Extremely Small 20-mm Versus Standard-Size Balloon-Expandable Transcatheter Heart Valves

Abstract

Background

The 20-mm balloon-expandable transcatheter heart valve (THV) represents the smallest available option for transcatheter aortic valve replacement (TAVR). Its current underutilization stems from concerns regarding prosthesis-patient mismatch, durability, and potential adverse outcomes.

Objectives

The purpose of this study was to compare the long-term outcomes between the 20-mm balloon-expandable THVs and standard-size balloon-expandable THVs.

Methods

Patients who underwent transfemoral TAVR with SAPIEN THVs were sourced from the OCEAN-TAVI (Optimized Transcatheter Valvular Intervention) registry, an ongoing, multicenter cohort study that has enrolled over 7,000 TAVR patients in Japan. A 1:3 propensity-matched analysis, based on 24 baseline clinical and echocardiographic variables, was used to contrast the 20-mm with >20-mm balloon-expandable THVs.

Results

Of 5,086 eligible patients, 284 (5.6%) received the 20-mm balloon-expandable THV. After propensity-matching, the 20-mm THV group (n = 276) and the >20-mm THV group (n = 828) demonstrated balanced baseline characteristics, with an absolute standardized difference <0.10. The average follow-up duration for patients who were alive was 955 ± 512 days, and the average time to death was 584 ± 543 days. The 20-mm group showed a higher frequency of prosthesis-patient mismatch (PPM) (moderate PPM: 29.2% vs 10.8%; severe PPM: 4.9% vs 1.5%; P < 0.001). Over a 5-year period, all-cause mortality and heart failure rehospitalization rates were comparable between the 2 groups (all-cause mortality: 34.2% vs 38.0%; HR: 1.01; 95% CI: 0.74-1.37; P = 0.970; heart failure rehospitalization: 15.2% vs 16.3%; HR: 0.81; 95% CI: 0.50-1.29; P = 0.371).

Conclusions

This registry-based study suggests that the initially observed inferior forward hemodynamics associated with the 20-mm THV do not translate into heightened long-term mortality or heart failure rehospitalization risks. (The OCEAN-TAVI registry [Optimized Transcatheter Valvular Intervention-Transcatheter Aortic Valve Implantation]; UMINID:000020423)

Central Illustration

The 20-mm SAPIEN balloon-expandable (Edwards Lifesciences) transcatheter heart valve (THV) represents the smallest available device for transcatheter aortic valve replacement (TAVR) in patients with an extremely small aortic annulus of <345 mm².¹ Nevertheless, the extremely small THV is underutilized, and larger self-expanding THVs are generally preferred because of concerns regarding the risk of prosthesis-patient mismatch (PPM) and potential long-term adverse outcomes such as valve thrombosis and early degeneration,2, 3, 4, 5 Current evidence from randomized controlled TAVR trials is not comprehensive enough to support the use of this extremely small THV, because they encompass only a limited number of patients treated with a 20-mm THV.⁶ In the present study, we used data from a nationwide multicenter registry to compare 5-year outcomes between the extremely small 20-mm balloon-expandable THVs and other standard-size balloon-expandable THVs using propensity-score matched analysis.

Methods

Study cohort

The OCEAN-TAVI (Optimized Transcatheter Valvular Intervention) registry is an ongoing nationwide, prospective, multicenter cohort study enrolling patients with aortic stenosis undergoing TAVR at collaborating centers in Japan. The consecutive patient enrollment in the registry, adherence to the registry protocol, and providing patient information and clinical outcomes during follow-up are mandated for the participating centers. The study protocol was approved by the ethics committee of each center, and all patients provided written informed consent for participation. The study was conducted in compliance with the Declaration of Helsinki. This registry was registered with the University Hospital Medical Information Network Clinical Trial Registry and accepted by the International Committee of Medical Journal (UMINID:000020423).⁷

The present analysis included consecutive patients who underwent transfemoral TAVR with the balloon-expandable THV between October 2013 and December 2019. For the purpose of the present study, patients who underwent TAVR for a degenerated surgical bioprosthesis were excluded.

