- Email: [email protected]
Predictors of Paravalvular Regurgitation After Transcatheter Aortic Valve Implantation for Aortic Stenosis Using New-Generation Balloon-Expandable SAPIEN 3
Predictors of Paravalvular Regurgitation After Transcatheter Aortic Valve Implantation for Aortic Stenosis Using New-Generation Balloon-Expandable SAPIEN 3 Hidehiro Kaneko, MD, PhDa, Frank Hoelschermann, MDa, Grit Tambor, MDa, Sung-Han Yoon, MDb, Michael Neuss, MDa, and Christian Butter, MDa,* Paravalvular regurgitation (PVR) is a common and serious complication after transcatheter aortic valve implantation (TAVI). New-generation balloon-expandable SAPIEN 3 has an outer sealing skirt to minimize PVR. However, the predictors of PVR after SAPIEN 3 transcatheter heart valve (THV) implantation have not been well investigated. We sought to clarify the determinants of PVR after TAVI using SAPIEN 3 with quantitative multidetector computed tomography (MDCT) assessment. This study analyzed 281 patients with severe symptomatic aortic stenosis who underwent TAVI using SAPIEN 3. Quantitative assessment of aortic root dimensions and calcium volume for leaflet, annulus, and left ventricular outflow tract were retrospectively performed with MDCT. MDCT nominal area oversizing was calculated using the following formula: % oversizing [ (THV nominal area/ MDCT derived annular area L 1) 3 100. Logistic regression analysis was performed to determine the predictors of PVR greater than or equal to mild. PVR greater than or equal to mild was observed in 19% (53 of 281). Quantity and asymmetry of aortic valve calcium of annulus, left ventricular outflow tract, and leaflet were associated with higher incidence of PVR greater than or equal to mild, except leaflet asymmetry. Lower percentage of THV oversizing was also associated with PVR. Multivariable logistic regression analysis showed that larger calcification volume of annulus and lower percentage of THV oversizing were independent predictors of PVR greater than or equal to mild. These results suggest that prosthesis/annulus incongruence and aortic annulus calcification predicted PVR greater than or equal to mild after TAVI using SAPIEN 3. Ó 2016 Elsevier Inc. All rights reserved. (Am J Cardiol 2017;119:618e622) Transcatheter aortic valve implantation (TAVI) is an effective therapeutic option for patients with severe aortic stenosis (AS) with high conventional surgical risk.1,2 Despite the continuous development of this procedure, paravalvular regurgitation (PVR) still remains a common complication of TAVI and is associated with higher mortality.3e5 To overcome this, new-generation balloonexpandable SAPIEN 3 (Edwards Lifesciences, Irvine, California)6 has been developed featuring a higher metal frame with an outer skirt designed to avoid PVR. The incidence of PVR after SAPIEN 3 implantation was lower than that of after TAVI using early generation balloon-expandable prosthesis.7 In contrast, even after SAPIEN 3 implantation, PVR might affect the survival after TAVI.8 Because SAPIEN 3 is currently regarded as one of the standard
a Heart Center Brandenburg, Department of Cardiology, Medical School Brandenburg, Bernau, Germany; and bDepartment of Cardiology, Cedars Sinai Medical Center, Los Angeles, California. Manuscript received July 23, 2016; revised manuscript received and accepted October 25, 2016. Drs Kaneko and Hoelschermann contributed equally (share first authorship). This work was supported by the Japan Society for the Promotion of Science (Hidehiro Kaneko). See page 621 for disclosure information. *Corresponding author: Tel: þ49-3338-694-610; fax: þ49-3338-694644. E-mail address: [email protected] (C. Butter).
0002-9149/16/$ - see front matter Ó 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2016.10.047
devices for TAVI, it is important to clarify the predictors of PVR after SAPIEN 3 implantation. Here, we aimed to clarify the predictors of PVR after TAVI using SAPIEN 3. Methods This study included 281 patients who underwent transfemoral TAVI with a balloon-expandable SAPIEN 3 (Figure 1) due to severe AS in Heart Center Brandenburg (Bernau bei Berlin, Germany) from February 2014 to December 2015. Study patients were required to have undergone both preprocedural multidetector computed tomography (MDCT) and postprocedural transthoracic and/ or transesophageal echocardiography. Aortic stenosis was diagnosed on the basis of the mean transvalvular pressure gradient and aortic valve area, calculated using the continuity equation. The ethical committee of our institute approved the protocols of this study. All patients were informed about specific risks and alternative treatments and they gave informed consent. This study was performed in accordance with the Declaration of Helsinki. PVR was assessed by transthoracic and/or transesophageal echocardiography before hospital discharge according to Valve Academic Research Consortium-2 (VARC-2) definitions.9 Based on VARC2 criteria, we define the degree of PVR mainly according to the circumferential extent of prosthetic valve paravalvular regurgitation (mild: <10%, moderate: 10% to 29%, severe: 30%) (Supplementary Figure 1). www.ajconline.org
Valvular Heart Disease/Predictors of PVR after TAVI using SAPIEN 3
Figure 1. Edwards SAPIEN 3 transcatheter heart valve. New-generation balloon-expandable SAPIEN 3 is designed to reduce PVR by an outer sealing skirt.
