Assessment of Paravalvular Aortic Regurgitation after Transcatheter Aortic Valve Replacement: Intra–Core Laboratory Variability Rebecca T. Hahn, MD, FACC, Philippe Pibarot, DVM, PhD, FACC, Neil J. Weissman, MD, FACC, Leonardo Rodriguez, MD, FACC, and Wael A. Jaber, MD, FACC, New York, New York; Que bec City, Que bec, Canada; Washington, District of Columbia; and Cleveland, Ohio
Background: There is significant disparity in the reported incidence of moderate and severe paravalvular aortic regurgitation (PAR) between the Placement of Aortic Transcatheter Valves (PARTNER) I and PARTNER II trials, which may be related to the echocardiographic methodologies used by separate core laboratories. To further explore the variability in echocardiographic interpretation of PAR, agreement between the grading of PAR by the core laboratory of PARTNER IIB was compared with that by a consortium of echocardiography core laboratory directors. Methods: The PARTNER IIB core laboratory reevaluated patients using primarily the circumferential extent of the regurgitant jet for PAR. A consortium of echocardiography core laboratory directors was formed to evaluate the echocardiographic images and to grade PAR and central and total aortic regurgitation in a randomly chosen subset of the randomized patients in the PARTNER IIB trial using a multiwindow, multiparametric approach. Both a four-class scale (none or trace, mild, moderate, and severe) and a seven-class (none, trace, mild, mild to moderate, moderate, moderate to severe, and severe) scale were used. Levels of grading agreement between the consortium and original core laboratory in both scales were determined using weighted k statistics. Results: Only 87 patients assessed for PAR by the consortium could be paired with readings by the PARTNER IIB core laboratory. Using the four-class grading scheme the weighted k statistic for PAR was 0.481 (95% confidence limits, 0.367, 0.595). Using the seven-class scale, the weighted k statistic for PAR was 0.517 (95% confidence limits, 0.431, 0.607). For either grading scheme, 15.9% of patients graded by the PARTNER IIB core laboratory as having moderate PAR would have been graded as having mild PAR using the multiparametric approach. Similar results were seen for central and total aortic regurgitation assessments. Conclusions: Using primarily the circumferential extent criteria, the PARTNER IIB core laboratory overestimated the severity of PAR compared to the consortium using a multi-parametric approach. Although a more granular classification scheme for PAR may slightly improve concordance between core laboratories, differences in the incidence of moderate or severe PAR are likely related to differences in grading methodology. A multiparametric approach is advocated, and other echocardiographic methods for assessing PAR deserve further study. (J Am Soc Echocardiogr 2015;28:415-22.) Keywords: Paravalvular regurgitation, TAVR, TAVI, Aortic stenosis
Transcatheter aortic valve replacement (TAVR) has rapidly emerged as a reasonable alternative to surgical aortic valve replacement in high-risk and inoperable patients with severe, symptomatic aortic stenosis
(AS).1-4 Multiple studies have shown a higher incidence of paravalvular aortic regurgitation (PAR) in the TAVR population, with moderate or severe PAR seen in 0% to 24%.1,2,5-13 The
From Columbia University Medical Center/New York-Presbyterian Hospital, New bec Heart and Lung Institute, Laval University, York, New York (R.T.H.); Que bec City, Que bec, Canada (P.P.); Medstar Health Research Institute, Que Washington, District of Columbia (N.J.W.); and Cleveland Clinic Foundation, Cleveland, Ohio (L.R., W.A.J.).
Medical, Boston Scientific, Medtronic, Biostable, Sorin, Abbott Vascular, Direct Flow, and Mitralign for which he receives no direct compensation. Leonardo Rodriguez, MD, FACC, has Core Lab contracts with Edwards Lifesciences for which he receives no direct compensation. Wael A. Jaber, MD, FACC, has Core Lab contracts with Edwards Lifesciences for which he receives no direct compensation.