Data collection and endpoint definitions

Baseline clinical, procedural, and follow-up data were prospectively captured and recorded in a web-based database at each participating center. Regular follow-ups were scheduled at 1 month, 6 months, 1 year, and annually thereafter. Clinical follow-up data were comprehensively collected through medical records at each center, documentation from referring physicians, and/or telephone interviews. To ensure data integrity, the web-based database underwent systematic audits for completeness and accuracy, conducted by the data committee members. In cases of data incompleteness or inaccuracies, responding to queries was mandatory for all participating centers.

Transthoracic echocardiography was performed before TAVR and at discharge. In accordance with the updated Valve Academic Research Consortium-3 (VARC-3) criteria,⁸ prosthesis-patient mismatch was categorized based on prosthesis effective orifice area (EOA) indexed to body surface area as severe (≤0.65 cm²/m²) or moderate (>0.65-0.85 cm²/m²) in the nonobese population, and as severe (≤0.55 cm²/m²) or moderate (>0.55-0.70 cm^2/m²) in the obese population (body mass index ≥30 kg/m²). All procedural complications were defined according to the VARC criteria, and were systematically collected. Clinical endpoints included all-cause and cardiovascular mortality and rehospitalization because of heart failure.

Statistical analysis

Categorical variables are reported as frequencies (percentages), and the differences are evaluated with the chi-square test or 2-tailed Fisher exact test. Continuous variables are presented as mean ± SD or median (IQR), and compared between groups using the 2-sample Student's t-test or the Mann-Whitney U test as appropriate. For comparisons within the same group under different conditions, the mean ± SD were analyzed using the paired Student's t-test. Time-to-event curves were depicted using the Kaplan-Meier method, with censoring occurring at the last valid contact if the patient was awaiting the next follow-up or had withdrawn consent. Cox proportional hazards model was used to calculate HRs and 95% CIs for clinical endpoints. All P values were 2-sided, and a P value <0.05 was considered significant for all tests.

To control for confounding caused by baseline differences between patients treated with a 20-mm THV and with a >20-mm THV, propensity score matching was used. The outcome measure for the propensity score calculation was the receipt of a 20-mm THV vs a >20-mm THV. The propensity scores were calculated using a multivariable logistic regression model based on 24 baseline variables that may affect study outcomes. The variables included clinical variables: age, sex, body mass index, Society of Thoracic Surgeons Predicted Risk of Mortality (STS-PROM), clinical frailty scale, NYHA heart failure symptoms III or IV, hypertension, diabetes mellitus, dyslipidemia, chronic kidney disease (estimated glomerular filtration rate <60 mL/min/1.73 m²), chronic obstructive pulmonary disease, atrial fibrillation, history of percutaneous coronary intervention, history of coronary artery bypass grafting, history of myocardial infarction, history of stroke, peripheral artery disease, previous pacemaker implantation, and echocardiographic variables: aortic valve area (cm²), aortic valve mean gradient (mmHg), left ventricular ejection fraction (≥50%: preserved; ≥40% to <50%: midrange; <40%: reduced), moderate or severe aortic regurgitation, moderate or severe mitral regurgitation, and moderate or severe tricuspid regurgitation. A 1:3 greedy nearest neighbor matching protocol with a caliper of 0.2 and without replacement was used for matching. Absolute standardized differences (ASD) were estimated for all of the baseline variables, and an ASD of <0.10 was considered as an indicator of good balance. ASD were calculated using the formula: ASD = |(Mean1 − Mean2)|/√((SD1² + SD2²)/2), where Mean1 and Mean2 are the means of the groups being compared, and SD1 and SD2 are their respective SDs. To further evaluate the robustness of the propensity score model, an inverse probability treatment weighting (IPTW) approach was also applied using the same set of variables as in the propensity score matching.

All statistical analyses were performed using EZR software (Saitama Medical Center, Jichi Medical University) a graphical user interface for R version 4.2.1 (The R Foundation for Statistical Computing).

