PARTNER Trial Design

The PARTNER IIB trial was a multicenter, randomized trial evaluating the comparative efficacy of TAVR with the Edwards SAPIEN 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. 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. Unlike the methods used by the PARTNER I core laboratory for PAR assessment, 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, <10%; moderate, 10% to 20%; and severe, >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 guidelines and the PARTNER I trial. 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 approach 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 parameters into a final interpretation. Importantly, jet length and total jet area were not used, as per recommendations of the guidelines. 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. Continuous-wave Doppler parameters of jet density and pressure half-time, as well as pulsed-wave Doppler of reversal of flow in the descending 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 <5% of the reads. In addition, the consortium categorized the level of confidence each study’s PAR grade as high, intermediate, or low, as well as uninterpretable. Reasons for inability to interpret most frequently involved missing views, preventing accurate interpretation of the severity of aortic regurgitation (AR). These repeat readings of the core laboratory were then compared with the consortium reads; only those studies with high and intermediate confidence levels were used for the analysis. Central AR was also interpreted using a multiwindow, multiparametric approach, with total AR integrating the severity of PAR and central AR.

Statistical Analysis

Concordance between initial and repeat PAR grading by the core laboratory was performed using Kendall’s τ coefficient of concordance, a nonparametric approach. Weighted κ statistics were used to assess grading agreement between the consortium and the core laboratory.