Edwards Lifesciences is the sponsor for the PARNTER trial and consented to give access to the echocardiographic studies use in this study. No additional funding was provided. Rebecca T. Hahn, MD, FACC, has Core Lab contracts with Edwards Lifesciences for which she receives no direct compensation and is a speaker for Philips Healthcare, St. Jude Medical, and Boston Scientific. Philippe Pibarot, DVM, PhD, FACC, has Core Lab contracts with Edwards Lifesciences for which he receives no direct compensation and is a speaker for St. Jude Medical. Neil J. Weissman, MD, FACC, has Core Lab contracts with Edwards Lifesciences, St. Jude
Randolph P. Martin, MD, FACC, FASE, FESC, served as guest editor for this report. Reprint requests: Rebecca T. Hahn, MD, FACC, Columbia University Medical Center, New York-Presbyterian Hospital, 177 Fort Washington Avenue, New York, NY 10032 (E-mail: [email protected]). 0894-7317/$36.00 Copyright 2015 by the American Society of Echocardiography. http://dx.doi.org/10.1016/j.echo.2015.01.007
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inconsistencies in reported incidences of PAR are AR = Aortic regurgitation multifactorial. These differences may be due in large part to AS = Aortic stenosis differences in the methods of ASE = American Society of assessment (cine angiography vs Echocardiography hemodynamics vs cardiac magnetic resonance [CMR] vs CMR = Cardiac magnetic echocardiography). Pitfalls resonance inherent in assessing prosthetic PAR = Paravalvular aortic valve regurgitation differ for each regurgitation of these modalities: ventricular PARTNER = Placement of size and function for cine Aortic Transcatheter Valves angiography, heart rate and diastolic function for RF = Regurgitant fraction hemodynamics, flow turbulences SAX = Short-axis for CMR, and acoustic shadowing for echocardiography, TAVR = Transcatheter aortic to name just a few. valve replacement The inherent differences between surgical and transcatheter PAR jets make assessment by echocardiographic methods challenging. Post-TAVR PAR jets are frequently multiple, irregular in shape, and eccentric in direction of flow. Echocardiographic guidelines for assessing the severity of prosthetic regurgitation were developed for surgical prostheses14 and have not been well validated for transcatheter valves.15 The accuracy of published echocardiographic guidelines has recently been called into question, particularly with studies comparing echocardiographic assessment with other modalities, such as CMR.16-18 These studies have shed light on the methodologic differences in quantifying PAR by echocardiography, which may help explain some of the betweenstudy inconsistencies in reported PAR incidence. The incidence of moderate or severe PAR in the Placement of Aortic Transcatheter Valves (PARTNER) IB (inoperable) trial for the Edwards SAPIEN valve (Edwards Lifesciences, Irvine, CA) was 11.8% of patients at 30 days and 10.5% at 1 year. The incidence of moderate or severe PAR in the PARTNER IIB trial for the Edwards SAPIEN valve was 16.9% of patients at 30 days and 20.9% at 1 year. This important difference in the incidence of PAR reported by different trials using the same model of transcatheter valve and targeting similar populations may be related to differences in the methods used to grade PAR or to the grading scheme itself. In addition, the three-class grading scheme suggested by the American Society of Echocardiography (ASE) guidelines (mild, moderate, and severe)14 and used by core laboratories for a number of randomized trials2,4 may be more difficult to translate into a fourclass clinical or angiographic grading scheme used by multiple other studies (grades 1, 2, 3, and 4).16,19,20 A new grading scheme that subdivides the broader categories of mild and moderate, thus generating a seven-class grading scheme (Table 1), may improve agreement laboratories. The objective of this study was thus to examine the variability in reported incidences of PAR by (1) assessing differences in PAR grading that may be attributable to the broad three-class grading scheme and (2) assessing differences in PAR grading that may be attributable to differences in methods of assessing PAR. Abbreviations
METHODS PARTNER Trial Design The PARTNER IIB trial was a multicenter, randomized trial evaluating the comparative efficacy of TAVR with the Edwards SAPIEN