Results

Study population and baseline characteristics

Among 7,393 patients who underwent TAVR between October 2013 and December 2019, 5,086 patients met the inclusion criteria and were analyzed for the present study. Of these, 284 patients were treated with a 20-mm THV. A 1:3 propensity score matching resulted in 273 patients treated with a 20-mm THV and 819 patients with a standard-size THV. Baseline characteristics of the unmatched and matched cohorts are detailed in Table 1. Before propensity score matching, patients treated with a 20-mm THV were older (85.7 ± 5.3 years vs 84.1 ± 5.2 years; P < 0.001), had a significantly lower proportion of men (1.1% vs 34.9%; P < 0.001), a lower body mass index (21.6 ± 3.7 kg/m² vs 22.6 ± 3.8 kg/m²; P < 0.001), and were more frail (clinical frailty scale: 4 [3-5] vs 4 [3-4]; P = 0.010). Although dyslipidemia was more frequent (61.3% vs 54.8%; P = 0.037), chronic obstructive pulmonary disease (3.5% vs 9.2%; P = 0.001) and history of coronary artery bypass grafting (1.1% vs 3.8%; P = 0.013) were less frequent in patients with a 20-mm THV than those with a standard-size THV. In echocardiographic assessment, patients with a 20-mm THV had a smaller aortic valve area (0.56 ± 0.16 cm² vs 0.66 ± 0.19 cm²; P < 0.001) and a higher mean pressure gradient (56.1 ± 20.2 mm Hg vs 48.7 ± 17.9 mm Hg; P < 0.001), and were more likely to have preserved left ventricular ejection fraction (91.2% vs 79.9%; P < 0.001). After matching, patients with a 20-mm THV and those with a standard-size THV were well balanced, with an ASD <0.10 across all measured baseline characteristics.

Table 1.

Baseline With Imaging Characteristics of Prematching and Matched Cohorts

	Prematching Cohort				Matched Cohort
	Small THV (n = 284)	Standard THV (n = 4,802)	P Value	ASD	Small THV (n = 273)	Standard THV (n = 819)	P Value	ASD
Age, y	85.7 ± 5.3	84.1 ± 5.2	<0.001	0.304	85.6 ± 5.3	85.5 ± 4.9	0.823	0.015
	86.0 (83.0-89.0)	84.0 (81.0-87.0)	<0.001		86.0 (83.0-89.0)	86.0 (83.0-89.0)	0.706
Male	3 (1.1)	1,674 (34.9)	<0.001	0.981	3 (1.1)	5 (0.6)	0.420	0.053
Body mass index, kg/m2	21.6 ± 3.7	22.6 ± 3.8	<0.001	0.274	21.7 ± 3.6	21.7 ± 3.5	0.874	0.011
	21.3 (19.0-24.1)	22.4 (20.0-24.9)	<0.001		21.4 (19.1-24.1)	21.3 (19.0-23.8)	0.592
STS calculated risk of mortality	8.0 ± 6.2	7.4 ± 5.9	0.126	0.092	7.8 ± 6.0	7.7 ± 5.2	0.688	0.027
	6.4 (4.4-9.3)	5.9 (4.1-8.8)	0.018		6.4 (4.4-9.4)	6.7 (4.8-9.5)	0.268
Clinical frailty scale	4.1 ± 1.3	3.8 ± 1.2	0.002	0.179	4.0 ± 1.3	4.0 ± 1.1	0.649	0.036
Clinical frailty scale	4 (3-5)	4 (3-4)	0.010		4 (3-5)	4 (3-5)	0.442
NYHA functional class III or IV	123 (43.3)	1,967 (41.0)	0.457	0.047	115 (42.1)	355 (43.3)	0.778	0.025
Concomitant diseases
Hypertension	232 (81.7)	3,968 (82.6)	0.687	0.025	225 (82.4)	669 (81.7)	0.856	0.028
Diabetes mellitus	71 (25.0)	1,319 (27.5)	0.411	0.056	69 (25.3)	213 (26.0)	0.873	0.017
Dyslipidemia	174 (61.3)	2,633 (54.8)	0.037	0.131	163 (59.7)	483 (59.0)	0.887	0.015
Chronic kidney disease (eGFR <60 mL/min/1.73 m2)	205 (72.2)	3,308 (68.9)	0.262	0.072	196 (71.8)	590 (72.0)	0.938	0.005
COPD	10 (3.5)	442 (9.2)	0.001	0.234	9 (3.3)	28 (3.4)	1.000	0.007
Atrial fibrillation	50 (17.6)	1,016 (21.2)	0.177	0.090	46 (16.8)	152 (18.6)	0.586	0.045
Previous history
History of PCI	59 (20.8)	1,093 (22.8)	0.466	0.048	52 (19.0)	172 (21.0)	0.545	0.049
History of CABG	3 (1.1)	183 (3.8)	0.013	0.179	3 (1.1)	9 (1.1)	1.000	<0.001
History of MI	13 (4.6)	227 (4.7)	1.000	0.007	11 (4.0)	34 (4.2)	1.000	0.006
History of stroke	23 (8.1)	522 (10.9)	0.166	0.095	23 (8.4)	65 (7.9)	0.798	0.018
Peripheral artery disease	24 (8.5)	389 (8.1)	0.823	0.013	22 (8.1)	67 (8.2)	1.000	0.004
Previous pacemaker	21 (7.4)	246 (5.1)	0.100	0.094	15 (5.5)	50 (6.1)	0.770	0.026
Echocardiographic data
Aortic valve area, cm2	0.56 ± 0.16	0.66 ± 0.19	<0.001	0.546	0.57 ± 0.16	0.56 ± 0.16	0.918	0.007
	0.55 (0.45-0.65)	0.65 (0.52-0.77)	<0.001		0.55 (0.45-0.65)	0.56 (0.46-0.68)	0.517
Aortic valve mean gradient, mm Hg	56.1 ± 20.2	48.7 ± 17.9	<0.001	0.392	56.0 ± 20.1	55.3 ± 18.7	0.570	0.039
	55.0 (41.0-69.0)	46.0 (36.5-59.0)	<0.001		54.9 (41.0-69.0)	52.1 (41.9-66.2)	0.516
LVEF			<0.001	0.334			0.886	0.028
Preserved, ≥50%	259 (91.2)	3812 (79.9)			248 (90.8)	750 (91.6)
Midrange, ≥40-<50%	17 (6.0)	541 (11.3)			17 (6.2)	48 (5.9)
Reduced, <40%	8 (2.8)	417 (8.7)			8 (2.9)	21 (2.6)
Aortic regurgitation ≥ moderate	31 (10.9)	472 (9.8)	0.540	0.035	30 (11.0)	77 (9.4)	0.481	0.052
Mitral regurgitation ≥ moderate	33 (11.6)	551 (11.5)	0.924	0.004	32 (11.7)	98 (12.0)	1.000	0.008
Tricuspid regurgitation ≥ moderate	29 (10.2)	434 (9.0)	0.524	0.040	28 (10.3)	82 (10.0)	0.908	0.008

