There are limited data regarding predictors and impact of permanent pacemaker implantation (PPI) among patients with raphe-type bicuspid aortic valve (BAV) stenosis undergoing transcatheter aortic valve replacement (TAVR). The aim is to evaluate the incidence, predictors and clinical impact of PPI among patient with raphe-type BAV treated with TAVR. The AD-HOC is an international registry enrolling patients with raphe-type BAV stenosis undergoing TAVR. We investigated the incidence of PPI; clinical, anatomical and procedural predictors of PPI were assessed. The impact of PPI on overall survival and on the Valve Academic Research Consortium-3 (VARC-3) clinical efficacy endpoint, defined as freedom from death, heart failure (HF) hospitalizations or TIA/stroke, was evaluated. Among the 912 patients, PPI after TAVR was required in 141 cases (15.5%). The VARC-3 technical success and device success endpoints were met in 94.7% and 85.2% of patients with no differences between those with and without PPI. Independent predictors of PPI included peripheral vascular disease (OR: 2.05, 95% CI: 1.09-3.87, p = 0.026), chronic kidney disease (OR: 1.53, 95% CI: 1.04-2.26), right bundle branch block (RBBB- OR: 5.88, 05% CI: 3.33-10.38), R-L raphe localization (OR: 2.51, 95% CI: 1.24, 5.10) and use of Evolut R/Pro/Pro+ (OR: 1.68, 95% CI: 1.18-2.68, p = 0.006). At follow-up, VARC-3 clinical efficacy endpoint was similar (log-rank p = 0.579). In conclusions, PPI following TAVR in BAV is relatively common but without impact on mid-term clinical outcome. Beyond preprocedural RBBB and the use of Evolut valves, PPI had unique anatomical predictors within this population, such as the R-L raphe localization. The AD-HOC is an observational, international, multicenter registry enrolling patients with raphe-type 1 BAV stenosis undergoing TAVR at 24 Institutions from 2016 to 2023. Among the 912 included patients, new PPI was required in 141 cases (15.5%). The VARC-3 technical success and device success endpoints were met in 94.7% and 85.2% of patients, respectively, with no differences between those with and without PPI. At multivariable logistic regression analysis, independent predictors of PPI after TAVR included peripheral vascular disease, chronic kidney disease, preprocedural RBBB, the R-L raphe localization and the use of Evolut R/Pro/Pro+ valves. No differences were noticed between PPI and no-PPI recipients in terms of the VARC-3 efficacy endpoint at the 3-year follow-up.
Transcatheter aortic valve replacement (TAVR) is a well-established treatment option for severe aortic valve stenosis (AS) and its use is progressively expanding to younger and lower-risk patients in whom the prevalence of bicuspid aortic valve (BAV) anatomy is higher. While the impact of permanent pacemaker implantation (PPI) following TAVR in tricuspid aortic valves (TAV) is well established, there are still few data about the incidence, predictors and prognostic relevance of PPI following TAVR in raphe-type BAV.
BAVs present unique anatomical characteristics with potential impact on procedural complications after TAVR. At first, raphe presence and localization and calcium bridge can influence the interaction between the transcatheter heart valve (THV) and the conduction system. Secondly, the distribution and pattern of annular and aortic root calcifications differ between tricuspid and bicuspid anatomy. Thirdly, THV sizing in BAV is challenging, with several potential approaches being described, potentially impacting on the development of either conduction disturbances or paravalvular regurgitation (PVR).
The continuous pacemaker stimulation following TAVR in TAVs can lead to progressive left ventricular dysfunction, translating into high rates of death and heart failure (HF) hospitalizations during follow-up. The nonphysiological pacemaker stimulation might have an even worse impact among younger patients with BAV, who have longer life expectancies. For the aforementioned reasons, our study sought to evaluate the incidence, predictors and clinical outcomes of PPI among patients with BAV stenosis treated with TAVR.
Methods
Study population
The “Characteristics, sizing, and outcomes of stenotic raphe-type bicuspid aortic valves treated with transcatheter device implantation” (AD HOC) is an observational, retrospective, international, multicenter registry that aimed to describe the phenotypic characteristics of severe, Sievers type 1 BAV stenosis treated with TAVR and to evaluate the safety and efficacy of contemporary-generation THVs. The study’s rationale and design have been previously detailed. Briefly, all consecutive patients with severe AS and Sievers type 1 BAV who underwent transfemoral TAVR at 24 international centers between January 2016 and January 2023 were included ( Supplementary Table 1 ).
