Author + information
- Received May 24, 2016
- Revision received October 28, 2016
- Accepted November 10, 2016
- Published online October 2, 2017.
- Yoshio Maeno, MD, PhD,
- Yigal Abramowitz, MD,
- Hiroyuki Kawamori, MD,
- Yoshio Kazuno, MD,
- Shunsuke Kubo, MD,
- Nobuyuki Takahashi, MD,
- Geeteshwar Mangat, MD,
- Kazuaki Okuyama, MD,
- Mohammad Kashif, MD,
- Tarun Chakravarty, MD,
- Mamoo Nakamura, MD,
- Wen Cheng, MD,
- John Friedman, MD,
- Daniel Berman, MD,
- Raj R. Makkar, MD and
- Hasan Jilaihawi, MD∗ ()
- ↵∗Address for correspondence:
Dr. Hasan Jilaihawi, Heart Valve Center, NYU Langone Medical Center, Suite 9V, 530 1st Avenue, New York, New York 10016.
Objectives This study sought to develop a robust and definitive risk model for new permanent pacemaker implantation (PPMI) after SAPIEN 3 (third generation balloon expandable valve) (Edwards Lifesciences, Irvine, California) transcatheter aortic valve replacement (third generation balloon expandable valve TAVR), including calcification in the aortic-valvular complex (AVC).
Background The association between calcium in the AVC and need for PPMI is poorly delineated after third generation balloon expandable valve TAVR.
Methods At Cedars-Sinai Heart Institute in Los Angeles, California, a total of 240 patients with severe aortic stenosis underwent third generation balloon expandable valve TAVR and had contrast computed tomography. AVC was characterized precisely by leaflet sector and region.
Results The total new PPMI rate was 14.6%. On multivariate analysis for predictors of PPMI, pre-procedure third generation balloon expandable valve TAVR, right bundle branch block (RBBB), shorter membranous septum (MS) length, and noncoronary cusp device-landing zone calcium volume (NCC-DLZ CA) were included. Predictive probabilities were generated using this logistic regression model. If 3 pre-procedural risk factors were present, the c-statistic of the model for PPMI was area under the curve of 0.88, sensitivity of 77.1%, and specificity of 87.1%; this risk model had high negative predictive value (95.7%). The addition of the procedural factor of device depth to the model, with the parameter of difference between implantation depth and MS length, combined with RBBB and NCC-DLZ CA increased the c-statistic to 0.92, sensitivity to 94.3%, specificity to 83.8%, and negative predictive value to 98.8%
Conclusions By using a precise characterization of distribution of calcification in the AVC in a single-center, retrospective study, NCC-DLZ CA was found to be an independent predictor of new PPMI post–third generation balloon expandable valve TAVR. The findings also reinforce the importance of short MS length, pre-existing RBBB, and ventricular implantation depth as important synergistic PPMI risk factors. This risk model will need validation by future prospective multicenter studies.
- transcatheter aortic valve implantation
- transcatheter aortic valve replacement
Transcatheter aortic valve replacement (TAVR) is a well-established alternative to surgical aortic valve replacement for intermediate and high-risk patients with severe aortic valve stenosis (1). Cardiac conduction disturbance requiring new permanent pacemaker implantation (PPMI) is an important complication of TAVR that has been associated in some studies with increased mortality and rehospitalization rates (2). The exact frequency of new PPMI varies according to the valve design used and was previously noted to be signiﬁcantly lower with balloon-expandable (BE) TAVR (Edwards Lifesciences, Irvine, California) than with the self-expanding CoreValve (Medtronic, Minneapolis, Minnesota) (3). Nonetheless, there is considerable heterogeneity in the average PPMI rates, ranging from 5.9% to 20.7% for BE-bioprosthesis (2–7). With the SAPIEN 3 (third generation balloon expandable valve) (Edwards Lifesciences, Irvine, California) bioprosthesis, PPMI rates have been higher than generally reported for earlier generations of BE bioprostheses but lower than seen with self-expanding bioprostheses (6–9). Previously identified predictors of PPMI after BE TAVR are pre-existing right bundle branch block (RBBB) (2,7), the ratio of bioprosthesis diameter to left ventricular outflow tract diameter (2), end-diastolic left ventricular diastolic dimension (2), and low depth of implantation of bioprosthesis (10), but these data were restricted to earlier generations of BE TAVR prostheses. More recently, short membranous septum (MS) length was further determined to be a predictor of PPMI (11).
