Abstract
Background
Effective orifice area (EOA) is flow dependent. However, established methods for the assessment of predicted prosthesis-patient mismatch (PPM) do not consider flow status and therefore may underestimate the rate and impact of PPM in patients with abnormal flow status. This study aimed to investigate the clinical impact of flow status-based predicted PPM in patients undergoing transcatheter aortic valve replacement (TAVR).
Methods
Patients undergoing TAVR in a prospective TAVR registry were stratified by the presence of moderate or severe PPM (EOA index to body surface area [EOAi]: 0.65-0.85 or ≤0.65 and 0.55-0.70 or ≤0.55 cm 2 /m 2 if obese). PPM was defined according to echocardiographically measured EOAi (measured PPM) or predicted or flow status-based predicted EOAi. Predicted EOAs were based on reference values of EOA for each valve generation and size (predicted PPM THV ) or native aortic annulus dimension (predicted PPM CT ).
Results
Among 1510 patients included (August 2007-June 2022), rates of moderate or severe PPM differed according to method of assessment: 27.0 and 8.7% according to measured PPM, 11.3 and 1.2% according to predicted PPM THV , 12.0 and 0.1% according to PPM CT , 21.6 and 0.2% according to flow status-based predicted PPM THV , and 25.1 and 0.4% according to flow status-based predicted PPM CT . Five-year mortality was comparable in patients with and without flow status-based predicted PPM defined by either method. These results were consistent when patients were stratified by flow status.
Conclusions
Rates of PPM differ considerably when flow status is considered. There was no consistent signal of increased risk of adverse events up to 5 years in patients with flow status-based predicted PPM.
Clinical Trial Registration
Highlights
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In the assessment of prosthesis-patient mismatch (PPM) after transcatheter aortic valve replacement, the use of predicted vs. measured effective orifice area results in a lower estimate of PPM frequency.
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Consideration of flow status significantly recategorized the severity of PPM.
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Flow status-based predicted PPM was not associated with an increased risk of adverse events up to 5 years of follow-up irrespective of flow status.
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Further studies are warranted to optimize accurate assessment of bioprosthetic hemodynamics and to evaluate the impact of PPM on long-term clinical outcomes after transcatheter aortic valve replacement.
Introduction
Prosthesis-patient mismatch (PPM) is a condition of nonstructural bioprosthetic valve dysfunction in which the effective orifice area (EOA) of a normally functioning prosthesis is small relative to the patient’s body surface area (BSA), resulting in an increased transprosthetic pressure gradient. In surgical series, PPM is an established predictor of adverse clinical outcomes. In transcatheter aortic valve replacement [TAVR] populations, the clinical impact of PPM remains controversial due to differences in the methods used to determine PPM. Historically, PPM in the TAVR population has been defined using EOA measured directly by transthoracic echocardiography (measured PPM). , Recent evidence suggests that predicted EOA, calculated by dividing the reference EOA based on prosthesis model and size of the native aortic annulus dimension, defines PPM more specifically compared to measured EOA and therefore may be more useful in assessing its impact on clinical outcomes. However, standard predicted EOA does not take flow variability into account and may therefore distort PPM assessment in patients with reduced flow. Recently, Akinmolayemi and colleagues proposed new reference values of predicted EOA according to flow status (flow status-based EOA) based on data from the PARTNER trials and registry. The clinical relevance of PPM based on flow status-based EOA (flowstatus-based predicted PPM) has not been evaluated so far. The present study aimed to systematically evaluate the frequency and clinical impact of flow status-based predicted PPM in a prospective TAVR registry.
Methods
Study Design and Population
The Bern TAVI registry, part of the nationwide SwissTAVI registry (registered at clinicaltrials.gov with NCT01368250 ), is a prospective TAVR registry enrolling consecutive patients undergoing TAVR for severe, symptomatic aortic stenosis at Bern University Hospital, Switzerland. The present analysis included patients who underwent TAVR with balloon-expandable devices (SAPIEN XT, SAPIEN 3, SAPIEN 3 Ultra [Edwards Lifesciences, Irvine, California]) between August 2007 and June 2022. For the purpose of the present study, patients who underwent intervention but had no device implanted, who were treated with nonstudy devices, or patients with incomplete information for the assessment of PPM (body mass index [BMI], BSA, measured EOA, or stroke volume [SV] indexed to BSA [SVI] at discharge) were excluded. The registry was approved by the Bern ethics committee, and patients provided written informed consent to participate.