Values are mean ± SD, median (Q1-Q3), or n (%). P values from Fisher test (2 × 2 comparison), chi-square test (n × 2 comparisons) or t-tests (continuous parameters).

ASD = absolute standardized difference; CABG = coronary artery bypass grafting; COPD = chronic obstructive pulmonary disease; eGFR = estimated glomerular filtration rate; LVEF = left ventricular ejection fraction; MI = myocardial infarction; PCI = percutaneous coronary intervention; THV = transcatheter heart valve.

Procedural characteristics, complications, and echocardiographic outcomes

Procedures, complications, and echocardiographic outcomes in the matched cohort are presented in Table 2. The majority of the patients were treated with a newer-generation THV, with no significant difference between the groups (88.3% vs 86.3%; P = 0.47). Although the rate of predilation was similar, postdilatation was more frequently performed in patients with a 20-mm THV compared with those with a standard-size THV (28.6% vs 19.3%; P = 0.002). The oversizing rate, calculated as: (THV nominal area/computed tomography annulus area − 1) × 100, was found to be significantly greater in the 20-mm THV group than in the standard-size THV group (5.8% [0.2%-13.3%] vs 12.0% [5.7%-19.6%]; P < 0.001). There were no significant differences in the incidences of procedural complications between the groups, including coronary obstruction, disabling stroke, major or life-threatening bleeding, major vascular complication, new permanent pacemaker implantation, new-onset atrial fibrillation, and conversion to surgery. Postprocedural echocardiography revealed a smaller EOA (1.28 ± 0.29 cm² vs 1.56 ± 0.38 cm²; P < 0.001), a higher mean pressure gradient (16.9 ± 6.2 mm Hg vs 12.5 ± 4.9 mm Hg; P < 0.001), a higher incidence of PPM (severe PPM: 4.9% vs 1.5%, moderate PPM: 29.2% vs 10.8%; P < 0.001), and a higher incidence of residual gradient ≥20 mm Hg (26.8% vs 6.7%; P < 0.001) in the 20-mm THV group compared with the standard-size THV group. Paravalvular regurgitation (PVR) was more frequently observed in patients treated with a 20-mm THV (mild PVR: 34.6% vs 23.5%, ≥ moderate PVR: 1.8% vs 1.5%; P < 0.001) (Figure 1).