Moreover, calcium in the aortic-valvular complex is a well-known predictor of paravalvular leak following TAVR (12,13). Device-landing zone (DLZ) or left coronary cusp leaflet calcification has also been shown to be predictive of PPMI after TAVR (14,15). However, the association between calcium in the aortic-valvular complex, including various locations of the aortic-valvular complex (total leaflet, upper leaflet, DLZ, and left ventricular outflow tract [LVOT]), and PPMI has not been studied with the third generation balloon expandable valve bioprosthesis. The aim of this study was to delineate the predictive factors for PPMI after third generation balloon expandable valve TAVR further with a view to developing a robust and comprehensive predictive model.
Study population and procedure
Between November 2013 and December 2015, a total of 321 patients with severe symptomatic aortic stenosis were treated with third generation balloon expandable valve TAVR at Cedars-Sinai Medical Center in Los Angeles, California, and they were prospectively included in our TAVR database. After excluding patients with previous PPMI, previous bioprosthesis, congenital bicuspid valve, and poor computed tomography (CT) imaging quality, a total of 240 patients were included in the ﬁnal analysis (Figure 1, Online Table 1). The decision to proceed with TAVR was made with the consensus of a dedicated heart team including experienced clinical and interventional cardiologists and cardiovascular surgeons. Sizing for bioprosthesis was made at the operator’s discretion, by using data from all available imaging modalities (multidetector CT or 3-dimensional transesophageal echocardiography, the latter performed immediately pre-procedure). Following the procedure, the decision to perform in-hospital PPMI was made by an experienced cardiac electrophysiology specialist team. The study complies with the Declaration of Helsinki: a locally appointed ethics committee approved the research protocol, and informed consent was obtained from all subjects.
Multidetector computed tomography image acquisition and analysis
An electrocardiographically gated multidetector CT study was performed only if the patient’s renal function was considered satisfactory, as is routine clinical practice; this was generally when the serum creatinine was ≤2.0 mg/dl. Patients were evaluated using a Siemens Somatom Cardiac 64 or Siemens Somatom Flash scanner (Siemens Medical Solutions USA, Inc., Malvern, Pennsylvania) using collimation of 0.6 mm at a fixed pitch of 0.2 with an injection of 50 to 110 ml of Iopamidol (Isovue-370). A dedicated protocol was formulated, with 120 kV and tube current modified according to the patient’s size. Image acquisition was, for the most part, performed with retrospective electrocardiographic gating. CT Digital Imaging and Communications in Medicine (DICOM) data were analyzed by a dedicated advanced imaging core laboratory, using 3mensio Valves software version 7.0 (Pie Medical Imaging, Maastricht, the Netherlands). For reconstruction of midsystolic data, the cine or movie feature of this software was used to determine the point in the cardiac cycle when the aortic valve was maximally open (16).
Aortic annulus analysis
The aortic annulus was deﬁned as a virtual plane containing the basal attachment points of the 3 aortic valve leaflets in the LVOT (hinge point). A line was generated through the center point of the proximal ascending aorta, aortic valve, annulus, and LVOT (multiplanar reconstruction view). The basal annular plane or ring was defined as a plane perpendicular to the curved multiplanar reconstruction line that touched the nadir of the 3 leaflets. A perpendicular plane along the center line provided a short-axis view of the aortic valve annulus. The perpendicular plane can be manually adjusted and positioned immediately beneath the lowest insertion points of all 3 aortic cusps (hinge points). The tracing of this “ring” provided accurate data on orthogonal major and minor dimensions, area, and perimeter (17). The area cover index representing the percentage of oversizing of bioprosthesis by area as compared with the measured annulus size was calculated as follows: (nominal bioprosthesis area / measured area − 1) × 100%. The nominal area of a fully expanded third generation balloon expandable valve is 3.28 cm2 for the 20-mm valve, 4.09 cm2 for the 23-mm valve, 5.19 cm2 for the 26-mm valve, and 6.49 cm2 for the 29-mm valve.