Definition of PPM
PPM was classified as no, moderate, or severe PPM on the basis of EOA indexed to BSA (EOAi) according to the Valve Academic Research Consortium (VARC)-3 definitions. For patients with BMI <30 kg/m 2 , no PPM was defined as EOAi >0.85 cm 2 /m 2 , moderate PPM as EOAi >0.65 and ≤ 0.85 cm 2 /m 2 , and severe PPM as EOAi ≤0.65 cm 2 /m 2 . For patients with BMI ≥30 kg/m 2 , no PPM was defined as EOAi >0.70 cm 2 /m 2 , moderate as EOAi >0.55 and ≤ 0.70 cm 2 /m 2 , and severe PPM as EOAi ≤0.55 cm 2 /m 2 .
Assessment of EOA
Measured and predicted EOA were assessed as previously described. Measured EOA was calculated by the continuity equation using the left ventricular stroke volume, derived as the outer-to-outer border of the stented valve, multiplied by the pulsed-wave Doppler time-velocity integral of flow at that location. , Predicted EOA was based on the reference values of EOA indicated by the published data for each size and generation of balloon-expandable valve implanted (predicted EOA THV ) or on the reference values of EOA derived from aortic annulus dimension measured by preprocedural computed tomography (CT) (predicted EOA CT ). The reference values for predicted EOA were derived from published data, which were calculated using data from pooled cohorts of the randomized clinical trials. For the assessment of flow status-based predicted EOA, patients were stratified by post-TAVR flow status. Flow status was determined by SVI at discharge (low flow; SVI <35 mL/m 2 and normal flow; SVI ≥35 mL/m 2 ). The published normal reference values of EOA for each balloon-expandable device size and generation (flow status-based predicted EOA THV ) or native aortic annulus area (flow status-based predicted EOA CT ) were then applied ( Supplementary Tables 1 and 2 ). The reference values of predicted and flow status-based predicted EOA CT were used in patients who underwent TAVR with SAPIEN 3/3 Ultra. Preprocedural CT examinations and post-TAVR echocardiography were independently re-evaluated by dedicated imaging specialists, and the measurements were integrated into the database. ,
Data Collection and Clinical Endpoints
All baseline clinical, procedural, and follow-up data were prospectively recorded in a dedicated database held at the Clinical Trials Unit at the University of Bern, Switzerland. In the SwissTAVI registry, regular follow-up is standardized at 30 days and at 1, 5, and 10 years. Clinical follow-up data were obtained by standardized interviews, documentation from referring physicians, and hospital discharge summaries. All adverse events were systematically collected and adjudicated by an independent clinical events committee based on the VARC definitions. , An independent analyst at the Clinical Trials Unit is responsible for central data monitoring to verify the completeness and accuracy of the data and for statistical analysis. The outcomes of interest in the present study included all-cause and cardiovascular mortality, structural valve deterioration, and unplanned repeat aortic valve intervention at 1 and 5 years after TAVR. Structural valve deterioration was defined according to the VARC criteria between 2007 and 2013 and has since been defined according to the VARC-2 criteria. , , Unplanned repeat aortic valve intervention was defined as a composite of valve-in-valve procedure, balloon valvuloplasty, surgical revision, and paravalvular leak closure.
Statistical Analysis
Categorical variables are presented as frequencies and percentages, and the differences between groups were evaluated with the chi-square test or Fisher exact test. Continuous variables are presented as mean values ± SD and compared between groups using Student’s t-test. Risk ratios with 95% CIs from Poisson regressions were provided where appropriate. Cumulative incidence curves were constructed using the Kaplan-Meier method. Cox proportional hazards models were used to calculate hazard ratios and 95% CIs for the clinical outcomes. Multivariable adjustment was performed with predefined baseline variables potentially related to clinical outcomes including age, sex, and the Society of Thoracic Surgeons Predicted Risk of Mortality. The Fine and Gray method was used to model the cumulative incidence function of the outcomes of interest in the present study and to determine the subdistribution hazard ratio under competing risk with death, or in the case of cardiovascular death under competing risk with noncardiovascular death. , All statistical tests were two-sided, and p -values of <0.05 were considered significant. Statistical analyses were performed using Stata 17 (StataCorp, College Station, TX).
Results
Study Population and Frequency of PPM
Among 3588 patients enrolled in the institutional TAVR registry, 1510 and 1368 patients were included in the analysis of flow status-based predicted PPM defined by flow status-based predicted EOA THV (PPM THV ) and flow status-based predicted PPM defined by flow status-based predicted EOA CT (PPM CT ), respectively ( Figure 1 ). Normal and low flow were present in 857 (56.8%) and 653 (43.2%) patients, respectively, at discharge after TAVR. The frequencies of moderate and severe PPM defined by measured EOA were 30.1 and 8.3% in the overall population, 18.7 and 2.8% in patients with normal flow, and 45 and 15.6% in patients with low flow. The frequencies of moderate and severe PPM were lower using predicted EOA THV (15 and 0% in the overall population, 15.4 and 0% in patients with normal flow, and 14.4 and 0% in patients with low flow) and predicted EOA CT (17.4 and 0.1% in the overall population, 18.7 and 0% in patients with normal flow, and 15.8 and 0.2% in patients with low flow). When flow status-based predicted EOA was applied, the frequency of moderate or severe predicted PPM substantially increased in patients with low flow status (37.2 and 0.5% for predicted PPM THV and 37 and 0.8% for predicted PPM CT ), whereas the frequencies decreased in patients with normal flow (9.7 and 0% for predicted PPM THV and 16 and 0% for predicted PPM CT ) ( Table 1 and Figure 2 ).