Table 2.

Procedure, Complications, and Echocardiographic Outcomes in the Propensity-Matched Cohort

	Small THV (n = 273)	Standard THV (n = 819)	P Value
Type of valve			0.470
SAPIEN XT	28 (10.3)	(13.7)
SAPIEN 3	241 (88.3)	707 (86.3)
CT-based annulus area, mm2	308.4 ± 29.9	383.7 ± 48.2	<0.001
Valve size
20-mm	273 (100)		<0.001
23-mm		673 (82.2)
26-mm		141 (17.2)
29-mm		5 (0.6)
Local anesthesia	99 (36.3)	332 (40.5)	0.225
Predilation	120 (44.0)	369 (45.1)	0.779
Postdilation	78 (28.6)	158 (19.3)	0.002
Oversizing ratea	+5.8 (0.2-13.3)	+12.0 (5.7-19.6)	<0.001
Borderline annulus sizeb (338-345 mm2)	18 (6.6)	55 (6.7)	>0.999
Procedural complications
Coronary artery occlusion	3 (1.1)	9 (1.1)	>0.999
Disabling stroke	2 (0.7)	7 (0.9)	>0.999
Major/life-threatening bleeding	30 (11.0)	68 (8.3)	0.180
Major vascular complication	12 (4.4)	29 (3.5)	0.581
New permanent pacemaker	15 (5.5)	55 (6.7)	0.569
New-onset atrial fibrillation	7 (2.7)	15 (1.9)	0.457
Conversion to surgery	3 (1.1)	4 (0.5)	0.376
Discharge or Postprocedure
Effective orifice area, cm2	1.28 ± 0.29	1.56 ± 0.38	<0.001
Prosthetic valve mean gradient, mm Hg	16.9 ± 6.2	12.5 ± 4.9	<0.001
Prosthetic valve mean gradient ≥20 mm Hg	72 (26.8)	54 (6.7)	<0.001
Paravalvular regurgitation			0.001
None	173 (63.6)	612 (75.0)
Mild	94 (34.6)	192 (23.5)
Moderate	5 (1.8)	12 (1.5)
Prosthesis-patient mismatch			<0.001
Insignificant	176 (65.9)	710 (87.8)
Moderate	78 (29.2)	87 (10.8)
Severe	13 (4.9)	12 (1.5)

Values are n (%), mean ± SD, or median (Q1-Q3). P values from Fisher test (2 × 2 comparison), chi-square test (n × 2 comparisons) or Student’s t-tests (continuous parameters).

CT = computed tomography; other abbreviations as in Table 1.

^aOversizing rate is calculated as: (THV nominal area/CT annulus area − 1) × 100.

^bBorderline annulus size refers to an annulus size that falls between the thresholds for 20- and 23-mm valve sizes (338-345 mm²), indicating that it could potentially accommodate either valve size.

Figure 1.

Echocardiographic Outcomes of the Small- and Standard-Size Transcatheter Heart Valves

Bar graphs compare the incidence and severity of A) paravalvular regurgitation (PVR) and B) prosthesis-patient mismatch (PPM). PPM (severe PPM: 4.9% vs 1.5%, moderate PPM: 29.2% vs 10.8%; P < 0.001) and PVR were more frequently observed in patients treated with a 20-mm transcatheter heart valve (mild PVR: 34.6% vs 23.5%, ≥ moderate PVR: 1.8% vs 1.5%; P < 0.001).