Inclusion criteria were age ≥18 years, severe AS, type 1 BAV pattern based on Sievers’ classification, and the availability of preprocedural multislice computed tomography (MSCT). Exclusion criteria were Sievers type 0 or type 2 BAV, valve-in-valve procedure, pure aortic regurgitation, and nontransfemoral approaches. In the present analysis, patients with prior pacemaker implantation were also excluded.
All participants provided written informed consent for the procedure and data collection, following local practices and/or local institutional review board approval. Local multidisciplinary Heart Teams evaluated all patients and confirmed the indications for TAVR. The choice of THV (type and size) and all intraprocedural steps were at the discretion of the operators.
MSCT analysis
All included patients underwent preprocedural MSCT and pre and postprocedural transthoracic echocardiography. MSCT and echocardiographic images were analyzed by board-certified expert readers in each center according to current recommendations. Maximum length of the raphe and antiraphe space were captured and analyzed on MSCT. The extent of raphe calcification was graded semiquantitatively into fibrotic (absence of calcification), mild (spotty calcification extending over no more than half of the raphe), moderate (bulky or linear calcification extending over more than half) and severe (bulky and linear calcification covering the entire raphe). The degree of calcification was also assessed at the level of aortic leaflets, annulus, left ventricular outflow tract (LVOT), and nonfused coronary cusps. The pattern of calcium of the nonfused cusp was classified as restrictive, unrestrictive or intermediate. Virtual raphe ring (VRR) was defined as the supra-annular plane that cuts the raphe at its maximum protrusion along the aortic root; VRR perimeter was measured by drawing the internal leaflets margin with the valve open in systole, and intercommissural distance was defined as the major supra-annular diameter.
The measurements on the aortic annulus were performed in a plane aligned with the most basal attachment points of the three aortic valve cusps, as recommended. Annular area ≤430 mm 2 was used to define a small aortic annulus. A tapered configuration (in which supra-annular dimensions are smaller compared to annular ones) was retrospectively defined if at least one of the supra-annular sizing methods (BAVARD, LIRA, CASPER, and CIRCLE- method, calculated in all the enrolled patients with latter applied only for balloon-expandable THV, Supplementary Table 2 ) indicated narrower dimensions at the supra-annular level than the annulus level, which may require THV downsizing. ,,,, Aortic angle was defined as the angle between the virtual raphe ring and the horizontal plane, as previously described.
Study endpoints
Clinical follow-up was conducted via either inpatient or outpatient visit or telephone interviews. All adverse events were site reported.
New permanent pacemaker implantation (PPI) was defined as any PPI occurring within 30 days after TAVR. The primary endpoint was Valve Academic Research Consortium-3 (VARC-3) clinical efficacy at the longest available follow-up, defined as freedom from death, heart failure (HF) hospitalizations or TIA and stroke. Secondary endpoints included the individual components of the VARC-3 clinical efficacy endpoint and early endpoints of interest such as VARC-3 technical success (at exit from procedure room), device success and hemodynamic valve performance (at 30 days). All secondary endpoints were assessed and defined according to VARC-3 recommendations. For endpoints assessed at 30 days, in-hospital data were used if 30-day data were not available.
Statistical analysis
Continuous variables are reported as mean ± standard deviation or median (interquartile range [IQR]) and compared using Student’s t-test or the Mann-Whitney U or Wilcoxon test on the basis of normality of data, verified using the Kolmogorov-Smirnov goodness-of-fit test. Categorical variables are reported as number (percentage) and compared using the chi-square test with Yates’s correction for continuity or the Fisher exact test as appropriate.
Multivariable logistic regression analysis was conducted to identify the independent predictors of PPI. Only covariates with a univariable p-value < 0.10 were included in the multivariable analysis. The Hosmet-Lemeshow goodness-of-fit test and the C-statistic were used to evaluate the validity of the multivariable models.
Cumulative incidence of adverse events at the longest available follow-up was assessed using the Kaplan-Maier method and compared between groups using the log-rank test for time to first event. Clinical follow-up was censored at the date of death or latest available follow-up. Cox proportional hazard regression analysis was also performed to assess the prognostic impact of PPI on clinical outcomes at the longest available follow-up. Such impact was evaluated by means of multivariable analysis adjusting PPI after TAVR for the following covariates of interest: sex, age, body mass index (BMI), coronary artery disease (CAD), peripheral vascular disease, chronic obstructive pulmonary disease (COPD), New York Heart Association (NYHA) class, glomerular filtration rate (GFR), left ventricular ejection fraction (LVEF), aortic valve area (AVA), hemodynamic valve performance. All reported p-values were 2-sided and a p < 0.05 was considered statistically significant. Statistical analyses were conducted using Stata version 17 (Stata Corp, College Station, TX, USA).