Before TAVI, patients underwent cardiac computed tomographic angiography using a 128-slice system (SOMATON ASþ; Siemens, Munich, Germany) with tube voltage of 100 to 120 kV and tube current according to patient size. We performed a single-volume acquisition with prospective electrocardiographic trigger during an inspiratory breathhold. Nonionic contrast agent (Iodixanol) was intravenously injected at a rate of 3.5 ml/s (100 to 120 ml). Images were reconstructed with a slice thickness of 0.75 mm. Aortic annulus measurements were performed using 3mensio Structural Heart software (3mensio Structural Heart, version 7.2; 3mensio Medical Imaging BV, Bilthoven, Netherlands), as previously described.10,11 Briefly, 3-dimensional MDCT aortic annulus measurements included area, perimeter, and minimal and maximal diameter. Aortic root measurements were performed as previously described.12 Aortic root measurements were performed in mid-systole. All observers were blinded to background characteristics and previous measurements. Aortic valve calcium (AVC) was measured using 3mensio Structural Heart software with the thresholds of 850 Hounsfield units.13 Calcium in left, right, and noncoronary cusp was quantified separately using the “Mercedes Benz” tool for localization. For the calcium quantification, the aortic root was separated in the craniocaudal axis along the double-oblique long axis of the aortic root into the following parts: left ventricular outflow tract (LVOT, from 5 mm inferior to annulus plane to annulus plane), annulus (from 2 mm inferior to annulus plane to 3 mm superior to annulus plane), and leaflet (from annulus plane to superior edge of leaflets) (Figure 2), as previously described.11,14 Asymmetry was assessed using the maximum absolute difference in volume scores between any 2 leaflet sectors for each region (DLVOT calcium, Dannulus calcium, and Dleaflet calcium). The nominal external valve area of SAPIEN 3 THV is 409 mm2 (23 mm), 519 mm2 (26 mm), and 649 mm2 (29 mm). The percentage of oversizing was calculated using the following formula: % oversizing ¼ (THV nominal area/ MDCT derived annular area 1) 100.15
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Figure 2. Regions of the aortic valve complex. LVOT region (blue bracket) is defined as the region from 5 mm inferior to annulus plane (orange line) to annular plane. Annulus region (green bracket) is defined as the region from 2 mm inferior to annulus plane to 3 mm superior to annulus plane. Leaflet region (pink bracket) is defined as the region from annulus plane to the superior edge of leaflets.
Categorical and consecutive data regarding patient background were presented as numbers (%) and means SD, respectively. The unpaired t test was used for comparison of consecutive variables. We conducted the univariate and stepwise multivariable logistic regression analysis to identify the predictors for PVR greater than or equal to mild. A probability value of <0.05 was considered to indicate a statistically significant difference. We performed statistical analyses using SPSS (SPSS Inc., Chicago, Illinois), version 19.0 software. Results Table 1 summarized the characteristics of study patients. Mean age was 80 6 years and 53% of patients were men. Mean logistic euroSCORE was 15 11%. Left ventricular ejection fraction was 51 13% on average. Mean aortic valve area and pressure gradient were 0.8 0.2 cm2 and 48 16 mm Hg, respectively. The following sizes of SAPIEN 3 THV were implanted: 23 mm in 104 patients (37%), 26 mm in 119 patients (42%), and 29 mm in 58 patients (21%). PVR greater than or equal to mild was seen in 53 patients (19%), mild 38 patients, and moderate 15 patients after TAVI using SAPIEN 3 THV. No patient had severe PVR. Distribution of AVC volume is listed in Table 2. The average total volume of calcium was 21 45 mm3 (LVOT), 42 44 mm3 (annulus), and 330 288 mm3 (leaflet), respectively. Calcium volume by each sector is also listed in Table 2. Table 3 compares calcium volume and asymmetry between patients with and without PVR greater than or equal to mild. Patients with PVR greater than or equal to mild had significantly more calcium and asymmetry than those without in LVOT and annulus. Total calcium volume and D calcium volume in leaflet were seemingly larger in patients with PVR greater than or equal to mild than those without. However, the differences did not reach statistical significance.