Aortic-valvular complex calcium quantification
Contrast scans were used to facilitate precise anatomic localization of aortic-valvular complex calcium. An 850-Hounsfield unit threshold was used to detect areas of calcium in the region of interest (12). Regions of the aortic-valvular complex were separated in the craniocaudal axis of the LVOT or aortic valve into the following regions (Figure 2A): upper leaflet, DLZ, and LVOT. The DLZ consisted of the basal leaflet and upper LVOT region (13). The leaflet sector of each region (noncoronary cusp [NCC], right coronary cusp, and left coronary cusp) were separated using the “Mercedes Benz” tool for localization (Figure 2B) (13). Anatomic localization of calcium volume (CA) was also recorded by leaflet sector for each region.
Depth of bioprosthesis and membranous septum length
The depth of bioprosthesis implantation in the LVOT was also studied. This parameter was measured using a final fluoroscopic aortic angiogram acquisition after bioprosthesis deployment. The depth of delivery was defined as the maximum distance from the native aortic annular margin on the side of the NCC to the lower edge of the stent frame in the LVOT (10). MS length was determined using the coronal view (11).
Continuous variables were tested for a normality of distribution by using the Shapiro-Wilk test and were reported and analyzed appropriately thereafter. Categorical variables were compared by chi-square statistics or the Fisher exact test. Mann-Whitney U test were used in case of abnormal distribution. Receiver-operating characteristic curves were generated using new PPMI as the endpoint. Area under the curve comparisons were made using the method of DeLong et al. (18), where there was a direct comparison of the discriminatory value of 1 measurement with another. Multivariate analysis was also performed using a forward–logistic regression stepwise method and generated a predictive model for PPMI that was further evaluated using c-statistics of the receiver-operating characteristic curve. All parameters significant for prediction of pre-procedural or post-procedural new PPMI (p < 0.05) were entered into a multivariable regression model. Sensitivity, specificity, negative predictive value, and positive predictive value were calculated using specific cutoffs by using the Youden index generated from the receiver-operating characteristic curve on the basis of the predictive probability for PPMI. All the analyses were considered significant at a 2-tailed p value <0.05. SPSS statistics software version 22.0 (SPSS, Chicago, Illinois) and MedCalc version 11.70 (MedCalc, Ostend, Belgium) were used to perform all statistical evaluations.
Patients and procedural characteristics
Baseline clinical and procedural characteristics for the 240 participants are shown in Table 1. Of all patients, 14.6% (35 patients) needed new PPMI after TAVR. The indication for a pacemaker was complete heart block in 28 patients (80.0%), and the remaining 7 patients had severe symptomatic bradycardia with lesser degrees of conduction disturbances (3 patients had left bundle branch block, 3 patients had left bundle branch block with second-degree atrioventricular block, and 1 patient had atrial fibrillation with a slow ventricular rate). RBBB was significantly associated with the incidence of PPMI (60.0% vs. 12.2%; p < 0.001). Baseline heart rate was not related to the need for PPMI (p = 0.48). Patients who underwent new PPMI had significantly lower (ventricular) implanted bioprostheses (7.0 ± 2.3 mm vs. 5.2 ± 1.3 mm; p < 0.001). Patients who required new PPMI had a significantly shorter MS length or a greater difference between MS length and implantation length (Δ MSID) (MS length 6.4 ± 1.7 mm vs. 7.7 ± 1.9 mm; Δ MSID, 0.60 ± 2.9 mm vs. −2.5 ± 2.4 mm; p < 0.001 for both). With regard to the degree of oversizing, there was no association between new PPMI and the degree of oversizing (PPMI 10.3 ± 7.6% vs. no PPMI 9.9 ± 10.0%; p = 0.81). There was a trend for higher new PPMI rates in patients with an increased ratio of bioprosthesis diameter to LVOT diameter (1.34 ± 0.11 vs. 1.30 ± 0.11; p = 0.07) or with baseline PR interval prolongation (200.0 ± 42.8 m/s vs. 185.8 ± 39.4 m/s; p = 0.07). End-diastolic left ventricular dimension was similar between patients with or without the need for PPMI (42.7 ± 6.1 mm vs. 44.4 ± 7.9 mm, respectively; p = 0.21).
