MDCT (OR: 1.84; 95% CI: 1.46–2.32, P<0.001) was significantly associated with PPM within 30 days.

Table 2. Clinical and Echocardiographic Outcomes Within 30 Days

	Small annulus (n=647)	Normal-sized annulus (n=5,223)	P value
Clinical outcomes
30-day mortality	9 (1.4)	35 (0.7)	0.05
New pacemaker implantation	42 (6.5)	287 (5.5)	0.30
Stroke	14 (2.2)	75 (1.4)	0.15
Echocardiographic outcomes
Effective orifice area (cm2)	1.5 (1.2–1.8)	1.7 (1.4–2.0)	<0.001
Indexed effective orifice area (cm2/m2)	1.10 (0.92–1.35)	1.16 (0.96–1.39)	<0.001
Mean pressure gradient (mmHg)	10.0 (6.9–14.2)	8.5 (6.0–11.5)	<0.001
Paravalvular leakage ≥moderate	112 (17.3)	1,272 (24.4)	<0.001
Prosthesis-patient mismatch			0.002
Severe	17 (2.6)	107 (2.0)
Moderate	101 (15.6)	580 (11.1)
Insignificant	529 (81.8)	4,536 (86.8)

Data are presented as n (%) and continuous variables are presented as medians (interquartile range).

Table 3. Significant Predictors of Patient-Prosthesis Mismatch Within 30 Days in Multivariate Analysis

	Odds ratio (95% CI)	P value
Male	0.51 (0.40–0.65)	<0.001
Height (per 1 cm)	1.03 (1.02–1.05)	<0.001
Weight (per 1 kg)	1.03 (1.02–1.04)	<0.001
Hyperlipidemia	1.25 (1.06–1.46)	0.01
End-stage renal disease	0.47 (0.14–1.63)	0.23
Prior CABG	1.30 (0.97–1.75)	0.08
Prior stroke	0.86 (0.64–1.15)	0.30
Pacemaker	1.26 (0.93–1.71)	0.13
Left ventricular ejection fraction (per 1%)	0.993 (0.987–0.999)	0.03
Mean aortic pressure gradient (per 1 mmHg)	1.005 (1.001–1.009)	0.03
Aortic insufficiency grade ≥3	1.33 (1.01–1.75)	0.04
Mitral insufficiency grade ≥3	1.34 (1.01–1.78)	0.04
Bicuspid valve	1.75 (1.13–2.70)	0.01
Transfemoral approach	0.822 (0.678–0.997)	0.047
Small annulus	1.84 (1.46–2.32)	<0.001

CI, confidence interval; CABG, coronary artery bypass grafting.

Supplementary Tables 1–3 present the analysis that excluded the patients with a small annulus who received a 29-mm THV and patients with a normal-sized annulus who received a 20-mm THV. Thirty-day mortality remained higher in patients with a small annulus compared to patients with a normal-sized annulus (1.5% vs. 0.7%, P=0.04). Further, the small annulus measured by MDCT (OR: 2.04; 95% CI: 1.61–2.59, P<0.001) was significantly associated with PPM within 30 days in this cohort.

Comparison of 20-mm Intra- and 23-mm Supra-Annular THV in Patients With a Small Annulus

Among those patients with a small annulus, currently available intra-annular THV with a 20-mm diameter (SAPIEN 3 20 mm, n=90) and supra-annular THV with a 23-mm diameter (Evolut R 23 mm, n=103) were compared. The baseline and procedural characteristics of patients with SAPIEN 3 20 mm and Evolut R 23 mm in a small annulus are summarized in Table 4. Patients with SAPIEN 3 20 mm were more likely to be heavier (45 kg [IQR: 40–50] vs. 42 kg [IQR: 38–42], P=0.04), less likely to have undergone prior cardiac surgery (6.7% vs. 16.5%, P=0.04), more likely to have a lower Logistic EuroSCORE (11.5% [IQR: 8.5–16.1] vs. 15.2% [IQR: 9.0–24.0], P=0.03), and to have a larger annulus area (2.9 cm² [IQR: 2.7–3.0] vs. 2.8 cm² [IQR: 2.7–3.0], P=0.03) and perimeter (61.7 mm [IQR: 60.0–63.0] vs. 60.8 mm [IQR: 56.6–62.4], P=0.02) compared to those with Evolut R 23 mm.