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The American Journal of Cardiology (www.ajconline.org)
Table 1 Characteristics of study patients
Table 3 Calcium volume scores (mm3) and asymmetry Total (n ¼ 281)
Variable
80 6 150 (53%) 15 11 110 (39%) 106 (38%) 111 (40%) 35 (13%)
Age (years) Men Logistic euroSCORE (%) Diabetes Mellitus Chronic Kidney Disease Prior Percutaneous Coronary Intervention Prior Coronary Artery Bypass Grafting Echocardiography Left Ventricular Ejection Fraction (%) Mean Pressure Gradient (mmHg) Aortic Valve Area (mm2) AR Moderate Mitral Regurgitation Moderate Tricuspid Regurgitation Moderate SAPIEN 3 Transcatheter Heart Valve (mm) 23 26 29
51 13 48 16 0.8 0.2 21 (8%) 34/242 (12%) 19/196 (7%) 104 (37%) 119 (42%) 58 (21%)
Data are expressed as mean standard deviation, or number (percentage).
Table 2 Distribution of calcium volume Variable
Left
Right
None
Total
21 45 Left Ventricular Outflow 13 36 1.2 5.0 6.4 21 Tract Calcium (mm3) Annular Calcium (mm3) 18 26 7.3 12 17 27 42 44 Leaflet Calcium (mm3) 89 98 87 85 155 155 330 288 Data are expressed as mean standard deviation. Left Ventricular Outflow Tract Calcification, volume of calcification 5 mm inferior to the annulus extending to the level of the annulus; Annulus Calcification, volume of calcification 2 mm inferior to the annulus to 3 mm superior to the annulus; Leaflet Calcification, volume of calcification from annulus plane to superior edge of leaflets.
Percentage of THV oversizing was significantly lower in patients with PVR greater than or equal to mild than those without (3.7 11.5% vs 10.1 12.3%, p ¼ 0.001). Table 4 lists the result of logistic regression analysis. The univariate analysis showed that larger volume of LVOT calcium, D LVOT calcium, annular calcium, D annular calcium, and lower percentage of THV oversizing were associated with the incidence of PVR greater than or equal to mild. The step-wise multivariable analysis including these parameters demonstrated that larger volume of annular calcium and lower percentage of THV oversizing were independently associated with the incidence of PVR greater than or equal to mild. Discussion The principal findings of our study are the following: (1) PVR greater than or equal to mild was seen in 19% of patients who underwent transfemoral TAVI using SAPIEN 3; (2) calcification in all regions of the aortic valve complex and asymmetry in LVOT and annulus predicted PVR greater than or equal to mild; and (3) larger calcium volume in annulus and lower percentage of THV oversizing were
Variable
Left Ventricular Outflow Tract Calcium (mm3) D Left Ventricular Outflow Tract Calcium (mm3) Annular Calcium (mm3) DAnnular Calcium (mm3) Leaflet Calcium (mm3) DLeaflet Calcium (mm3)
Paravalvular Regurgitation No/Trace (n ¼ 228)
Paravalvular Regurgitation Mild (n ¼ 53)
p-Value
15 35
46 67
0.002
13 30
41 61
0.002
0.001 0.002 0.102 0.373
36 22 317 115
37 24 286 113
68 42 389 131
62 41 290 131
Data are expressed as mean standard deviation.