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valve versus the SAPIEN XT valve for severe symptomatic AS in inoperable surgical candidates. Similar inclusion and exclusion criteria were used as previously reported for the PARTNER IB trial.1 In the PARNTER IIB trial, 560 inoperable patients were randomized to either transfemoral SAPIEN (n = 276) or SAPIEN XT (n = 284) prostheses. The results of this trial were presented at the American College of Cardiology Scientific Sessions on March 10, 2013. Study Design To assess the between-trial discordance in reported PAR incidence, 100 studies previously interpreted by the PARTNER IIB core laboratory were reread by (1) the original core laboratory using its original methods for assessing PAR severity but then using a seven-class grading scheme (Table 1) and (2) a consortium of core laboratory directors using the multiparametric approach to PAR assessment with the seven-class grading scheme. Thus, each study was interpreted three times: twice by the original core laboratory and once by the consortium. Comparisons of variability within and between laboratories were then performed. Echocardiography Core Laboratory Methodology The PARTNER IIB echocardiography core laboratory used similar transthoracic echocardiographic acquisition protocols and reliability testing as previously reported by PARTNER I.21 Unlike the methods used by the PARTNER I core laboratory for PAR assessment,13,15 the PARTNER IIB core laboratory used the ASE guidelines with the lower circumferential extent criteria (i.e., PAR was considered severe when the regurgitant jet was >20% of the short-axis [SAX] annular circumference). In addition, circumferential extent was weighted more heavily than other parameters. Two readers (W.A.J. and L.R.) from the PARTNER IIB core laboratory who had initially interpreted the 100 studies reinterpreted a randomly chosen subset of 100 PARTNER IIB 30-day post-TAVR echocardiograms using their usual methods, which included preferential use of the SAX annular circumference criteria: mild, 20%. For the original reads, the severity of PAR was graded as none, mild, moderate, or severe. To align the grading scheme with the commonly used clinical scheme, a more granular grading scheme was used for the repeat reads. Table 1 shows the quantitative grading scheme, which divides mild PAR into two separate grades: mild and mild to moderate. It further divides moderate PAR into moderate and moderate to severe. This results in a seven-class grading scheme, which can be easily collapsed into the four-class scheme used in the ASE guidelines14 and the PARTNER I trial.21 The proposed quantitative equivalents of each grade are also listed in Table 1. A consortium of echocardiographic core laboratory directors (R.T.H., P.P., and N.J.W.) was used to evaluate PAR in the same subset of 100 PARTNER IIB 30-day post-TAVR echocardiograms independent of the PARTNER IIB core laboratory. The consortium used the ASE guidelines and Valve Academic Research Consortium 2 criteria to assess PAR using a multiwindow, multiparametric approach14,15 but relying heavily on color Doppler parameters of jet width just beneath the stent and in relation to the left ventricular outflow tract diameter, circumferential extent of the jet in the SAX views (taking care to image the vena contracta and not jet spray), vena contracta width, and the number of jets (integrating all views). The experience of each reader was relied on to subcategorize each parameter into the seven-class scheme and to integrate all the
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Table 1 PAR grading scheme used by the consortium and PARTNER IIB core laboratory for the 100-patient rereads of the PARTNER IIB study Seven-class grading scheme
1. None
Four-class grading scheme (PARTNER I/ASE guidelines)
1. None/trace
Regurgitant volume (mL)
RF (%)
EROA (mm2)
(Not quantifiable or within the error of the methods)
2. Trace 3. Mild
2. Mild
4. Mild to moderate 5. Moderate
3. Moderate
6. Moderate to severe 7. Severe
4. Severe
30
EROA, Effective regurgitant orifice area; PAR, paravalvular aortic regurgitation; RF, regurgitant fraction.
Figure 1 Incidence of PAR, CAR, and TAR at 30 days after transcatheter aortic valve replacement for the subset of 100 patients by PARTNER IIB (PIIB) core laboratory and consortium grading. Panel (A) shows the incidence of AR using the 4 grade scheme and Panel (B) shows the incidence of AR using the 7 grade scheme (see Table 1 for reference). The paired columns in each panel compare readings by the core laboratory and consortium. AR, Aortic regurgitation. parameters into a final interpretation. Importantly, jet length and total jet area were not used, as per recommendations of the guidelines.14 The multiparametric method weighs each parameter on an individual basis, taking into account the quality of the information from each
echocardiographic view. As such, no one color Doppler criterion was consistently weighed more heavily than another. Continuouswave Doppler parameters of jet density and pressure half-time, as well as pulsed-wave Doppler of reversal of flow in the descending
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Table 2 Number of patients in each PAR grade for the PARTNER IIB core laboratory and the consortium: four-grade scale
Table 3 Number of patients in each PAR grade for the PARTNER IIB core laboratory and the consortium: sevengrade scale
Consortium PARTNER IIB core laboratory
1
2
Consortium 3
†
4
PARTNER IIB core laboratory
1
2
4
5
6
7
1
31*
1
0
0
1
11*
0
0
0
0
0
2
17‡
21*
0
0
2
8‡
11*
1†
0
0
0
0
3
0
14‡
1*
0
3
0
16‡
9*
3†
0
0
0
§
‡
7
2*
0
0
0
‡
1
3 †
0*
4
0
1
PAR, Paravalvular aortic regurgitation. Grading scheme: 1 = none/trace; 2 = mild; 3 = moderate; 4 = severe. *Agreement between core laboratory and consortium. † Underestimation by the core laboratory. ‡ One-grade overestimation by the core laboratory.