| All patients (N = 1510) | Patients with normal flow (N = 857) | Patients with low flow (N = 653) | |
|---|---|---|---|
| Measured PPM | |||
| Measured EOAi (cm 2 /m 2 ) | 0.93 ± 0.28 | 1.04 ± 0.29 | 0.79 ± 0.20 |
| Moderate or severe measured PPM, n (%) | 580 (38.4%) | 184 (21.5%) | 396 (60.6%) |
| Moderate measured PPM, n (%) | 454 (30.1%) | 160 (18.7%) | 294 (45.0%) |
| Severe measured PPM, n (%) | 126 (8.3%) | 24 (2.8%) | 102 (15.6%) |
| Predicted PPM THV | |||
| Predicted EOAi THV (cm 2 /m 2 ) | 0.92 ± 0.12 | 0.92 ± 0.12 | 0.91 ± 0.12 |
| Moderate or severe predicted PPM THV , n (%) | 226 (15.0%) | 132 (15.4%) | 94 (14.4%) |
| Moderate predicted PPM THV , n (%) | 226 (15.0%) | 132 (15.4%) | 94 (14.4%) |
| Severe predicted PPM THV , n (%) | 0 | 0 | 0 |
| Flow status-based predicted PPM THV | |||
| Flow status-based predicted EOAi THV (cm 2 /m 2 ) | 0.91 ± 0.14 | 0.97 ± 0.13 | 0.84 ± 0.11 |
| Moderate or severe flow status-based predicted PPM THV , n (%) | 329 (21.8%) | 83 (9.7%) | 246 (37.7%) |
| Moderate flow status-based predicted PPM THV , n (%) | 326 (21.6%) | 83 (9.7%) | 243 (37.2%) |
| Severe flow status-based predicted PPM THV , n (%) | 3 (0.2%) | 0 | 3 (0.5%) |
| Predicted PPM CT | N = 1368 | N = 779 | N = 589 |
| Predicted EOAi CT (cm 2 /m 2 ) | 0.91 ± 0.12 | 0.92 ± 0.12 | 0.90 ± 0.12 |
| Moderate or severe predicted PPM CT , n (%) | 240 (17.5%) | 146 (18.7%) | 94 (16.0%) |
| Moderate predicted PPM CT , n (%) | 239 (17.5%) | 146 (18.7%) | 93 (15.8%) |
| Severe predicted PPM CT , n (%) | 1 (0.1%) | 0 | 1 (0.2%) |
| Flow status-based predicted PPM CT | |||
| Flow status-based predicted EOAi CT (cm 2 /m 2 ) | 0.90 ± 0.14 | 0.95 ± 0.14 | 0.84 ± 0.11 |
| Moderate or severe flow status-based predicted PPM CT , n (%) | 348 (25.4%) | 125 (16.0%) | 223 (37.9%) |
| Moderate flow status-based predicted PPM CT , n (%) | 343 (25.1%) | 125 (16.0%) | 218 (37.0%) |
| Severe flow status-based predicted PPM CT , n (%) | 5 (0.4%) | 0 | 5 (0.8%) |
Baseline and procedural characteristics according to flow status-based predicted PPM are shown in Table 2 . TAVR was performed by transfemoral access in more than 90% of patients with no difference between groups. Patients with flow status-based predicted PPM were younger and had a lower prevalence of BMI ≥30 kg/m 2 , despite a higher mean BMI overall. Indexed aortic valve area was smaller in patients with flow status-based predicted PPM than in those without PPM. Patients with moderate or severe flow status-based predicted PPM were more likely to have a transcatheter heart valve (THV) size ≤23 mm compared with those without PPM. These results were consistent when patients were stratified into normal and low flow status after TAVR ( Supplementary Tables 3 and 4 ).