Results
A total of 980 patients with BAV undergoing TAVR were included in the AD HOC registry. Of these, 68 had a previously implanted pacemaker and were therefore excluded. Among the 912 included patients, new PPI after TAVR was required in 141 cases (15.5%). When stratified by valve type, the incidence of PPI was lowest among patients receiving the Acurate Neo/ Neo 2 (Boston Scientific; N = 8/86, 9.3%) and progressively higher with the Sapien 3, Sapien 3 Ultra or MyVal (Edwards Lifesciences and Meril, respectively; N = 39/383, 10.2%), Evolut R, Pro or Pro+ (Medtronic; N = 71/350, 20.3%), Portico or Navitor (Abbott; N = 8/39, 20.5%) and other THVs including Lotus, Venus-A-Plus, Taurus and Prizvalve (N = 12/42, 28.6%; p for trend < 0.001).
Baseline characteristics
Patients requiring PPI had a higher burden of comorbidities at the time of TAVR, including peripheral vascular disease, COPD and CKD, as shown in Table 1 . Mean Society of Thoracic Surgeon Mortality (STS-M) score was 2.5% (IQR: 1.5, 3.8), with no differences between the PPI and no PPI groups. The prevalence of right bundle branch block (RBBB) at baseline EKG was higher in the PPI group (21.3% vs 5%, p < 0.001). Similarly, patients requiring PPI had a numerically higher prevalence of type 1 atrio-ventricular block, although not statistically significant (21.3% vs 15.5%, p = 0.092), while left bundle branch block was equally common in both groups. A severely depressed LVEF (<40%) was observed in 13.2% of patients overall, with no between-group differences.
Table 1
Clinical, EKG and echocardiographic features of the study population
| PPI (N = 141) | No PPI (N = 771) | p-value | |
|---|---|---|---|
| Male sex | 97 (68.8%) | 470 (61.0%) | 0.078 |
| Age at procedure (years), median (IQR) | 79.0 (75.0, 83.5) | 78.0 (73.0, 82.2) | 0.15 |
| Age ≥75 years | 102 (72.3%) | 504 (65.4%) | 0.11 |
| BMI (kg/m 2), median (IQR) | 25.9 (23.7, 29.1) | 25.3 (22.9, 28.2) | 0.070 |
| Obesity | 31 (22.0%) | 125 (16.2%) | 0.094 |
| Hypertension | 111 (78.7%) | 549 (71.2%) | 0.066 |
| Diabetes | 24 (17.0%) | 134 (17.4%) | 0.92 |
| Coronary artery disease | 54 (38.3%) | 238 (30.9%) | 0.082 |
| Peripheral vascular disease | 19 (13.5%) | 56 (7.3%) | 0.014 |
| Carotid artery disease | 3 (2.1%) | 37 (4.8%) | 0.15 |
| Atrial fibrillation | 37 (26.2%) | 208 (27.0%) | 0.86 |
| Previous TIA/stroke | 10 (7.1%) | 73 (9.5%) | 0.36 |
| Chronic obstructive pulmonary disease | 32 (22.7%) | 115 (14.9%) | 0.021 |
| NYHA class pre-TAVI | 0.081 | ||
| I | 12 (8.5%) | 29 (3.8%) | |
| II | 55 (39.0%) | 307 (39.8%) | |
| III | 66 (46.8%) | 376 (48.8%) | |
| IV | 8 (5.7%) | 59 (7.7%) | |
| Euroscore II (%), median (IQR) | 2.5 (1.7, 3.9) | 2.5 (1.6, 3.7) | 0.77 |
| STS-M score (%), median (IQR) | 2.5 (1.6, 3.7) | 2.5 (1.5, 3.8) | 0.67 |
| Preprocedural GFR (ml/min/1.73), median (IQR) | 63.6 (46.0, 80.0) | 68.0 (53.0, 84.1) | 0.014 |
| Stage ≥3 CKD | 66 (46.8%) | 267 (34.6%) | 0.006 |
| History of atrial fibrillation | 37 (26.2%) | 208 (27.0%) | 0.86 |
| Type 1 atrio-ventricular block | 30 (21.3%) | 118 (15.5%) | 0.092 |
| Preprocedural right bundle branch block | 30 (21.3%) | 38 (5.0%) | <0.001 |
| Preprocedural left bundle branch block | 13 (9.2%) | 71 (9.3%) | 0.99 |
| Left ventricular ejection fraction (%), median (IQR) | 60.0 (50.0, 65.0) | 60.0 (47.0, 64.0) | 0.22 |
| Left ventricular ejection fraction <40% | 15 (10.6%) | 105 (13.6%) | 0.34 |
| Aortic gradient (mmHg), median (IQR) | 47.0 (40.0, 58.0) | 49.0 (41.0, 60.0) | 0.44 |
| Low-flow low-gradient aortic stenosis | 24 (17.0%) | 141 (18.3%) | 0.72 |
| Aortic valve area (cm 2), median (IQR) | 0.7 (0.6, 0.8) | 0.7 (0.5, 0.8) | 0.003 |
| Moderate to severe aortic regurgitation | 23 (16.3%) | 105 (13.6%) | 0.40 |
| Moderate to severe mitral regurgitation | 13 (9.2%) | 109 (14.1%) | 0.11 |
Categorical variables are reported as number (percentage). p-values < 0.05 are indicated in bold.