Table 4. Baseline and Procedural Characteristics in Patients With SAPIEN 3 20 mm and Evolut R 23 mm in the Small Annulus

	SAPIEN 3 20 mm (n=90)	Evolut R 23 mm (n=103)	P value
Baseline characteristics
Age (years)	84 (82–88)	85 (82–88)	0.29
Female	87 (96.7)	102 (99.0)	0.34
Height (cm)	144 (138–147)	143 (138–147)	0.99
Weight (kg)	45 (40–50)	42 (38–42)	0.04
BMI (kg/m2)	21.5 (19.8–24.5)	20.6 (19.0–23.3)	0.06
BSA (m2)	1.32 (1.23–1.40)	1.29 (1.22–1.35)	0.07
NYHA functional class III or IV	18 (20.0)	28 (27.2)	0.24
Hypertension	69 (76.7)	80 (77.7)	0.86
Hyperlipidemia	42 (46.7)	56 (54.4)	0.29
Diabetes mellitus	26 (28.9)	21 (20.4)	0.17
End-stage renal disease	0 (0.0)	1 (1.0)	0.53
COPD	3 (3.3)	5 (4.9)	0.73
Coronary artery disease	16 (17.8)	29 (28.2)	0.12
Prior PCI	9 (10.0)	19 (18.4)	0.10
Prior CABG	5 (5.6)	4 (3.9)	0.74
Prior cardiac surgery	6 (6.7)	17 (16.5)	0.04
Prior stroke	12 (13.3)	7 (6.8)	0.13
Pacemaker	9 (10.0)	5 (4.9)	0.17
Atrial fibrillation or flutter	11 (12.2)	16 (15.5)	0.54
STS score (%)	5.8 (4.6–8.1)	6.4 (5.0–9.1)	0.06
Logistic EuroSCORE (%)	11.5 (8.5–16.1)	15.2 (9.0–24.0)	0.03
Blood test
Creatinine (mg/dL)	0.8 (0.6–1.0)	0.8 (0.7–1.1)	0.29
Hemoglobin (g/dL)	11.3 (10.2–12.1)	10.9 (10.1–12.1)	0.35
Albumin	3.8 (3.5–4.1)	3.7 (3.4–4.1)	0.52
Imaging characteristics
Left ventricular ejection fraction (%)	68 (64–74)	69 (63–77)	0.23
Aortic valve area (cm2)	0.6 (0.5–0.7)	0.5 (0.4–0.7)	0.15
Mean pressure gradient (mmHg)	49.5 (40.5–66.0)	47.0 (41.0–60.0)	0.36
Aortic insufficiency grade ≥3	8 (8.9)	3 (2.9)	0.07
Mitral insufficiency grade ≥3	7 (7.8)	4 (3.9)	0.24
Bicuspid valve	1 (1.1)	0 (0.0)	0.46
Annulus area (cm2)	2.9 (2.7–3.0)	2.8 (2.7–3.0)	0.03
Annulus perimeter (mm)	61.7 (60.0–63.0)	60.8 (56.6–62.4)	0.02
Procedural characteristics
Procedural time (min)	88 (66–108)	84 (62–113)	0.77
Transfemoral approach	86 (95.6)	97 (94.2)	0.75
Device success	85 (94.4)	93 (90.3)	0.28
Annulus rupture	0 (0.0)	0 (0.0)	1.00
Coronary obstruction	0 (0.0)	1 (1.0)	1.00
Conversion to open heart surgery	0 (0.0)	3 (2.9)	0.25

Abbreviations as in Table 1. Data are presented as n (%) and continuous variables are presented as medians (interquartile range).