| Flow status-based predicted PPM THV | Flow status-based predicted PPM CT | |||||
|---|---|---|---|---|---|---|
| No PPM (N = 1181) | Moderate or severe PPM (N = 329) | p -value | No PPM (N = 1020) | Moderate or severe PPM (N = 348) | p -value | |
| Age, y | 81.5 ± 6.5 | 80.6 ± 7.0 | 0.028 | 81.5 ± 6.5 | 80.5 ± 6.7 | 0.009 |
| Female, n (%) | 433 (36.7%) | 129 (39.2%) | 0.402 | 378 (37.1%) | 130 (37.4%) | 0.949 |
| Body mass index, kg/m 2 | 26.5 ± 5.0 | 28.7 ± 5.4 | <0.001 | 26.4 ± 5.0 | 28.7 ± 5.4 | <0.001 |
| Body mass index ≥30 kg/m 2 , n (%) | 308 (26.1%) | 62 (18.8%) | 0.007 | 265 (26.0%) | 69 (19.8%) | 0.021 |
| Body surface area, m 2 | 1.9 ± 0.2 | 2.0 ± 0.2 | <0.001 | 1.9 ± 0.2 | 2.0 ± 0.2 | <0.001 |
| STS-PROM, % | 4.7 ± 3.6 | 4.5 ± 3.8 | 0.372 | 4.6 ± 3.5 | 4.2 ± 3.6 | 0.086 |
| NYHA III or IV, n (%) | 689 (58.4%) | 205 (62.3%) | 0.205 | 603 (59.2%) | 195 (56.0%) | 0.314 |
| TAVR for degenerative prosthesis, n (%) | 22 (1.9%) | 9 (2.7%) | 0.377 | 15 (1.5%) | 7 (2.0%) | 0.466 |
| Concomitant diseases | ||||||
| Hypertension, n (%) | 1033 (87.5%) | 300 (91.2%) | 0.066 | 888 (87.1%) | 319 (91.7%) | 0.021 |
| Diabetes mellitus, n (%) | 322 (27.3%) | 105 (31.9%) | 0.111 | 267 (26.2%) | 108 (31.0%) | 0.082 |
| Renal failure (eGFR <60 mL/min/1.73 m 2 ), n (%) | 740 (62.7%) | 174 (52.9%) | 0.001 | 630 (61.8%) | 172 (49.4%) | <0.001 |
| Coronary artery disease, n (%) | 711 (60.2%) | 185 (56.2%) | 0.205 | 613 (60.1%) | 198 (56.9%) | 0.312 |
| Previous history | ||||||
| Atrial fibrillation, n (%) | 375 (31.8%) | 118 (35.9%) | 0.163 | 321 (31.5%) | 118 (33.9%) | 0.425 |
| Peripheral artery disease, n (%) | 140 (11.9%) | 44 (13.4%) | 0.447 | 120 (11.8%) | 43 (12.4%) | 0.774 |
| Baseline echocardiography | ||||||
| Indexed aortic valve area, cm 2 /m 2 | 0.28 ± 0.09 | 0.25 ± 0.08 | <0.001 | 0.28 ± 0.08 | 0.27 ± 0.08 | 0.050 |
| Mean aortic valve gradient, mmHg | 39.5 ± 15.7 | 39.1 ± 14.9 | 0.693 | 39.7 ± 15.8 | 39.5 ± 15.1 | 0.822 |
| Left ventricular ejection fraction, % | 55.2 ± 13.5 | 54.4 ± 14.1 | 0.373 | 54.8 ± 13.9 | 56.8 ± 12.0 | 0.017 |
| Moderate or severe aortic regurgitation, n (%) | 100 (8.5%) | 32 (9.8%) | 0.507 | 86 (8.4%) | 33 (9.5%) | 0.581 |
| Moderate or severe mitral regurgitation, n (%) | 172 (16.8%) | 57 (20.9%) | 0.129 | 147 (16.9%) | 44 (14.8%) | 0.467 |
| Moderate or severe tricuspid regurgitation, n (%) | 100 (10.4%) | 35 (14.5%) | 0.087 | 82 (10.0%) | 34 (12.5%) | 0.258 |
| Procedural characteristics | ||||||
| General anesthesia, n (%) | 204 (17.3%) | 67 (20.4%) | 0.195 | 169 (16.6%) | 61 (17.5%) | 0.679 |
| Femoral main access site, n (%) | 1082 (91.6%) | 303 (92.1%) | 0.822 | 943 (92.5%) | 324 (93.1%) | 0.812 |
| Valve size, mm | 26.4 ± 2.1 | 24.8 ± 1.9 | <0.001 | 26.5 ± 2.1 | 25.0 ± 1.9 | <0.001 |
| Valve size ≤23 mm, n (%) | 204 (17.3%) | 150 (45.6%) | <0.001 | 174 (17.1%) | 147 (42.2%) | <0.001 |
| Predilations, n (%) | 679 (57.5%) | 175 (53.4%) | 0.186 | 572 (56.1%) | 172 (49.4%) | 0.034 |
| Postdilations, n (%) | 149 (12.6%) | 54 (16.4%) | 0.082 | 135 (13.2%) | 52 (14.9%) | 0.417 |
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