independent determinants of PVR greater than or equal to mild. New-generation balloon-expandable SAPIEN 3 consists of bovine pericardial leaflets sutured to a cobalt chromium frame with the outer skirt (polyethylene terephthalate) to reduce PVR.16 SAPIEN 3 received US Food and Drug Administration approval in June 2015. The initial results were excellent,17,18 and this device is now widely used in the clinical practice because of its superior safety and efficacy. PVR is not only a common complication of TAVI but also associated with increased mortality.5,19e21 Although the incidence of PVR is low after SAPIEN 3 implantation,7,18 PVR still remains as a concern.8 Preceding studies demonstrated that AVC was an important predictor of PVR after TAVI through impairing the appropriate sealing of THV to the aortic annulus and LVOT.19,22e25 Not only volume of AVC but also location of AVC is important and AVC at the aortic wall of each valve cusp was reported to be strongly associated with the occurrence of PVR.22 Furthermore, AVC quantity of annulus, LVOT, and leaflet independently predicted PVR after TAVI using SAPIEN XT.14 However, little was known about the determinants of PVR after new-generation SAPIEN 3 implantation. Regarding PVR after SAPIEN 3 implantation, Yang et al15 demonstrated that AVC might play a role in the development of PVR. However, calcium volume was assessed in a semiquantitative fashion in the study of Yang et al. Therefore, we assessed AVC using quantitative evaluation. In addition, asymmetry of AVC was also analyzed. In line with recent studies,16,18 the incidence of significant PVR was low and approximately 80% of study patients showed none/trace PVR. Patients with PVR greater than or equal to mild had significantly greater calcification and more asymmetry in annulus and LVOT. In contrast, asymmetry in leaflet was comparable between patients with and without PVR greater than or equal to mild. Multivariable logistic regression analysis that larger calcium in annulus was independently associated with the development of PVR, suggesting that calcium in a THV landing zone might be most important in the development of PVR after SAPIEN 3 implantation. As well as larger calcium volume of annulus, lower percentage of THV oversizing was also a predictor of PVR greater
Valvular Heart Disease/Predictors of PVR after TAVI using SAPIEN 3
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Table 4 Determinants of PVR greater than or equal to mild Variable Left Ventricular Outflow Tract Calcium D Left Ventricular Outflow Tract Calcium Annular Calcium DAnnular Calcium Leaflet Calcium DLeaflet Calcium Oversizing of Transcatheter Heart Valve
Univariate OR 1.012 1.014 1.013 1.020 1.001 1.001 0.951
(1.006 (1.007 (1.007 (1.010 (1.000 (0.999 (0.923
e e e e e e e
1.018) 1.021) 1.020) 1.020) 1.002) 1.003) 0.980)
p-Value < < < <
0.001 0.001 0.001 0.001 0.108 0.374 0.001
Multivariable OR
p-Value
1.009 (1.002 e 1.017)
0.018
0.954 (0.926 e 0.984)
0.002
Odds ratios are presented with 95% confidence intervals. OR ¼ odds ratio; PVR ¼ paravalvular regurgitation.
than or equal to mild. Concordant with preceding studies,19,26 prosthesis/annulus incongruence is a main cause of PVR after balloon-expandable prosthesis implantation and selecting the optimal size of THV is essential to minimize the risk of PVR even after SAPIEN 3 implantation. Because SAPIEN 3 cannot be recaptured after deployment, post-dilation is an important therapeutic options for PVR. In this study, we performed post-dilation in 46 patients (16%) to reduce PVR. However, post-dilation is not always effective, and 16 patients (35%) remained PVR greater than or equal to mild after post-dilation. Furthermore, post-dilation is sometimes hesitated in patients with severe calcification in annulus due to fear of annulus rupture. Also from this point of view, assessing the calcification distribution and selecting the optimal size of THV are essential for this procedure. We recognize several limitations in this study. Because of the limited sample size, the statistical power might not be strong enough for any negative data to be conclusive. Number of patients with PVR greater than or equal to moderate was small. Therefore, we used PVR greater than or equal to mild as a primary outcome. Because the incidence of PVR greater than or equal to moderate is very low in the era of SAPIEN 3, the clinical significance of this study is limited to a small number of patients. Annulus region partly overlaps with LVOT and leaflet (Figure 2), and it can affect the analysis. Acknowledgment: The authors thank all staff of the intervention laboratory and the department of radiology in our institute. Disclosures The authors have no conflict of interest for this study. Supplementary Data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j. amjcard.2016.10.047. 1. Leon MB, Smith CR, Mack M, Miller DC, Moses JW, Svensson LG, Tuzcu EM, Webb JG, Fontana GP, Makkar RR, Brown DL, Block PC, Guyton RA, Pichard AD, Bavaria JE, Herrmann HC, Douglas PS, Petersen JL, Akin JJ, Anderson WN, Wang D, Pocock S. Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. N Engl J Med 2010;363:1597e1607.