Follow-up echocardiographic data at 1 year was available in 775 of 944 alive patients (82.1%). At the 1-year follow-up, the EOA was decreased from the postprocedure values in both groups (Figure 2). In the 20-mm THV group, the EOA was 1.15 ± 0.28 cm² at 1 year vs 1.28 ± 0.29 cm² postprocedure, with a difference of −0.10 ± 0.28 cm² (Student’s paired t-test P < 0.001). In the standard-size THV group, the EOA was 1.51 ± 0.36 cm² at 1 year vs 1.56 ± 0.38 cm² postprocedure, with a difference of −0.05 ± 0.37 cm² (Student’s paired t-test P < 0.001). The mean pressure gradient significantly increased at 1 year compared with postprocedure in the 20-mm THV group (18.8 mm Hg at 1 year vs 16.9 mm Hg postprocedure, difference +1.6 ± 6.6 mm Hg; Student’s paired t-test P = 0.001), but it remained stable in the standard-size THV group (12.6 ± 5.2 mm Hg at 1 year vs 12.5 ± 4.9 mm Hg postprocedure, difference 0.0 ± 4.6 mm Hg; Student’s paired t-test P = 0.883) (Figure 2).

Figure 2.

Temporal Changes in Echocardiographic Forward Hemodynamics

Line graphs display temporal changes in echocardiographic forward hemodynamics for small-size (red) and standard-size transcatheter heart valves (THVs) (blue). (A) Mean effective orifice area and (B) transprosthetic mean pressure gradient are compared immediately postprocedure and at 1-year follow-up. In the 20-mm THV group, the effective orifice area was 1.15 ± 0.28 cm² at 1 year vs 1.28 ± 0.29 cm² postprocedure, with a difference of -0.10 ± 0.28 cm² (Student’s paired t-test P < 0.001). In the standard-size THV group, the effective orifice area was 1.51 ± 0.36 cm² at 1 year vs 1.56 ± 0.38 cm² postprocedure, with a difference of -0.05 ± 0.37 cm² (Student’s paired t-test P < 0.001). The mean pressure gradient significantly increased at 1 year compared with postprocedure in the 20-mm THV group (18.8 mm Hg at 1 year vs 16.9 mm Hg postprocedure, difference +1.6 ± 6.6 mm Hg; Student’s paired t-test P = 0.001), while it remained stable in the standard-size THV group (12.6 ± 5.2 mm Hg at 1 year vs 12.5 ± 4.9 mm Hg postprocedure, difference 0.0 ± 4.6 mm Hg; Student’s paired t-test P = 0.883). THV = transcatheter heart valve.

Clinical outcomes

The average follow-up duration for patients who were alive was 955 ± 512 days, while the average time to death was 584 ± 543 days. Throughout the study period, there were no significant differences in all-cause mortality, cardiovascular mortality, or rehospitalization caused by heart failure between the groups (Table 3). Kaplan-Meier curves depicting the clinical outcomes according to the group are presented in Central Illustration. At 5 years, all-cause mortality occurred in 34.2% of the 20-mm THV group and 38.0% of the standard-size THV group, and cardiovascular mortality was 16.1% and 17.1% in these groups, respectively (all-cause mortality HR: 1.01; 95% CI: 0.74-1.37; P = 0.970, cardiovascular mortality HR: 1.20; 95% CI: 0.73-1.96; P = 0.475). The incidence of rehospitalization because of heart failure was 15.2% in patients with a 20-mm THV and 16.3% in those with a standard-size THV (HR: 0.81; 95% CI: 0.50-1.29; P = 0.371). Sensitivity analysis using IPTW also demonstrated no significant differences between the groups in clinical outcomes (all-cause death: HR: 0.61; 95% CI: 0.33-1.13; P = 0.115, cardiovascular mortality: HR: 0.78; 95% CI: 0.37-1.64; P = 0.506, rehospitalization caused by heart failure: HR: 0.46; 95% CI: 0.20-1.08; P = 0.073). Additionally, sensitivity analysis focusing on the newer-generation balloon-expandable THV (n = 948) yielded HRs for all-cause mortality (HR: 1.00; 95% CI: 0.71-1.42; P = 0.993), cardiovascular mortality (HR: 1.26; 95% CI: 0.72-2.20; P = 0.427), and heart failure rehospitalization (HR: 0.68; 95% CI: 0.39-1.17; P = 0.164) that were qualitatively consistent with the overall findings.

Table 3.