5
0
0
5§
9‡
1*
0
0
6
0
0
0
0
0
0*
0
7
0
0
0
0
2§
0
0*
4
0
0
2
aorta, were also integrated into the approach, but as the guidelines make clear, these parameters lack specificity because of the influence of other hemodynamic parameters such as ventricular or aortic compliance. The interpretations for the consortium were initially performed by each laboratory director independently, blinded to the other readers’ interpretations. If unanimous agreement was not obtained on unblinding, the case was discussed openly, and a consensus interpretation was performed. A consensus interpretation was required in 40%, severe. Ribeiro et al.26 used different PAR severity cut points: RF < 5%, absent or minimal; RF of 5% to 19%, mild; RF of 20% to 29%, moderate; and RF $ 30%, severe.32 In both studies, the cut points were significantly lower than those used in echocardiography. Gelfand et al.33 determined the CMR RFs that optimized the correlation with integrative echocardiographic grades, suggesting significantly higher cut points: mild, #15%; moderate, 16% to 25%; moderate to severe, 26% to 48%; and severe, >48%. Similar findings in the pediatric and young adult populations have been reported.34 These studies suggest that the CMR RF cut points used in previous studies are in fact too low. If these higher cut points were used, the results of the comparison studies would be quite different, and the correlation might be much closer. Outcome studies in large numbers of patients with transcatheter heart valves are needed to validate the cut point of CMR RF that should be used to define PAR severity and predict adverse events. In light of the limitations of qualitative and semiquantitative echocardiographic parameters for assessing PAR, quantitative echocardiographic evaluation of AR in prosthetic valves may be inherently more reliable. Quantitation of prosthetic regurgitant volume, effective regurgitant orifice area, and RF should be performed using ASE methods,14,27 with the regurgitant volume calculated as the difference between the stroke volume across any nonregurgitant orifice (right ventricular outflow tract or mitral valve) and the stroke volume across the left ventricular outflow tract. Interobserver variability of this calculation is reasonable, although higher than for CMR.18 Three-dimensional echocardiography may overcome the limitations of twodimensional and standard Doppler measurements for quantifying regurgitation.35-37 Studies have shown the feasibility of measuring the three-dimensional vena contracta area (narrowest
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portion of the regurgitant jet) by echocardiography,36,38-40 with the calculation of regurgitant volume as product with the velocity-time integral. Using this technique for post-TAVR assessment (by transthoracic echocardiography) is also feasible,37 and Altiok et al.17 recently compared regurgitant volume calculations in patients after TAVR using CMR, two-dimensional transthoracic echocardiographic methods, and three-dimensional transthoracic color Doppler methods. The narrowest confidence intervals for regurgitant volume and RF were between CMR and the threedimensional color Doppler vena contracta method; there was no significant difference between these two modalities in the moderate and severe grades. Inter- and intraobserver variability was lowest for CMR and next lowest for three-dimensional color Doppler. Besides three-dimensional color Doppler methods for calculating regurgitation volume, stroke volumes may be calculated by realtime three-dimensional volume color flow Doppler techniques, which allow rapid, accurate, and reproducible quantitation of relative stroke volumes.41,42 Using the velocity information encoded in the volume color Doppler data, stroke volume across specific target such as the right ventricular outflow tract, mitral valve inflow tract, and left ventricular outflow tract could be calculated and compared, offering another method for quantifying regurgitation volume.
LIMITATIONS Only a modest subset (20%) of the patients in the PARTNER IIB trial was evaluated in this study, but reinterpretation of the entire cohort B of the trial is neither standard for regulatory compliance nor required for core laboratory best practices.43 The 13% dropout in reads by the core laboratory or consortium may also affect the percentage change in reads reported. This may indicate a different threshold for acceptability for interpretation. Furthermore, direct comparison between interpretation of PAR by echocardiography in the PARTNER I and PARTNER II trials was not attempted by either the consortium or the core laboratory, and the conclusions about differences between trials are speculative. The present study also did not address the within-subject or repeated-measures variability but only the variability between laboratories of the reported incidence of PAR at a single time point. Finally, rereading of the 100 patients by the core laboratory using the multiparametric approach might support our theory that PAR grading methodology was the reason for the discrepant readings and could be the subject of future study.
CONCLUSIONS Using the ASE guidelines and relying heavily on the circumferential extent of the regurgitant jet, the PARTNER IIB core laboratory reported a higher prevalence of moderate and severe PAR compared with the consortium using a multiwindow, multiparametric approach. Concordance between core laboratories may be slightly improved by increasing the granularity of the grading scheme, but the differences in PAR incidence are more likely related to differences in PAR grading methods used by PARTNER IIB core laboratory. We advocate a multiparametric assessment of PAR by two-dimensional transthoracic
echocardiography until advanced echocardiographic methods for assessing PAR are fully validated.