2. Smith CR, Leon MB, Mack MJ, Miller DC, Moses JW, Svensson LG, Tuzcu EM, Webb JG, Fontana GP, Makkar RR, Williams M, Dewey T, Kapadia S, Babaliaros V, Thourani VH, Corso P, Pichard AD, Bavaria JE, Herrmann HC, Akin JJ, Anderson WN, Wang D, Pocock SJ. Transcatheter versus surgical aortic-valve replacement in high-risk patients. N Engl J Med 2011;364:2187e2198. 3. Hayashida K, Lefevre T, Chevalier B, Hovasse T, Romano M, Garot P, Bouvier E, Farge A, Donzeau-Gouge P, Cormier B, Morice MC. Impact of post-procedural aortic regurgitation on mortality after transcatheter aortic valve implantation. JACC Cardiovasc Interv 2012;5:1247e1256. 4. Kodali SK, Williams MR, Smith CR, Svensson LG, Webb JG, Makkar RR, Fontana GP, Dewey TM, Thourani VH, Pichard AD, Fischbein M, Szeto WY, Lim S, Greason KL, Teirstein PS, Malaisrie SC, Douglas PS, Hahn RT, Whisenant B, Zajarias A, Wang D, Akin JJ, Anderson WN, Leon MB. Two-year outcomes after transcatheter or surgical aortic-valve replacement. N Engl J Med 2012;366:1686e1695. 5. Tamburino C, Capodanno D, Ramondo A, Petronio AS, Ettori F, Santoro G, Klugmann S, Bedogni F, Maisano F, Marzocchi A, Poli A, Antoniucci D, Napodano M, De Carlo M, Fiorina C, Ussia GP. Incidence and predictors of early and late mortality after transcatheter aortic valve implantation in 663 patients with severe aortic stenosis. Circulation 2011;123:299e308. 6. Binder RK, Rodes-Cabau J, Wood DA, Mok M, Leipsic J, De Larochelliere R, Toggweiler S, Dumont E, Freeman M, Willson AB, Webb JG. Transcatheter aortic valve replacement with the SAPIEN 3: a new balloon-expandable transcatheter heart valve. JACC Cardiovasc Interv 2013;6:293e300. 7. Kong WK, van Rosendael PJ, van der Kley F, de Weger A, Kamperidis V, Regeer MV, Marsan NA, Bax JJ, Delgado V. Impact of different iterations of devices and degree of aortic valve calcium on paravalvular regurgitation after transcatheter aortic valve implantation. Am J Cardiol 2016;118:567e571. 8. Leon MB, Smith CR, Mack MJ, Makkar RR, Svensson LG, Kodali SK, Thourani VH, Tuzcu EM, Miller DC, Herrmann HC, Doshi D, Cohen DJ, Pichard AD, Kapadia S, Dewey T, Babaliaros V, Szeto WY, Williams MR, Kereiakes D, Zajarias A, Greason KL, Whisenant BK, Hodson RW, Moses JW, Trento A, Brown DL, Fearon WF, Pibarot P, Hahn RT, Jaber WA, Anderson WN, Alu MC, Webb JG. Transcatheter or surgical aortic-valve replacement in intermediate-risk patients. N Engl J Med 2016;374:1609e1620. 9. Kappetein AP, Head SJ, Genereux P, Piazza N, van Mieghem NM, Blackstone EH, Brott TG, Cohen DJ, Cutlip DE, van Es GA, Hahn RT, Kirtane AJ, Krucoff MW, Kodali S, Mack MJ, Mehran R, RodesCabau J, Vranckx P, Webb JG, Windecker S, Serruys PW, Leon MB. Updated standardized endpoint definitions for transcatheter aortic valve implantation: the Valve Academic Research Consortium-2 consensus document. J Am Coll Cardiol 2012;60:1438e1454. 10. Watanabe Y, Morice MC, Bouvier E, Leong T, Hayashida K, Lefevre T, Hovasse T, Romano M, Chevalier B, Donzeau-Gouge P, Farge A, Cormier B, Garot P. Automated 3-dimensional aortic annular assessment by multidetector computed tomography in transcatheter aortic valve implantation. JACC Cardiovasc Interv 2013;6:955e964. 11. Yoon SH, Ohno Y, Araki M, Barbanti M, Lin MS, Ahn JM, Yang DH, Kim YH, Imme S, Gulino S, Tamburino CI, Sgroi C, Park DW, Kang SJ, Lee SW, Lee CW, Park SW, Muramatsu T, Kao HL, Tamburino C, Park SJ. Comparison of aortic root anatomy and calcification distribution between Asian and Caucasian patients who
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a Heart Center Brandenburg, Department of Cardiology, Medical School Brandenburg, Bernau, Germany; and bDepartment of Cardiology, Cedars Sinai Medical Center, Los Angeles, California. Manuscript received July 23, 2016; revised manuscript received and accepted October 25, 2016. Drs Kaneko and Hoelschermann contributed equally (share first authorship). This work was supported by the Japan Society for the Promotion of Science (Hidehiro Kaneko). See page 621 for disclosure information. *Corresponding author: Tel: þ49-3338-694-610; fax: þ49-3338-694644. E-mail address: [email protected] (C. Butter).