Calcium volume in the aortic-valvular complex
The median total leaflet CA was 184.8 mm3 (interquartile range [IQR]: 78.9 to 324.3 mm3). CA was highest in the NCC (68.1 [IQR: 28.3 to 161.5 mm3]), followed by the left coronary cusp (45.9 mm3 [IQR: 16.3 to 96.9 mm3]) and the right coronary cusp (34.7 mm3 [IQR: 11.5 to 92.0 mm3]) (Online Table 2). Table 2 compares CA in the different leaflet sectors and regions of the aortic-valvular complex according to the need for new PPMI after TAVR. For upper leaflet regions, CA in the right coronary cusp and left coronary cusp sectors was associated with new PPMI. Conversely, for the DLZ or LVOT regions, significantly higher NCC-DLZ CA and NCC-LVOT CA were observed in patients who required PPMI. From a repeated measurement for a subset of 20 randomly selected patients, intraobserver and interobserver variability for DLZ-CA was satisfactory (intraobserver: intraclass correlation coefficient: 0.99; p < 0.001; interobserver: intraclass correlation coefficient: 0.97; p < 0.001).
Detailed aortic-valvular complex analysis and the need for new permanent pacemaker implantation
We systematically assessed calcification by multiple aortic-valvular complex regions for the impact on the need for PPMI by using receiver-operating characteristic curve analyses (Online Table 3). Total leaflet CA and upper leaflet CA alone, including each sector, were not predictive of the need for PPMI (Online Table 3). Conversely, DLZ CA or LVOT CA in the region of the NCC (and not in the regions of the left coronary cusp or right coronary cusp) predicted new PPMI (NCC-DLZ CA: area under the curve, 0.702; p < 0.001; NCC-LVOT CA: area under the curve, 0.707; p < 0.001, respectively) (Online Table 3).
Independent predictors of new permanent pacemaker implantation
Independent predictors of PPMI pre-procedural TAVR included RBBB (odds ratio [OR]: 14.3; 95% confidence interval [CI]: 5.01 to 40.9; p < 0.001), NCC-DLZ CA (OR: 1.04; 95% CI: 1.02 to 1.06; p < 0.001), and MS length (OR: 0.63; 95% CI: 0.48 to 0.82; p < 0.001) (Table 3, Online Table 4). For predictors of PPMI pre-TAVR and post-TAVR, instead of MS length, Δ MSID was found to be an independent predictor of PPMI (OR: 1.68; 95% CI: 1.36 to 2.08; p < 0.001) (Table 3, Online Table 4). Predictive probabilities were generated using this logistic regression model, and the c-statistic for the model for PPMI pre-procedural TAVR was area under the curve of 0.875 (95% CI: 0.808 to 0.941; p < 0.001; sensitivity, 77.1%; specificity, 87.7%; positive predictive value, 50.9%; negative predictive value, 95.7%); for pre-TAVR and post-TAVR, the c-statistic was area under the curve of 0.916 (95% CI: 0.857 to 0.975; p < 0.001; sensitivity, 94.3%; specificity, 83.8%; positive predictive value, 49.3%; negative predictive value, 98.8%) (Table 4). This observation was robust for third generation balloon expandable valve devices (Table 4). In a head-to-head comparison of the new PPMI prediction using the Delong method (18), for the incremental predictive value of RBBB versus others, the addition of MS length was strongly associated with an exponential rise in the need for new PPMI (RBBB alone vs. RBBB + MS length; p = 0.002). For the combination of risk factors, however, there were no significant differences in area under the curve between all risk factors (RBBB, MS length, and NCC-DLZ CA) and the combination of RBBB and MS length (p = nonsignificant for all). Importantly, regardless of the number of risk factors or the combination of risk factors, this risk model had high negative predictive value (Table 4).
