Early Clinical Outcomes of Transcatheter Aortic Valve Replacement in Left Ventricular Outflow Tract Calcification: New-Generation Device vs Early-Generation Device

Abstract: Background. Transcatheter aortic valve replacement (TAVR) in cases with left ventricular outflow tract calcification (LVOT-CA) remains a challenging procedure. The aim of this study was to compare the early outcomes of patients undergoing TAVR in LVOT-CA with new-generation devices vs early-generation devices. Methods. Between January 2014 and December 2016, a total of 433 patients with severe aortic stenosis who had a preprocedural multidetector computed tomography underwent TAVR in a LVOT-CA. After propensity matching, data from 119 patients in each group were analyzed. TAVR endpoints and adverse events were defined according to the Valve Academic Research Consortium-2. Results. Compared with early-generation devices (Edwards Sapien/Sapien XT/CoreValve), new-generation devices (Sapien 3/Evolut R) had significantly lower incidence of mild-moderate paravalvular leak (PVL) (1.7% new vs 7.6% early; P=.03), tended to have lower incidence of moderate or severe PVL (5.0% new vs 11.8% early; P=.06), had no significant difference in device success (89.1% new vs 83.2% early; P=.19), and had a significantly higher early safety rate at 30 days (93.3% new vs 84.9% early; P=.04). For cardiac conduction disturbances, new-generation and early-generation devices had similarly high rates of new permanent pacemaker implantation (16.8% new vs 15.1% early; P=.72), whereas the number of patients who developed new-onset left bundle-branch block (LBBB) were significantly higher in those with new-generation devices (16.0% new vs 6.7% early; P=.03). Conclusion. In the setting of LVOT-CA, patients with new-generation devices compared to those with early-generation devices had acceptable clinical outcomes except for cardiac conduction disturbances, especially in new-onset LBBB. 

J INVASIVE CARDIOL 2018;30(11):421-427.

Key words: LVOT calcification, TAVI, TAVR

Transcatheter aortic valve replacement (TAVR) has become a well-accepted option for treating patients with symptomatic severe aortic stenosis at intermediate to high or extreme surgical risk.^1-4 New-generation devices (Sapien 3 [Edwards Lifesciences]; Evolut R [Medtronic]) have been shown to improve long-term or early clinical outcomes compared to early-generation devices (Sapien and Sapien XT [Edwards Lifesciences] and CoreValve [Medtronic]).^3,4 However, many trials have established TAVR as the standard treatment in patients with intermediate to high or extreme surgical risk.^1-4 Previous studies have shown that TAVR for calcification in the aortic-valvular complex, especially left ventricular outflow tract calcification (LVOT-CA), resulted in various procedure-related complications and remains a major concern.^5-11 Although new-generation devices showed favorable outcomes in patients with high surgical risk as well as in inoperable patients,^3,4 the experience of TAVR in LVOT-CA with new-generation devices has not been reported. Therefore, the aim of this study was to compare the early outcomes of patients undergoing TAVR in LVOT-CA using new-generation devices vs early-generation devices.

Methods    

Study population and procedure. Between January 2014 and December 2016, a total of 843 patients with inoperable or severe aortic stenosis who had a preprocedural multidetector computed tomography (CT) underwent TAVR at Cedars-Sinai Heart Institute. After excluding patients without LVOT-CA and patients with poor CT imaging quality, a total of 433 patients were included in this cohort. These patients were divided into two groups according to new-generation (Sapien 3/Evolut R) or early-generation (Sapien/Sapien XT/CoreValve) device designs (Figure 1). The decision to proceed with TAVR was made with the consensus of a dedicated heart team. Device sizes were based on the operator’s discretion using preprocedural multidetector CT or three-dimensional transesophageal echocardiography findings. Clinical data, echocardiographic data, and procedural variables were prospectively recorded. TAVR endpoints, procedural device success, composite safety endpoint at 30 days, and adverse events were defined according to the Valve Academic Research Consortium (VARC)-2.¹² Postprocedural paravalvular leak (PVL) was assessed in line with VARC-2 criteria using transesophageal echocardiography within 24-48 hours after the procedure and was reviewed retrospectively.¹²New-onset left bundle-branch block (LBBB) was defined as any new LBBB occurring during the hospitalization period after TAVR. 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.