0002-9149/16/$ - see front matter Ó 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2016.10.047
devices for TAVI, it is important to clarify the predictors of PVR after SAPIEN 3 implantation. Here, we aimed to clarify the predictors of PVR after TAVI using SAPIEN 3. Methods This study included 281 patients who underwent transfemoral TAVI with a balloon-expandable SAPIEN 3 (Figure 1) due to severe AS in Heart Center Brandenburg (Bernau bei Berlin, Germany) from February 2014 to December 2015. Study patients were required to have undergone both preprocedural multidetector computed tomography (MDCT) and postprocedural transthoracic and/ or transesophageal echocardiography. Aortic stenosis was diagnosed on the basis of the mean transvalvular pressure gradient and aortic valve area, calculated using the continuity equation. The ethical committee of our institute approved the protocols of this study. All patients were informed about specific risks and alternative treatments and they gave informed consent. This study was performed in accordance with the Declaration of Helsinki. PVR was assessed by transthoracic and/or transesophageal echocardiography before hospital discharge according to Valve Academic Research Consortium-2 (VARC-2) definitions.9 Based on VARC2 criteria, we define the degree of PVR mainly according to the circumferential extent of prosthetic valve paravalvular regurgitation (mild: <10%, moderate: 10% to 29%, severe: 30%) (Supplementary Figure 1). www.ajconline.org
Valvular Heart Disease/Predictors of PVR after TAVI using SAPIEN 3
Figure 1. Edwards SAPIEN 3 transcatheter heart valve. New-generation balloon-expandable SAPIEN 3 is designed to reduce PVR by an outer sealing skirt.
Before TAVI, patients underwent cardiac computed tomographic angiography using a 128-slice system (SOMATON ASþ; Siemens, Munich, Germany) with tube voltage of 100 to 120 kV and tube current according to patient size. We performed a single-volume acquisition with prospective electrocardiographic trigger during an inspiratory breathhold. Nonionic contrast agent (Iodixanol) was intravenously injected at a rate of 3.5 ml/s (100 to 120 ml). Images were reconstructed with a slice thickness of 0.75 mm. Aortic annulus measurements were performed using 3mensio Structural Heart software (3mensio Structural Heart, version 7.2; 3mensio Medical Imaging BV, Bilthoven, Netherlands), as previously described.10,11 Briefly, 3-dimensional MDCT aortic annulus measurements included area, perimeter, and minimal and maximal diameter. Aortic root measurements were performed as previously described.12 Aortic root measurements were performed in mid-systole. All observers were blinded to background characteristics and previous measurements. Aortic valve calcium (AVC) was measured using 3mensio Structural Heart software with the thresholds of 850 Hounsfield units.13 Calcium in left, right, and noncoronary cusp was quantified separately using the “Mercedes Benz” tool for localization. For the calcium quantification, the aortic root was separated in the craniocaudal axis along the double-oblique long axis of the aortic root into the following parts: left ventricular outflow tract (LVOT, from 5 mm inferior to annulus plane to annulus plane), annulus (from 2 mm inferior to annulus plane to 3 mm superior to annulus plane), and leaflet (from annulus plane to superior edge of leaflets) (Figure 2), as previously described.11,14 Asymmetry was assessed using the maximum absolute difference in volume scores between any 2 leaflet sectors for each region (DLVOT calcium, Dannulus calcium, and Dleaflet calcium). The nominal external valve area of SAPIEN 3 THV is 409 mm2 (23 mm), 519 mm2 (26 mm), and 649 mm2 (29 mm). The percentage of oversizing was calculated using the following formula: % oversizing ¼ (THV nominal area/ MDCT derived annular area 1) 100.15
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Figure 2. Regions of the aortic valve complex. LVOT region (blue bracket) is defined as the region from 5 mm inferior to annulus plane (orange line) to annular plane. Annulus region (green bracket) is defined as the region from 2 mm inferior to annulus plane to 3 mm superior to annulus plane. Leaflet region (pink bracket) is defined as the region from annulus plane to the superior edge of leaflets.