5-Year Clinical Outcomes in the Propensity-Matched Cohort

	Small THV (n = 273)	Standard THV (n = 819)	Small vs Standard
			HR (95% CI)	P Value
All-cause mortality	53 (34.2)	165 (38.0)	1.01 (0.74-1.37)	0.970
Cardiovascular mortality	22 (16.1)	56 (17.1)	1.20 (0.73-1.96)	0.475
Heart failure rehospitalization	22 (15.2)	80 (16.3)	0.81 (0.50-1.29)	0.371

Values are n (%) unless otherwise indicated.

THV = transcatheter heart valve.

Central Illustration.

5-Year Outcomes of 20-mm vs Standard-Size Balloon-Expandable Transcatheter Heart Valves

Kaplan-Meier curves show 5-year event-free survival rates for patients with 20-mm (red) vs standard-size balloon-expandable transcatheter heart valves (blue) from the OCEAN-TAVI registry. At 5 years, all-cause mortality occurred in 34.2% of the 20-mm transcatheter heart valve group and 38.0% of the standard-size transcatheter heart valve group, and cardiovascular mortality was 16.1% and 17.1% in these groups, respectively (all-cause mortality HR: 1.01; 95% CI: 0.74-1.37; P = 0.970, cardiovascular mortality HR: 1.20; 95% CI: 0.73-1.96; P = 0.475). The incidence of rehospitalization because of heart failure was 15.2% in patients with a 20-mm transcatheter heart valve and 16.3% in those with a standard-size transcatheter heart valve (HR: 0.81; 95% CI: 0.50-1.29; P = 0.371). TAVR = transcatheter aortic valve replacement.

Kaplan-Meier curves in the prematching cohort are presented in Supplemental Figure 1. Kaplan-Meier curves for the 3 valve size groups (20, 23, and ≥26 mm) are presented in Supplemental Figure 2.

Discussion

In this nationwide multicenter registry-based cohort study, the extremely small 20-mm THV was used in about 4% of TAVR procedures. The salient findings from the present analysis, comparing the 20-mm THV with the standard-size THV, are summarized as follows:

• •Patients receiving the 20-mm THV were predominantly petite women, exhibiting a slightly higher degree of frailty compared with those receiving a standard-size THV.
• •The 20-mm THV was associated with less-favorable forward hemodynamics, as evidenced by a smaller EOA, a higher mean pressure gradient, increased incidence of PPM, a higher occurrence of residual gradients ≥20 mm Hg, and increased incidence of mild or greater PVR compared with the standard-size THV, despite being more frequently treated with postdilation.
• •At the 1-year follow-up, echocardiographic assessments showed an increase in mean pressure gradients in the 20-mm THV group, unlike the stability observed in these parameters in the standard-size THV group.
• •Nevertheless, up to the 5-year follow-up, there was no discernible signal of increased mortality or heart failure rehospitalization risk in patients with a 20-mm THV compared to those with a standard-size THV.

Subsequent to the initial introduction of TAVR, the 20-mm THV was introduced as a key addition to the SAPIEN balloon-expandable THV series, specifically designed to address the needs of patients with extremely small aortic annuli.¹ However, despite the rapid accumulation of clinical evidence supporting TAVR, data on this specific valve size remains limited, mainly because of the rarity of patients requiring such small valves.^2,6,9 The general preference for self-expanding THVs with larger EOAs in cases of small annuli further curtails the use of the balloon-expandable 20-mm THV.⁴ Consequently, this valve size has been employed in only about 2% of TAVR procedures in the United States.⁹ In the PARTNER III (Placement of AoRTic TraNscathetER Valve Trial III) trial, a pivotal randomized controlled trial, only 11 patients received the 20-mm balloon-expandable THV, underscoring the scarcity of data on this small device.⁶

Early clinical feasibility and inferior echocardiographic outcomes of the balloon-expandable 20-mm THV have been documented in several observational studies, including our registry, aligning with the findings of the present study.² An intriguing aspect of this study was the observed higher incidence of mild PVR in the 20-mm THV group compared with the standard-size THV group. The underlying cause of this observation remains a matter of speculation; however, it may, at least in part, be attributed to the smaller oversizing rate, a natural consequence of utilizing the smallest available device.¹⁰