CT image acquisition and aortic annulus analysis. Aortic root measurements were performed using 3mensio Structural Heart software (3mensio Valves, Version 8.1; Pie Medical Imaging). Severity of LVOT-CA was assessed as follows: (1) mild = 1 nodule of calcium extending <5 mm and covering <10% of the perimeter of the annulus; (2) moderate = 2 nodules or 1 extending >5 mm or covering >10% of the perimeter of the annulus; and (3) severe = multiple nodules or a single focus extending >1 cm in length or covering >20% of the perimeter of the annulus (Figure 2).^6,7,11 An 850 HU threshold was used to detect areas of calcification in the region of the valve leaflet.^5,7,8 Predeployment and postdeployment CT images are shown in Figures 3 and 4.

Statistical analysis. Continuous variables were tested for normality of distribution using the Shapiro-Wilk test and reported and analyzed appropriately thereafter. Categorical variables were compared by Chi-square statistics or Fisher’s exact test. Mann-Whitney U-test was used in cases of abnormal distribution. The propensity score has been developed using a logistic regression model according to a non-parsimonious approach. All clinical variables (eg, age, gender, body surface area, hypertension, diabetes mellitus, peripheral artery disease, chronic obstructive pulmonary disease, ischemic heart disease, previous coronary artery bypass graft surgery, previous myocardial infarction, previous stroke/hemorrhage, previous pacemaker, New York Heart Association ≥3, estimated glomerular filtration rate, Society of Thoracic Surgery (STS) risk score, logistic EuroScore, atrial fibrillation, LBBB, right bundle-branch block, ejection fraction, aortic valve area, mean gradient, pulmonary hypertension, bicuspid valve, aortic annulus area, aortic annulus perimeter, leaflet calcium volume, and severity of LVOT-CA) as well as procedural data (alternative access and device type) were included in the analysis. For these variables, propensity-score matching was performed without replacement using a caliper of 0.1 of the standard deviation of the logit of the propensity score. After matching, continuous variables were compared using the Wilcoxon signed-rank test. For normal distribution, a paired t-test was used. Differences for matched categorical variables were analyzed with McNemar’s test. All statistical tests were two-sided, and P-values <.05 were considered significant. SPSS statistics software 22.0 (SPSS) was used to perform all statistical evaluations.

Results

Baseline characteristics and 30-day outcomes of the unadjusted cohort are shown in Supplemental Tables S1 and S2. Prevalence rates of right bundle-branch block and atrial fibrillation were significantly higher in the new-generation device group, whereas patients in the early-generation device group had higher STS score, previous use of a pacemaker, or pulmonary hypertension. For procedural outcomes, no significant differences were found in the leaflet calcium volume between the two groups, but the early-generation device group more frequently had ≥ moderate LVOT-CA. Alternative access was more frequently performed in the early-generation device group. Moreover, self-expanding devices were used more often in the early-generation device group. Other clinical baseline parameters were comparable. For clinical outcomes, patients with new-generation devices had greater device success and lower area over-sizing rate and PVL rate, and were associated with a higher rate of new-onset LBBB. At 30 days, compared to those with an early-generation device, patients with a new-generation device had a significantly higher early safety because no patient had all-cause mortality. After matching, data of 119 patients in each group were analyzed. Both groups were well balanced, with no significant differences in baseline characteristics or procedural variables (Table 1). The c-statistic of propensity for the logistic model used to generate the propensity score was 0.74 (95% confidence interval, 0.70-0.79), and the Hosmer-Lemeshow test was not significant (P=.24).