Validation cohort using a predictive model
Between January 2016 and April 2016, 105 consecutive patients were treated with the third generation balloon expandable valve prosthesis. We assessed NCC-DLZ CA or MS length, and the presence of RBBB was recorded; these parameters were assessed entirely blinded to the clinical data. By using the initial predictive model, all patients were divided into 7 categories, according to combination of risk factors. The findings observed in these groups were consistent with the predictive model (Table 5).
The aim of this study was to delineate the predictive factors for PPMI after third generation balloon expandable valve TAVR comprehensively. Our findings can be summarized as follows: 1) the rate of PPMI following third generation balloon expandable valve TAVR was 14.6% overall; 2) in the characterization of distribution of calcification in the aortic-valvular complex, NCC- DLZ CA was conﬁrmed to be the most relevant predictor of new PPMI after third generation balloon expandable valve TAVR; 3) as well as NCC-DLZ CA, there was a synergistic interaction of RBBB, short MS length, and more ventricular device implantation to increase the risk of PPMI; and 4) the combination of these factors yielded a strongly predictive model for PPMI.
Only scarce data are available regarding the anatomic predictors of PPMI after third generation balloon expandable valve TAVR. The PARTNER (Placement of Aortic Transcatheter Valves) trial reported that the PPMI rate was 16.8% following third generation balloon expandable valve TAVR (19). Although timing of pacemaker implantation and indications varies from institution to institution, PPMI rate in the present study (14.6%) was similar to that reported in the PARTNER trial and in other studies using balloon-expandable valves (6,8,9,19,20).
Previously identified risk factors for new PPMI, primarily with a self-expanding design, include RBBB, low valve implantation, conduction system abnormalities, and ratio of bioprosthesis diameter to LVOT diameter (2,7,10). Furthermore, Hamdan et al. (11) demonstrated that MS length, particularly implantation ventricular to the MS, predicted new PPMI following CoreValve (self-expanding valve) TAVR. With regard to an association between calcification and the need for PPMI, Fujita et al. (14) studied cohorts of both SAPIEN XT (second generation balloon expandable valve) TAVR and self-expanding valve TAVR and suggested a relationship between the severity or distribution of left coronary cusp leaflet calcification and the need for PPMI. Moreover, DLZ calcification emerged as an important predictor of new PPMI after self-expanding TAVR in a subsequent study (15). The present study assessed the influence of the precise distribution of aortic-valvular complex calciﬁcation on the need for PPMI following TAVR as well as scrutinizing the impact of MS length of implant on PPMI after third generation balloon expandable valve TAVR.
The current study examined leaflet sectors and craniocaudal regions of the aortic-valvular complex with respect to the need for PPMI. Interestingly, patients requiring PPMI had greater right coronary cusp or left coronary cusp sector calcification in the region of the leaflets. When a bioprosthesis is deployed within a severely and asymmetrically calcified leaflet, it is conceivable that there is a contre-coup effect in that the device is directed away from the more calcified leaflets. In our study, from the right and left coronary cusp sectors to the NCC sector, where there is less calcium and more space, greater pressure is exerted on the atrioventricular node, which passes adjacent to the ventricular aspect of this sector. Conversely, patients who underwent new PPMI had greater NCC sector calcification in the DLZ or LVOT regions; in the region of the DLZ or LVOT, the presence of excess calcium may result in extrusion or trauma, with the calcium compressed by the stent frame directly onto the cardiac conduction system in this region (a representative case is shown in Online Figure 1). This could account for the specific anatomic distribution of calcification that was observed to predict PPMI in the present cohort.