Clinical and echocardiographic outcomes within 30 days with SAPIEN 3 20 mm and Evolut R 23 mm in a small annulus are shown in Table 5. Thirty-day outcomes were comparable in patients with SAPIEN 3 20 mm and Evolut R 23 mm. Patients with SAPIEN 3 20 mm were more likely to have a smaller EOA (1.2 cm² [IQR: 1.0–1.4] vs. 1.4 cm² [IQR: 1.1–1.5], P=0.002), iEOA (0.94 cm²/m² [IQR 0.78–1.06] vs. 1.07 cm²/m² [IQR 0.84–1.24], P=0.001), and higher mPG (14.0 mmHg [IQR 10.0–18.5] vs. 11.0 mmHg [7.0–14.0], P<0.001). The distributions of iEOA in SAPIEN 3 20 mm and Evolut R 23 mm are shown in Figure 2. The frequency of PPM and the rate of PVL ≥moderate were comparable for the 2 THVs.

Table 5. Clinical and Echocardiographic Outcomes Within 30 Days in Patients With SAPIEN3 20 mm and Evolut R 23 mm

	SAPIEN 3 20 mm (n=90)	Evolut R 23 mm (n=103)	P value
Clinical outcomes
30-day mortality	0 (0.0)	0 (0.0)	1.00
New pacemaker implantation	4 (4.4)	10 (9.7)	0.16
Stroke	1 (1.1)	2 (1.9)	1.00
Echocardiographic outcomes
Effective orifice area (cm2)	1.2 (1.0–1.4)	1.4 (1.1–1.5)	0.002
Indexed effective orifice area (cm2/m2)	0.94 (0.78–1.06)	1.07 (0.84–1.24)	0.001
Mean pressure gradient (mmHg)	14.0 (10.0–18.5)	11.0 (7.0–14.0)	<0.001
Paravalvular leakage ≥moderate	13 (14.4)	17 (16.5)	0.69
Prosthesis-patient mismatch			0.21
Severe	7 (7.8)	3 (2.9)
Moderate	24 (26.7)	23 (22.3)
Insignificant	59 (65.6)	77 (74.8)

Data are presented as n (%) and continuous variables are presented as medians (interquartile range).

Figure 2.

Distributions of iEOA in SAPIEN 3 20 mm (A) and Evolut R 23 mm (B). iEOA, indexed effective orifice area.

Discussion

In the present study, 3 major findings concerning the small annulus in the TAVR procedure were identified. First, 11.0% of Japanese patients had a small annulus, with no significant differences in 30-day clinical outcomes from those without a small annulus. Second, a small annulus was also a significant predictor of PPM after TAVR in multiple regression analysis. Third, compared to intra-annular 20 mm THV, supra-annular 23 mm THV was associated with better echocardiographic improvements in patients with a small annulus without an increase in PVL.

In the present study, the procedural complications and device success rate were comparable in patients with and without a small annulus. A similar trend was seen for the 30-day clinical outcome, indicating that short-term procedural safety was well-maintained in patients with a small annulus. In contrast, an echocardiographic investigation revealed differences in the hemodynamic parameters after the procedure. The iEOA was smaller and the mPG was higher after TAVR, and PVL was less frequently observed in patients with a small annulus. However, the rate of PPM in patients with a small annulus was 18.2% in this study, and this rate was much lower than the rate among patients with a small annulus after a SAVR (45.1–93.0%).²² The absence of a sewing ring in a TAVR, allowing for a larger EOA, may contribute to the lower frequency of PPM compared to when SAVR occurs. PVL is a well-established predictor of long-term mortality.^23,24 In the present study, the cover index was significantly higher in patients with a small annulus,^25,26 most likely leading to less frequent PVL.