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Background: There is significant disparity in the reported incidence of moderate and severe paravalvular aortic regurgitation (PAR) between the Placement of Aortic Transcatheter Valves (PARTNER) I and PARTNER II trials, which may be related to the echocardiographic methodologies used by separate core laboratories. To further explore the variability in echocardiographic interpretation of PAR, agreement between the grading of PAR by the core laboratory of PARTNER IIB was compared with that by a consortium of echocardiography core laboratory directors. Methods: The PARTNER IIB core laboratory reevaluated patients using primarily the circumferential extent of the regurgitant jet for PAR. A consortium of echocardiography core laboratory directors was formed to evaluate the echocardiographic images and to grade PAR and central and total aortic regurgitation in a randomly chosen subset of the randomized patients in the PARTNER IIB trial using a multiwindow, multiparametric approach. Both a four-class scale (none or trace, mild, moderate, and severe) and a seven-class (none, trace, mild, mild to moderate, moderate, moderate to severe, and severe) scale were used. Levels of grading agreement between the consortium and original core laboratory in both scales were determined using weighted k statistics. Results: Only 87 patients assessed for PAR by the consortium could be paired with readings by the PARTNER IIB core laboratory. Using the four-class grading scheme the weighted k statistic for PAR was 0.481 (95% confidence limits, 0.367, 0.595). Using the seven-class scale, the weighted k statistic for PAR was 0.517 (95% confidence limits, 0.431, 0.607). For either grading scheme, 15.9% of patients graded by the PARTNER IIB core laboratory as having moderate PAR would have been graded as having mild PAR using the multiparametric approach. Similar results were seen for central and total aortic regurgitation assessments. Conclusions: Using primarily the circumferential extent criteria, the PARTNER IIB core laboratory overestimated the severity of PAR compared to the consortium using a multi-parametric approach. Although a more granular classification scheme for PAR may slightly improve concordance between core laboratories, differences in the incidence of moderate or severe PAR are likely related to differences in grading methodology. A multiparametric approach is advocated, and other echocardiographic methods for assessing PAR deserve further study. (J Am Soc Echocardiogr 2015;28:415-22.) Keywords: Paravalvular regurgitation, TAVR, TAVI, Aortic stenosis
Transcatheter aortic valve replacement (TAVR) has rapidly emerged as a reasonable alternative to surgical aortic valve replacement in high-risk and inoperable patients with severe, symptomatic aortic stenosis
(AS).1-4 Multiple studies have shown a higher incidence of paravalvular aortic regurgitation (PAR) in the TAVR population, with moderate or severe PAR seen in 0% to 24%.1,2,5-13 The
From Columbia University Medical Center/New York-Presbyterian Hospital, New bec Heart and Lung Institute, Laval University, York, New York (R.T.H.); Que bec City, Que bec, Canada (P.P.); Medstar Health Research Institute, Que Washington, District of Columbia (N.J.W.); and Cleveland Clinic Foundation, Cleveland, Ohio (L.R., W.A.J.).
Medical, Boston Scientific, Medtronic, Biostable, Sorin, Abbott Vascular, Direct Flow, and Mitralign for which he receives no direct compensation. Leonardo Rodriguez, MD, FACC, has Core Lab contracts with Edwards Lifesciences for which he receives no direct compensation. Wael A. Jaber, MD, FACC, has Core Lab contracts with Edwards Lifesciences for which he receives no direct compensation.