Clinical outcomes up to 1 year were previously reported from the Society of Thoracic Surgeons (STS)/American College of Cardiology (ACC) Transcatheter Valve Therapy (TVT) Registry.⁹ Within this registry, the 20-mm THV was linked to a higher incidence of severe PPM (21.5% vs 9.7%; P < 0.0001); yet, it exhibited comparable clinical outcomes up to 1-year follow-up, including all-cause mortality (13.0% vs 12.7%; P = 0.72), when compared with a propensity-matched cohort treated with ≥23-mm THVs. Despite keen interest in understanding the long-term implications of the increased PPM rates and higher echocardiographic gradients associated with the 20-mm THV, longer-term data beyond 1 year have been limited. Thus, our study makes a significant contribution by providing additional long-term data up to 5 years, enriching the current understanding in this area of research.

In this study, despite noting inferior initial hemodynamics and a trend toward increased pressure gradients at 1 year with the 20-mm THV, no signs of divergence in clinical outcomes were observed at the 5-year mark. It is uncertain whether our findings indicate a limited impact of PPM and mild PVR on long-term clinical outcomes, or if unrecognized confounding factors have diluted the effects of PPM and mild PVR.^4,11 The influence of PPM and mild PVR on outcomes following TAVR continues to be a contentious issue in the Published reports.11, 12, 13, 14 Nevertheless, these findings foster optimism regarding the longer-term clinical safety of this extremely small THV, and may encourage the use of this device in patients with small annuli. Consistent with the findings of this study, the long-term safety of ≤20-mm bioprostheses has been sporadically reported in surgical series15, 16, 17, 18 Currently, there is no clear evidence linking small bioprostheses to early bioprosthetic degeneration or thrombosis. However, the observed higher prevalence of PPM and residual gradients, along with the trend toward increased gradients over time, strongly suggest the need for careful and continued follow-up and investigation regarding changes in hemodynamics, thrombosis, and degeneration in longer-term echocardiographic follow-ups.¹⁹

Study limitations

To our knowledge, our study represents the first to evaluate long-term outcomes beyond 1 year for the small 20-mm THV in comparison with standard-size THVs. Several limitations of this study should be acknowledged. First, as an observational cohort study, our findings may be influenced by unmeasured variables and should be interpreted cautiously. Despite employing sophisticated statistical methods, the potential for bias because of such confounding factors cannot be entirely eliminated. Second, while echocardiographic data was systematically collected, it was not adjudicated by a core laboratory. Furthermore, it is recognized that echocardiography can frequently overestimate transprosthetic pressure gradients, an effect that may be more pronounced in smaller-size balloon-expandable THVs.²⁰ Ideally, hemodynamic comparison would benefit from invasive measurements to circumvent this limitation. Third, although bioprosthetic thrombosis and early degeneration, as well as changes in hemodynamics over time beyond 1 year, are important outcomes, comprehensive data of these outcomes was not available in the current data set and thus could not be assessed in this study. Fourth, because of propensity score matching, the majority of the comparator valve sizes used were 23-mm THVs. However, sensitivity analysis with 3 valve size groups (20, 23, and ≥26 mm) demonstrated similar outcomes among these groups, reinforcing the robustness of our results. Finally, although our cohort reflects the general TAVR population in Japan, with a mean age of 85 years, these results may not be generalizable to younger populations with longer life expectancies and greater exercise capacities.

Conclusions

This extensive registry-based study indicates that the initially observed inferior hemodynamics and the progressive increase in gradients associated with the 20-mm THV do not translate into heightened long-term mortality or heart failure rehospitalization risks. This finding underscores the potential viability of this device option in elderly patients with extremely small annuli.

Funding Support and Author Disclosures

The OCEAN-TAVI registry is supported by Edwards Lifesciences, Medtronic, Boston Scientific, Abbott Medical, and Daiichi-Sankyo. Dr Izumo is a screening proctor for Edwards Lifesciences. Drs Shirai, Watanabe, Tada, Yamamoto, and Hayashida, are clinical proctors for Edwards Lifesciences, Abbott Medical, and Medtronic. Drs Naganuma, Ueno, Takagi, and Mizutani are clinical proctors for Edwards Lifesciences and Medtronic. Drs Ohno, Nishina, Asami, and Yashima are clinical proctors for Medtronic. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.