In addition to the previously established clinical variables that are associated with the occurrence of PPM (e.g., male sex, height, weight, hyperlipidemia, left ventricular ejection fraction, mean aortic pressure gradient, aortic insufficiency, mitral insufficiency, bicuspid valve, and transfemoral approach), our study also revealed that a small annulus (area ≤314 mm²) was an independent predictor of PPM after TAVR.^13,14 Similarly, previous study has suggested that a smaller annulus area was one of the predictive factors of PPM.²⁷ Studies using the SAVR have reported that patients with PPM have worse functional class and are associated with a poorer prognosis than patients without PPM.^15,28 In contrast, whether PPM has a negative effect on the late clinical outcome after TAVR has not been well established.²⁷ A previous report from the PARTNER (Placement of AoRTic TraNscatheter Valve Trial) demonstrated that severe PPM had a significant effect on survival after TAVR in the subset of patients with no post-procedural aortic regurgitation.¹³ As seen in our analysis, patients with a smaller annulus tend to have a smaller iEOA but with less PVL as a consequence of a higher cover index; as a consequence, patients with a small annulus had both positive and negative predictors for long-term outcome, and this might partially explain the bidirectional effect of PPM on the late clinical outcome after TAVR. The studies on new-generation valve models designed to decrease the PVL may provide more insights.^23,24,29,30 For further expansion of indications of TAVR,^5,6 new generation of THVs need to show safety and efficacy in the longer term follow up.

We conducted a comparison between the currently available intra-annular (SAPIEN 3 20 mm) and supra-annular (Evolut R 23 mm) THVs, because they were the smallest size of THVs within each category. The clinical outcomes within 30 days of SAPIEN 3 20 mm and Evolut R 23 mm in patients with a small annulus were comparable. Although the comparison of the incidence of device success rate between SAPIEN 3 20 mm (94.4%) and EvolutR 23 mm (90.3%) was not statistically significant, the device success rate of EvolutR 23 mm in patients with a small annulus was substantially lower compared to that in patients with a normal-sized annulus (95.3%). Because it was reported that the EOA in the supra-annular THV was larger over a long period of time than that in surgical valves,^3,16 the supra-annular THV may contribute to preventing the occurrence of PPM. Although patient body weight, annulus area, and annulus perimeter in patients with the Evolut R 23 mm were lower than those in patients with the SAPIEN 3 20 mm, the iEOA in patients with the Evolut R 23 mm was significantly larger and the mPG was significantly smaller. We also observed that the point estimate for the crude incidence of severe PPM was higher for SAPIEN 3 20 mm compared to EvolutR 23 mm (7.8% vs. 2.9%, respectively), although this was not statistically significant, possibly due, in part, to the low number of patients with a small annulus size. Given that PPM has been associated with higher mortality and increased heart failure rehospitalization after TAVR in previous reports,¹² further investigations on the incidence and the clinical effect of PPM linked to differing THV types, with appropriate risk adjustments, are warranted. The incidences of PVL with the SAPIEN 3 20 mm and Evolut R 23 mm in patients with a small annulus were comparable. The rates of PVL ≥ moderate in patients with SAPIEN 3 and Evolut R were higher than those previously reported when current available devices are used.^2,5,6 The measurement of echocardiography was left to the facilities’ discretion, and thus the evaluation of PVL may have varied between facilities, resulting in a systematic overestimation in the incidence of PVL.