Edwards Lifesciences is the sponsor for the PARNTER trial and consented to give access to the echocardiographic studies use in this study. No additional funding was provided. Rebecca T. Hahn, MD, FACC, has Core Lab contracts with Edwards Lifesciences for which she receives no direct compensation and is a speaker for Philips Healthcare, St. Jude Medical, and Boston Scientific. Philippe Pibarot, DVM, PhD, FACC, has Core Lab contracts with Edwards Lifesciences for which he receives no direct compensation and is a speaker for St. Jude Medical. Neil J. Weissman, MD, FACC, has Core Lab contracts with Edwards Lifesciences, St. Jude
Randolph P. Martin, MD, FACC, FASE, FESC, served as guest editor for this report. Reprint requests: Rebecca T. Hahn, MD, FACC, Columbia University Medical Center, New York-Presbyterian Hospital, 177 Fort Washington Avenue, New York, NY 10032 (E-mail: [email protected]). 0894-7317/$36.00 Copyright 2015 by the American Society of Echocardiography. http://dx.doi.org/10.1016/j.echo.2015.01.007
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inconsistencies in reported incidences of PAR are AR = Aortic regurgitation multifactorial. These differences may be due in large part to AS = Aortic stenosis differences in the methods of ASE = American Society of assessment (cine angiography vs Echocardiography hemodynamics vs cardiac magnetic resonance [CMR] vs CMR = Cardiac magnetic echocardiography). Pitfalls resonance inherent in assessing prosthetic PAR = Paravalvular aortic valve regurgitation differ for each regurgitation of these modalities: ventricular PARTNER = Placement of size and function for cine Aortic Transcatheter Valves angiography, heart rate and diastolic function for RF = Regurgitant fraction hemodynamics, flow turbulences SAX = Short-axis for CMR, and acoustic shadowing for echocardiography, TAVR = Transcatheter aortic to name just a few. valve replacement The inherent differences between surgical and transcatheter PAR jets make assessment by echocardiographic methods challenging. Post-TAVR PAR jets are frequently multiple, irregular in shape, and eccentric in direction of flow. Echocardiographic guidelines for assessing the severity of prosthetic regurgitation were developed for surgical prostheses14 and have not been well validated for transcatheter valves.15 The accuracy of published echocardiographic guidelines has recently been called into question, particularly with studies comparing echocardiographic assessment with other modalities, such as CMR.16-18 These studies have shed light on the methodologic differences in quantifying PAR by echocardiography, which may help explain some of the betweenstudy inconsistencies in reported PAR incidence. The incidence of moderate or severe PAR in the Placement of Aortic Transcatheter Valves (PARTNER) IB (inoperable) trial for the Edwards SAPIEN valve (Edwards Lifesciences, Irvine, CA) was 11.8% of patients at 30 days and 10.5% at 1 year. The incidence of moderate or severe PAR in the PARTNER IIB trial for the Edwards SAPIEN valve was 16.9% of patients at 30 days and 20.9% at 1 year. This important difference in the incidence of PAR reported by different trials using the same model of transcatheter valve and targeting similar populations may be related to differences in the methods used to grade PAR or to the grading scheme itself. In addition, the three-class grading scheme suggested by the American Society of Echocardiography (ASE) guidelines (mild, moderate, and severe)14 and used by core laboratories for a number of randomized trials2,4 may be more difficult to translate into a fourclass clinical or angiographic grading scheme used by multiple other studies (grades 1, 2, 3, and 4).16,19,20 A new grading scheme that subdivides the broader categories of mild and moderate, thus generating a seven-class grading scheme (Table 1), may improve agreement laboratories. The objective of this study was thus to examine the variability in reported incidences of PAR by (1) assessing differences in PAR grading that may be attributable to the broad three-class grading scheme and (2) assessing differences in PAR grading that may be attributable to differences in methods of assessing PAR. Abbreviations
METHODS PARTNER Trial Design The PARTNER IIB trial was a multicenter, randomized trial evaluating the comparative efficacy of TAVR with the Edwards SAPIEN
Journal of the American Society of Echocardiography April 2015