Our findings are consistent with early data from the pre-CT era in which NCC thickness measured during pre-TAVR 3-dimensional transesophageal echocardiography predicted new PPMI following self-expanding valve TAVR (21). Increased pressure to the annulus, the fibrous skeleton, the interventricular septum, and the structures of the conduction system may be contributory. The atrioventricular node and its left bundle branch are adjacent to the NCC of the aortic valve within the central fibrous body (22).
In the present study, on multivariate analysis, significant factors for PPMI pre-TAVR included RBBB and MS length. Both these factors were shown to be independent predictors of new PPMI after TAVR in previous studies (2,7,11). Furthermore, with the precise distribution of calcification in the aortic-valvular complex, we demonstrated that NCC-DLZ CA was also independently predictive of PPMI following third generation balloon expandable valve TAVR. Incorporating all these risk factors, a contemporary and highly predictive model for PPMI post–third generation balloon expandable valve TAVR was created. The model demonstrates an important synergistic interaction of risk factors for PPMI that may help to identify patients at risk for PPMI before the procedure as a result of nonmodifiable factors such as RBBB, MS length, and NCC-DLZ CA, in addition to the modifiable factor of implantation depth. Finally, although our single-center retrospective findings manifested a highly predictive risk model, future prospective multicenter validation studies with larger number of patients may clarify this subject further.
The relatively low number of events (new PPMI in 35 patients) mandated the forward stepwise method of multivariable analysis that could have excluded relevant variables with a weaker predictive value. Recently, Edwards Lifesciences has changed the instructions for use in regard to device positioning, thus conceivably facilitating less ventricular implants with a lower need for PPMI. The model was robust and statistically valid, and it identifies the most important factors for PPMI, but it is not intended as an exhaustive analysis of weaker predictive factors that may be less relevant to decision making.
We demonstrated a highly predictive model for new PPMI after third generation balloon expandable valve TAVR. By using a precise characterization of distribution of calcification in the aortic-valvular complex, NCC-DLZ CA emerged as an independent predictor of new PPMI post-third generation balloon expandable valve TAVR. The procedural aspect of higher device implantation, particularly relative to MS length, mitigates PPMI for third generation balloon expandable valve TAVR. This study also highlights the importance of pre-procedural MS length measurement before TAVR, identification of pre-existing RBBB, and heavy NCC-DLZ calcification for risk evaluation for PPMI post-TAVR.
COMPETENCY IN MEDICAL KNOWLEDGE: By using a precise characterization of distribution of calcification in the aortic-valvular complex, NCC-DLZ CA emerged as an independent predictor of new PPMI post-third generation balloon expandable valve implantation. We describe a predictive model for PPMI after third generation balloon expandable valve TAVR that was found to have a high negative predictive value. Therefore, our findings demonstrate the importance of risk assessment of PPMI before third generation balloon expandable valve TAVR.
TRANSLATIONAL OUTLOOK: Future studies with different valve types should evaluate the relationship between NCC-DLZ CA and the need for new PPMI post-TAVR.
The authors thank Masataka Taguri, PhD, Assistant Director of Department of Biostatistics, University of Yokohama City, Japan, for his professional statistical support.
For supplemental tables and figures, please see the online version of this paper.
Dr. Jilaihawi is a consultant for Edwards Lifesciences, St. Jude Medical, and Venus MedTech. Dr. Makkar has received grant support from Edwards Lifesciences and St. Jude Medical; is a consultant for Abbott Vascular, Cordis, and Medtronic; and holds equity in Entourage Medical. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- calcium volume
- device landing zone
- left ventricular outflow tract
- membranous septum
- noncoronary cusp
- permanent pacemaker implantation
- right bundle branch block
- transcatheter aortic valve replacement
- Δ MSID
- difference between membranous septum length and implantation depth
- Received May 24, 2016.
- Revision received October 28, 2016.
- Accepted November 10, 2016.
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