Categorical and consecutive data regarding patient background were presented as numbers (%) and means SD, respectively. The unpaired t test was used for comparison of consecutive variables. We conducted the univariate and stepwise multivariable logistic regression analysis to identify the predictors for PVR greater than or equal to mild. A probability value of <0.05 was considered to indicate a statistically significant difference. We performed statistical analyses using SPSS (SPSS Inc., Chicago, Illinois), version 19.0 software. Results Table 1 summarized the characteristics of study patients. Mean age was 80 6 years and 53% of patients were men. Mean logistic euroSCORE was 15 11%. Left ventricular ejection fraction was 51 13% on average. Mean aortic valve area and pressure gradient were 0.8 0.2 cm2 and 48 16 mm Hg, respectively. The following sizes of SAPIEN 3 THV were implanted: 23 mm in 104 patients (37%), 26 mm in 119 patients (42%), and 29 mm in 58 patients (21%). PVR greater than or equal to mild was seen in 53 patients (19%), mild 38 patients, and moderate 15 patients after TAVI using SAPIEN 3 THV. No patient had severe PVR. Distribution of AVC volume is listed in Table 2. The average total volume of calcium was 21 45 mm3 (LVOT), 42 44 mm3 (annulus), and 330 288 mm3 (leaflet), respectively. Calcium volume by each sector is also listed in Table 2. Table 3 compares calcium volume and asymmetry between patients with and without PVR greater than or equal to mild. Patients with PVR greater than or equal to mild had significantly more calcium and asymmetry than those without in LVOT and annulus. Total calcium volume and D calcium volume in leaflet were seemingly larger in patients with PVR greater than or equal to mild than those without. However, the differences did not reach statistical significance.
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Table 1 Characteristics of study patients
Table 3 Calcium volume scores (mm3) and asymmetry Total (n ¼ 281)
Variable
80 6 150 (53%) 15 11 110 (39%) 106 (38%) 111 (40%) 35 (13%)
Age (years) Men Logistic euroSCORE (%) Diabetes Mellitus Chronic Kidney Disease Prior Percutaneous Coronary Intervention Prior Coronary Artery Bypass Grafting Echocardiography Left Ventricular Ejection Fraction (%) Mean Pressure Gradient (mmHg) Aortic Valve Area (mm2) AR Moderate Mitral Regurgitation Moderate Tricuspid Regurgitation Moderate SAPIEN 3 Transcatheter Heart Valve (mm) 23 26 29
51 13 48 16 0.8 0.2 21 (8%) 34/242 (12%) 19/196 (7%) 104 (37%) 119 (42%) 58 (21%)
Data are expressed as mean standard deviation, or number (percentage).
Table 2 Distribution of calcium volume Variable
Left
Right
None
Total
21 45 Left Ventricular Outflow 13 36 1.2 5.0 6.4 21 Tract Calcium (mm3) Annular Calcium (mm3) 18 26 7.3 12 17 27 42 44 Leaflet Calcium (mm3) 89 98 87 85 155 155 330 288 Data are expressed as mean standard deviation. Left Ventricular Outflow Tract Calcification, volume of calcification 5 mm inferior to the annulus extending to the level of the annulus; Annulus Calcification, volume of calcification 2 mm inferior to the annulus to 3 mm superior to the annulus; Leaflet Calcification, volume of calcification from annulus plane to superior edge of leaflets.
Percentage of THV oversizing was significantly lower in patients with PVR greater than or equal to mild than those without (3.7 11.5% vs 10.1 12.3%, p ¼ 0.001). Table 4 lists the result of logistic regression analysis. The univariate analysis showed that larger volume of LVOT calcium, D LVOT calcium, annular calcium, D annular calcium, and lower percentage of THV oversizing were associated with the incidence of PVR greater than or equal to mild. The step-wise multivariable analysis including these parameters demonstrated that larger volume of annular calcium and lower percentage of THV oversizing were independently associated with the incidence of PVR greater than or equal to mild. Discussion The principal findings of our study are the following: (1) PVR greater than or equal to mild was seen in 19% of patients who underwent transfemoral TAVI using SAPIEN 3; (2) calcification in all regions of the aortic valve complex and asymmetry in LVOT and annulus predicted PVR greater than or equal to mild; and (3) larger calcium volume in annulus and lower percentage of THV oversizing were
Variable
Left Ventricular Outflow Tract Calcium (mm3) D Left Ventricular Outflow Tract Calcium (mm3) Annular Calcium (mm3) DAnnular Calcium (mm3) Leaflet Calcium (mm3) DLeaflet Calcium (mm3)
Paravalvular Regurgitation No/Trace (n ¼ 228)
Paravalvular Regurgitation Mild (n ¼ 53)
p-Value
15 35
46 67
0.002
13 30
41 61
0.002
0.001 0.002 0.102 0.373
36 22 317 115
37 24 286 113
68 42 389 131
62 41 290 131
Data are expressed as mean standard deviation.