valve versus the SAPIEN XT valve for severe symptomatic AS in inoperable surgical candidates. Similar inclusion and exclusion criteria were used as previously reported for the PARTNER IB trial.1 In the PARNTER IIB trial, 560 inoperable patients were randomized to either transfemoral SAPIEN (n = 276) or SAPIEN XT (n = 284) prostheses. The results of this trial were presented at the American College of Cardiology Scientific Sessions on March 10, 2013. Study Design To assess the between-trial discordance in reported PAR incidence, 100 studies previously interpreted by the PARTNER IIB core laboratory were reread by (1) the original core laboratory using its original methods for assessing PAR severity but then using a seven-class grading scheme (Table 1) and (2) a consortium of core laboratory directors using the multiparametric approach to PAR assessment with the seven-class grading scheme. Thus, each study was interpreted three times: twice by the original core laboratory and once by the consortium. Comparisons of variability within and between laboratories were then performed. Echocardiography Core Laboratory Methodology The PARTNER IIB echocardiography core laboratory used similar transthoracic echocardiographic acquisition protocols and reliability testing as previously reported by PARTNER I.21 Unlike the methods used by the PARTNER I core laboratory for PAR assessment,13,15 the PARTNER IIB core laboratory used the ASE guidelines with the lower circumferential extent criteria (i.e., PAR was considered severe when the regurgitant jet was >20% of the short-axis [SAX] annular circumference). In addition, circumferential extent was weighted more heavily than other parameters. Two readers (W.A.J. and L.R.) from the PARTNER IIB core laboratory who had initially interpreted the 100 studies reinterpreted a randomly chosen subset of 100 PARTNER IIB 30-day post-TAVR echocardiograms using their usual methods, which included preferential use of the SAX annular circumference criteria: mild, 20%. For the original reads, the severity of PAR was graded as none, mild, moderate, or severe. To align the grading scheme with the commonly used clinical scheme, a more granular grading scheme was used for the repeat reads. Table 1 shows the quantitative grading scheme, which divides mild PAR into two separate grades: mild and mild to moderate. It further divides moderate PAR into moderate and moderate to severe. This results in a seven-class grading scheme, which can be easily collapsed into the four-class scheme used in the ASE guidelines14 and the PARTNER I trial.21 The proposed quantitative equivalents of each grade are also listed in Table 1. A consortium of echocardiographic core laboratory directors (R.T.H., P.P., and N.J.W.) was used to evaluate PAR in the same subset of 100 PARTNER IIB 30-day post-TAVR echocardiograms independent of the PARTNER IIB core laboratory. The consortium used the ASE guidelines and Valve Academic Research Consortium 2 criteria to assess PAR using a multiwindow, multiparametric approach14,15 but relying heavily on color Doppler parameters of jet width just beneath the stent and in relation to the left ventricular outflow tract diameter, circumferential extent of the jet in the SAX views (taking care to image the vena contracta and not jet spray), vena contracta width, and the number of jets (integrating all views). The experience of each reader was relied on to subcategorize each parameter into the seven-class scheme and to integrate all the
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Table 1 PAR grading scheme used by the consortium and PARTNER IIB core laboratory for the 100-patient rereads of the PARTNER IIB study Seven-class grading scheme
1. None
Four-class grading scheme (PARTNER I/ASE guidelines)
1. None/trace
Regurgitant volume (mL)
RF (%)
EROA (mm2)
(Not quantifiable or within the error of the methods)
2. Trace 3. Mild
2. Mild
4. Mild to moderate 5. Moderate
3. Moderate
6. Moderate to severe 7. Severe
4. Severe
30
EROA, Effective regurgitant orifice area; PAR, paravalvular aortic regurgitation; RF, regurgitant fraction.
Figure 1 Incidence of PAR, CAR, and TAR at 30 days after transcatheter aortic valve replacement for the subset of 100 patients by PARTNER IIB (PIIB) core laboratory and consortium grading. Panel (A) shows the incidence of AR using the 4 grade scheme and Panel (B) shows the incidence of AR using the 7 grade scheme (see Table 1 for reference). The paired columns in each panel compare readings by the core laboratory and consortium. AR, Aortic regurgitation. parameters into a final interpretation. Importantly, jet length and total jet area were not used, as per recommendations of the guidelines.14 The multiparametric method weighs each parameter on an individual basis, taking into account the quality of the information from each
echocardiographic view. As such, no one color Doppler criterion was consistently weighed more heavily than another. Continuouswave Doppler parameters of jet density and pressure half-time, as well as pulsed-wave Doppler of reversal of flow in the descending
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Table 2 Number of patients in each PAR grade for the PARTNER IIB core laboratory and the consortium: four-grade scale
Table 3 Number of patients in each PAR grade for the PARTNER IIB core laboratory and the consortium: sevengrade scale
Consortium PARTNER IIB core laboratory
1
2
Consortium 3
†
4
PARTNER IIB core laboratory
1
2
4
5
6
7
1
31*
1
0
0
1
11*
0
0
0
0
0
2
17‡
21*
0
0
2
8‡
11*
1†
0
0
0
0
3
0
14‡
1*
0
3
0
16‡
9*
3†
0
0
0
§
‡
7
2*
0
0
0
‡
1
3 †
0*
4
0
1
PAR, Paravalvular aortic regurgitation. Grading scheme: 1 = none/trace; 2 = mild; 3 = moderate; 4 = severe. *Agreement between core laboratory and consortium. † Underestimation by the core laboratory. ‡ One-grade overestimation by the core laboratory.