Details on the procedural outcomes after propensity-score matching are summarized in Table 2. Comparing both groups, mild-moderate PVL was significantly lower in the new-generation device group (1.7% for new devices vs 7.6% for early devices; P=.03), and moderate or severe PVL tended to lower in the new-generation device group (5.0% for new devices vs 11.8% for early devices; P=.06). There was no significant difference in device success for both groups (89.1% for new devices vs 83.2% for early devices; P=.19). Two procedure-related deaths were reported in the early-generation device group (1.7%), but none were reported in the new-generation device group. Area over-sizing rate was significantly lower in the new-generation device group (7.4% for new devices vs 16.4% for early devices; P<.001). At 30-day follow-up, no case of all-cause death occurred in the new-generation device group, which was significantly lower than in the early-generation device group (0.0% vs 4.3%, respectively; P=.03). Stroke was significantly greater in the early-generation device group than in the new-generation device group (0% vs 5.0%, respectively; P=.03). Although no differences were observed concerning the incidence of myocardial infarction, acute kidney injury, life-threatening bleeding, and major vascular complications between the two groups, patients with a new-generation device had a significantly higher early safety rate at 30 days vs those with an early-generation device (93.3% vs 84.9%, respectively; P=.04).

For conduction disturbances, new pacemaker implantation rates were similar for both groups (16.8% for new devices vs 15.1% for early devices; P=.72), whereas the new-generation device group had higher new-onset LBBB rate (16.0% for new devices vs 6.7% for early devices; P=.03). Among patients with a new-generation device, new-onset LBBB was present in 8 patients (53.3%) with Evolut R device and in 11 patients (10.6%) with Sapien 3 device.

Regarding long-term prognosis, cumulative all-cause mortality at 1 year between the two groups had no significant difference (7.2% for new devices vs 13.1% for early devices; P=.15 by log-rank test) (Figure 5).

Discussion

In the setting of LVOT-CA, our findings can be summarized as follows: (1) the rate of mild-moderate PVL was significantly decreased and moderate or severe PVL tended to decrease with new-generation devices when compared with early-generation devices; (2) early safety rate at 30 days was significantly higher in the new-generation device group; and (3) the use of new-generation device TAVR resulted in higher incidence of new-onset LBBB.

A previous study reported that moderate-severe PVL was associated with long-term morbidity and mortality.¹³ However, there has been no report on how much the left ventricular dysfunction caused by mild-moderate PVL influences long-term mortality in cases of mild-moderate PVL. As previously reported,^{3,4,7,9,14-16} compared with early-generation devices, the use of new-generation devices allows for an overall low incidence and extent of PVL. Regardless of device design, LVOT-CA is strongly associated with PVL following TAVR.^7,9,10,16 Nevertheless, only a few studies have reported the incidence of PVL post new-generation device in LVOT-CA. The present study is the first attempt to determine the influence of LVOT-CA on PVL using new-generation or early-generation device TAVR. In the setting of LVOT-CA, the use of new-generation devices for TAVR also resulted in a lower rate of PVL than using early-generation devices. These findings imply that the improved sealing skirts of both new devices designed to reduce PVL may have efficacy for LVOT-CA. In addition, compared with the Core-Valve device, the Evolut R device has an improved frame design to provide increased over-sizing and more consistent radial force across the annular range, and has the ability to recapture and reposition the device.^4,14 On the contrary, the Sapien 3 device has a flared inflow morphology unlike early balloon-expandable devices. These may contribute to a lesser degree of PVL with the new-generation devices.¹⁷

For all clinical outcomes at 30 days, stroke occurrence rate was significantly lower in the new-generation device group. The incidence of 30-day stroke was reported to be lower in the balloon-expandable new-generation device group vs the early-generation device group.^1,3 Considering the patient ratio in the balloon-expandable and self-expandable groups, the stroke occurrence rate in this study appeared to be a concordant result. In particular, stroke occurs after TAVR, and 30-day mortality was reported to increase by 6.5 times.¹⁸ This was presumed to be one of the reasons that all-cause mortality was significantly lower in the new-generation device group. Based on these factors, early safety in the new-generation device group was significantly higher. These findings reflect the advantages of the lower delivery system profile of new-generation devices.^3,4,14 Moreover, the Commander delivery catheter for the Sapien 3 device provides a stable platform to allow controlled coaxial alignment, and accurate positioning of the prosthesis within the native valve may help lower procedural complication rates.