independent determinants of PVR greater than or equal to mild. New-generation balloon-expandable SAPIEN 3 consists of bovine pericardial leaflets sutured to a cobalt chromium frame with the outer skirt (polyethylene terephthalate) to reduce PVR.16 SAPIEN 3 received US Food and Drug Administration approval in June 2015. The initial results were excellent,17,18 and this device is now widely used in the clinical practice because of its superior safety and efficacy. PVR is not only a common complication of TAVI but also associated with increased mortality.5,19e21 Although the incidence of PVR is low after SAPIEN 3 implantation,7,18 PVR still remains as a concern.8 Preceding studies demonstrated that AVC was an important predictor of PVR after TAVI through impairing the appropriate sealing of THV to the aortic annulus and LVOT.19,22e25 Not only volume of AVC but also location of AVC is important and AVC at the aortic wall of each valve cusp was reported to be strongly associated with the occurrence of PVR.22 Furthermore, AVC quantity of annulus, LVOT, and leaflet independently predicted PVR after TAVI using SAPIEN XT.14 However, little was known about the determinants of PVR after new-generation SAPIEN 3 implantation. Regarding PVR after SAPIEN 3 implantation, Yang et al15 demonstrated that AVC might play a role in the development of PVR. However, calcium volume was assessed in a semiquantitative fashion in the study of Yang et al. Therefore, we assessed AVC using quantitative evaluation. In addition, asymmetry of AVC was also analyzed. In line with recent studies,16,18 the incidence of significant PVR was low and approximately 80% of study patients showed none/trace PVR. Patients with PVR greater than or equal to mild had significantly greater calcification and more asymmetry in annulus and LVOT. In contrast, asymmetry in leaflet was comparable between patients with and without PVR greater than or equal to mild. Multivariable logistic regression analysis that larger calcium in annulus was independently associated with the development of PVR, suggesting that calcium in a THV landing zone might be most important in the development of PVR after SAPIEN 3 implantation. As well as larger calcium volume of annulus, lower percentage of THV oversizing was also a predictor of PVR greater
Valvular Heart Disease/Predictors of PVR after TAVI using SAPIEN 3
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Table 4 Determinants of PVR greater than or equal to mild Variable Left Ventricular Outflow Tract Calcium D Left Ventricular Outflow Tract Calcium Annular Calcium DAnnular Calcium Leaflet Calcium DLeaflet Calcium Oversizing of Transcatheter Heart Valve
Univariate OR 1.012 1.014 1.013 1.020 1.001 1.001 0.951
(1.006 (1.007 (1.007 (1.010 (1.000 (0.999 (0.923
e e e e e e e
1.018) 1.021) 1.020) 1.020) 1.002) 1.003) 0.980)
p-Value < < < <
0.001 0.001 0.001 0.001 0.108 0.374 0.001
Multivariable OR
p-Value
1.009 (1.002 e 1.017)
0.018
0.954 (0.926 e 0.984)
0.002
Odds ratios are presented with 95% confidence intervals. OR ¼ odds ratio; PVR ¼ paravalvular regurgitation.
than or equal to mild. Concordant with preceding studies,19,26 prosthesis/annulus incongruence is a main cause of PVR after balloon-expandable prosthesis implantation and selecting the optimal size of THV is essential to minimize the risk of PVR even after SAPIEN 3 implantation. Because SAPIEN 3 cannot be recaptured after deployment, post-dilation is an important therapeutic options for PVR. In this study, we performed post-dilation in 46 patients (16%) to reduce PVR. However, post-dilation is not always effective, and 16 patients (35%) remained PVR greater than or equal to mild after post-dilation. Furthermore, post-dilation is sometimes hesitated in patients with severe calcification in annulus due to fear of annulus rupture. Also from this point of view, assessing the calcification distribution and selecting the optimal size of THV are essential for this procedure. We recognize several limitations in this study. Because of the limited sample size, the statistical power might not be strong enough for any negative data to be conclusive. Number of patients with PVR greater than or equal to moderate was small. Therefore, we used PVR greater than or equal to mild as a primary outcome. Because the incidence of PVR greater than or equal to moderate is very low in the era of SAPIEN 3, the clinical significance of this study is limited to a small number of patients. Annulus region partly overlaps with LVOT and leaflet (Figure 2), and it can affect the analysis. Acknowledgment: The authors thank all staff of the intervention laboratory and the department of radiology in our institute. Disclosures The authors have no conflict of interest for this study. Supplementary Data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j. amjcard.2016.10.047. 1. Leon MB, Smith CR, Mack M, Miller DC, Moses JW, Svensson LG, Tuzcu EM, Webb JG, Fontana GP, Makkar RR, Brown DL, Block PC, Guyton RA, Pichard AD, Bavaria JE, Herrmann HC, Douglas PS, Petersen JL, Akin JJ, Anderson WN, Wang D, Pocock S. Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. N Engl J Med 2010;363:1597e1607.
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