We did not compare the same sizes of SAPIEN 3 23 mm and Evolut R 23 mm because the body weight, annulus area, and perimeter in patients with the Evolut R 23 mm were lower than those in patients with the SAPIEN 3 20 mm, and they were thought not to be comparable to those in patients with the SAPIEN 3 23 mm. Previous studies reported that supra-annular THVs, especially the use of the CoreValve, were associated with the occurrence of moderate or severe PVL.^31,32 This discrepancy between our study and previous studies might be explained partially by the fact that the cover index in the Evolut R in a small annulus was significantly larger than that in the Evolut R in a normal-size annulus (Table 1). Previous studies suggested that a low cover index was found to be an independent predictor of moderate or severe PVL after TAVR, and oversizing of the prosthesis relative to the annulus size might reduce PVL.^{20,24–26,33} In contrast, the use of the Evolut R system, which is a new-generation supra-annular THV and optimizes the THV position by its ability to reposition the THV, might contribute to the reduction of PVL. The use of the latest supra-annular THV, which has a porcine pericardial tissue wrap added around the outer sealing zone of the nitinol frame and provides advanced sealing,²⁹ might reduce the PVL further.

Several studies have also suggested various strategies to gain larger iEOA and avoid PPM after TAVR. Post dilation with a balloon is associated with reduced rates of moderate or severe PPM with no evidence of short-term structural deterioration of the balloon-expanding THV.³⁴ A previous propensity score-matching study reported that the use of the SAPIEN XT 23 mm was associated with a larger EOA and smaller mean pressure gradient compared to the use of the SAPIEN 3 20 mm after TAVR in patients with a small annulus (area <314 mm²).¹⁸ The additional ballooning and THV oversizing carry the inherent risk of annulus rupture, particularly with balloon-expanding THVs. The choice of a supra-annular THV might contribute to gaining the larger iEOA and lower mPG in patients with a small annulus without increasing the risk of annulus rupture when intra- and supra-annular devices are anatomically applicable.

Study Limitations

There are several limitations in this study. First, echocardiography was analyzed at each institution, not in a core laboratory, and a number of limitations exist for the semi-quantitative criteria used for grading PVL. In addition, anatomical measurements other than annulus area and perimeter, such as the coronary height, the size of sinus of Valsalva and severity of calcification, can also influence the THV selection. Second, some underreporting may exist because of the nature of data registration and study design. Third, study participants and physicians determining outcomes were not blinded to interventions. Fourth, despite the adjustment for potential confounders in multivariate analysis, we cannot rule out the possibility of selection bias in this cohort. Fifth, in comparison between a small annulus and a normal-sized annulus, the analysis included patients using new and old generation THVs. Our conclusions may not fully apply to patient populations using only the new generation THV. Sixth, because this study was not a prospective study, comparison between intra- and supra-annular devices needs to be interpreted with caution. For the comparison between 2 THVs, a prospective, randomized trial is needed to show the advantage of the supra-annular THV to achieve better hemodynamic improvement. Seventh, 116 cases of SAPIEN 3 20 mm and 8 cases of EvolutR 23 mm in a small annulus were excluded from this study due to absence of the registration of EOA within 30 days after TAVR. The number excluded from this study in patients with SAPIEN 3 20 mm was higher because the requirement for the registration of EOA in SAPIEN 3 20 mm was stopped earlier (April 2017) compared to Evolut R 23 mm (September 2017) in relation to the device post-marketing study. However, we believe that this administrative termination for the EOA registration requirement, which was unrelated to the characteristics of individual cases, should not systematically bias the comparative assessment between the 2 devices. Finally, only 30-day clinical and echocardiographic outcomes were available in this study. Further long-term follow-up studies are needed to evaluate the consequences of a small annulus and PPM after TAVR.

Conclusions

A small annulus was associated with less hemodynamic improvement. Among the patients with a small annulus, the observed greater hemodynamic improvement without increased PVL when a supra-annular device is used warrants further investigation.

Disclosures

The authors declare no conflicts of interest. J.A. is an Editorial Board member of Circulation Journal.

IRB Information

This study was conducted in accordance with the “Declaration of Helsinki” and Kitasato University Institutional Review Board. The Kitasato University Medical Ethics Organization (B 19-064) approved this study.

Data Availability

Deidentified data from this study will not be shared.

Supplementary Files

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-20-1084

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