TAVR-related new-onset conduction disturbances remain the most common complication.^1,2,19 In the setting of LVOT-CA, despite the higher rates of new-onset LBBB in the new-generation device group, both groups had similarly high rates of new permanent pacemaker implantation in our findings. Previous studies demonstrated that the presence of LVOT-CA predicted new-onset conduction disturbances following TAVR.^8,20 Our findings are consistent with prior studies. The CoreValve Evolut R U.S. Clinical Study reported that the need for permanent pacemaker or new-onset conduction disturbance was significantly lower for the Evolut R device, which has the ability to recapture and reposition to reduce conduction disturbances.⁴ On the contrary, optimal implantation depth of the Sapien 3 device kept permanent pacemaker implantation rate in the same range as observed with the Sapien XT device.²¹ Nevertheless, the present study showed that patients new-generation devices in LVOT-CA had high incidence of new-onset LBBB which was related to mortality.¹⁹ A possible explanation for this finding of new-onset LBBB is a flared inflow morphology or radial expansive force. The Evolut R device is an ongoing development of the inflow nitinol frame after device deployment. For balloon-expandable devices, the Sapien 3 device has a flared inflow morphology and sealing skirt, whereas the early-generation device has relatively constrained inflow morphology after the procedure.¹⁷ Therefore, in the cardiac conduction system, the left bundle branch might be susceptible to most conduction disturbances with new-generation devices. Moreover, unlike early-generation devices, new-generation devices have high radial expansive force.^4,14,17 Consequently, the mechanical damage on the cardiac conduction system might be more increased locally by the rough distribution of radial forces, especially the presence of LVOT-CA.

Finally, this study showed that new-generation devices may be more efficient compared to early-generation devices in the setting of LVOT-CA. We emphasize that less over-sizing is acceptable to decrease the rate of PVL in the setting of LVOT-CA; however, conduction disturbances, especially new-onset LBBB, should be considered. We should monitor conduction disturbances after implantation of new-generation devices. Furthermore, device durability for long-term follow-up is necessary. Future multicenter studies with larger study populations and longer follow-up may further clarify this subject.

Study limitations. The main limitations of the present study are as follows. First, this is a retrospective, single-center experience. Second, the higher volume of balloon-expandable devices compared with self-expanding devices may also have influenced the results. Third, valve size selection based on the operator’s decision was one of the confounding factors. Fourth, selection bias should be considered with this non-randomized study, even after the propensity-score matching. Fifth, PVL was not assessed by an echocardiography core laboratory.

Conclusion

In the setting of LVOT-CA, compared to using early- generation devices, TAVR using new-generation devices resulted in lower rates of stroke and all-cause mortality and a higher rate of early safety at 30 days. However, for cardiac conduction disturbances, new-onset LBBB after implantation of new-generation devices remains a major concern.

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From the ¹Cedars-Sinai Medical Center, Heart Institute, Los Angeles, ²New York university Langone Medical Center, New York.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Jilaihawi is a consultant for Edwards Lifesciences, St. Jude Medical, and Venus MedTech. Dr Makkar reports grant support from Edwards Lifesciences and St. Jude Medical; consultant income from Abbott Vascular, Cordis, and Medtronic; equity in Entourage Medical. The remaining authors report no potential conflicts of interest regarding the content herein. 

Manuscript submitted July 5, 2018, provisional acceptance given July 12, 2018, final version accepted July 24, 2018.

Address for correspondence: Yoshio Maeno, MD, PhD, Advanced Health Sciences Pavilion, Cedars-Sinai Heart Institute, 127 S. San Vicente Blvd, Third Floor, Suite A3600, Los Angeles, CA 90048. Email: yoshiomaeno@yahoo.co.jp