5
0
0
5§
9‡
1*
0
0
6
0
0
0
0
0
0*
0
7
0
0
0
0
2§
0
0*
4
0
0
2
aorta, were also integrated into the approach, but as the guidelines make clear, these parameters lack specificity because of the influence of other hemodynamic parameters such as ventricular or aortic compliance. The interpretations for the consortium were initially performed by each laboratory director independently, blinded to the other readers’ interpretations. If unanimous agreement was not obtained on unblinding, the case was discussed openly, and a consensus interpretation was performed. A consensus interpretation was required in 40%, severe. Ribeiro et al.26 used different PAR severity cut points: RF < 5%, absent or minimal; RF of 5% to 19%, mild; RF of 20% to 29%, moderate; and RF $ 30%, severe.32 In both studies, the cut points were significantly lower than those used in echocardiography. Gelfand et al.33 determined the CMR RFs that optimized the correlation with integrative echocardiographic grades, suggesting significantly higher cut points: mild, #15%; moderate, 16% to 25%; moderate to severe, 26% to 48%; and severe, >48%. Similar findings in the pediatric and young adult populations have been reported.34 These studies suggest that the CMR RF cut points used in previous studies are in fact too low. If these higher cut points were used, the results of the comparison studies would be quite different, and the correlation might be much closer. Outcome studies in large numbers of patients with transcatheter heart valves are needed to validate the cut point of CMR RF that should be used to define PAR severity and predict adverse events. In light of the limitations of qualitative and semiquantitative echocardiographic parameters for assessing PAR, quantitative echocardiographic evaluation of AR in prosthetic valves may be inherently more reliable. Quantitation of prosthetic regurgitant volume, effective regurgitant orifice area, and RF should be performed using ASE methods,14,27 with the regurgitant volume calculated as the difference between the stroke volume across any nonregurgitant orifice (right ventricular outflow tract or mitral valve) and the stroke volume across the left ventricular outflow tract. Interobserver variability of this calculation is reasonable, although higher than for CMR.18 Three-dimensional echocardiography may overcome the limitations of twodimensional and standard Doppler measurements for quantifying regurgitation.35-37 Studies have shown the feasibility of measuring the three-dimensional vena contracta area (narrowest
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portion of the regurgitant jet) by echocardiography,36,38-40 with the calculation of regurgitant volume as product with the velocity-time integral. Using this technique for post-TAVR assessment (by transthoracic echocardiography) is also feasible,37 and Altiok et al.17 recently compared regurgitant volume calculations in patients after TAVR using CMR, two-dimensional transthoracic echocardiographic methods, and three-dimensional transthoracic color Doppler methods. The narrowest confidence intervals for regurgitant volume and RF were between CMR and the threedimensional color Doppler vena contracta method; there was no significant difference between these two modalities in the moderate and severe grades. Inter- and intraobserver variability was lowest for CMR and next lowest for three-dimensional color Doppler. Besides three-dimensional color Doppler methods for calculating regurgitation volume, stroke volumes may be calculated by realtime three-dimensional volume color flow Doppler techniques, which allow rapid, accurate, and reproducible quantitation of relative stroke volumes.41,42 Using the velocity information encoded in the volume color Doppler data, stroke volume across specific target such as the right ventricular outflow tract, mitral valve inflow tract, and left ventricular outflow tract could be calculated and compared, offering another method for quantifying regurgitation volume.
LIMITATIONS Only a modest subset (20%) of the patients in the PARTNER IIB trial was evaluated in this study, but reinterpretation of the entire cohort B of the trial is neither standard for regulatory compliance nor required for core laboratory best practices.43 The 13% dropout in reads by the core laboratory or consortium may also affect the percentage change in reads reported. This may indicate a different threshold for acceptability for interpretation. Furthermore, direct comparison between interpretation of PAR by echocardiography in the PARTNER I and PARTNER II trials was not attempted by either the consortium or the core laboratory, and the conclusions about differences between trials are speculative. The present study also did not address the within-subject or repeated-measures variability but only the variability between laboratories of the reported incidence of PAR at a single time point. Finally, rereading of the 100 patients by the core laboratory using the multiparametric approach might support our theory that PAR grading methodology was the reason for the discrepant readings and could be the subject of future study.
CONCLUSIONS Using the ASE guidelines and relying heavily on the circumferential extent of the regurgitant jet, the PARTNER IIB core laboratory reported a higher prevalence of moderate and severe PAR compared with the consortium using a multiwindow, multiparametric approach. Concordance between core laboratories may be slightly improved by increasing the granularity of the grading scheme, but the differences in PAR incidence are more likely related to differences in PAR grading methods used by PARTNER IIB core laboratory. We advocate a multiparametric assessment of PAR by two-dimensional transthoracic
echocardiography until advanced echocardiographic methods for assessing PAR are fully validated.
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