Abbreviations: BMI = body mass index; CKD = chronic kidney disease; GFR: glomerular filtration rate; IQR = interquartile range; PPI = permanent pacemaker implantation; NYHA = New York Heart Association; STS-M = society of thoracic surgeon-mortality; TIA = transient ischemic attack; TAVR = transcatheter aortic valve replacement.
Table 2 shows the baseline MSCT data. The Right-Left (R-L) raphe localization was more common in patients needing PPI (92.9 vs 83.8%), as opposed to the Right-Non-Coronary (R-NC) raphe which was more prevalent in the no PPI group (5.7% vs 15.2%, p = 0.010). Annulus area, sinus of Valsalva diameter and aortic angle were larger in patients undergoing PPI, while there were no differences in terms of annulus and VRR perimeter, raphe/antiraphe index and intercommissural distance. Annular asymmetry, as indicated by an eccentricity index >0.25, was numerically higher in the PPI group, although not statistically significant (36.9% vs 29.4%, p = 0.078). The extent of calcification on the raphe, annulus and LVOT was similar in the two groups.
Table 2
MSCT data of the study population
| PPI ( N = 141) | No PPI ( N = 771) | p-value | |
|---|---|---|---|
| Raphe localization | 0.010 | ||
| R-L | 131 (92.9%) | 646 (83.8%) | |
| R-NC | 8 (5.7%) | 117 (15.2%) | |
| L-NC | 2 (1.4%) | 8 (1.0%) | |
| Raphe type | 0.89 | ||
| Fibrotic | 22 (15.6%) | 135 (17.5%) | |
| Mildy calcified | 31 (22.0%) | 182 (23.6%) | |
| Moderately calcified | 48 (34.0%) | 246 (31.9%) | |
| Severely calcified | 40 (28.4%) | 208 (27.0%) | |
| Index raphe/antiraphe, median (IQR) | 0.4 (0.3, 0.6) | 0.4 (0.3, 0.6) | 0.31 |
| Virtual raphe ring perimeter (mm), median (IQR) | 75.0 (68.3, 79.4) | 73.0 (67.1, 78.9) | 0.22 |
| Virtual raphe ring height (mm), median (IQR) | 8.2 (6.7, 9.8) | 7.8 (6.3, 9.2) | 0.022 |
| Virtual raphe ring inter-commisural distance (mm), median (IQR) | 28.8 (26.4, 31.0) | 28.0 (25.8, 30.4) | 0.054 |
| Inter-commissural distance at 4 mm (mm), median (IQR) | 27.5 (25.7, 29.6) | 27.1 (25.0, 29.0) | 0.089 |
| Tapered configuration, % | 106 (75.2%) | 579 (75.1%) | 0.98 |
| Annular asymmetry (eccentricity index >0.25) | 52 (36.9%) | 227 (29.4%) | 0.078 |
| Annulus area (mm 2), median (IQR) | 525.8 (471.0, 597.0) | 507.2 (442.0, 575.1) | 0.008 |
| Annulus perimeter (mm), mean (SD) | 82.8 (8.6) | 81.6 (8.0) | 0.11 |
| Small aortic annulus, %x | 18 (12.8%) | 161 (20.9%) | 0.026 |
| Mean SOV diameter (mm), median (IQR) | 35.1 (32.6, 37.7) | 34.2 (31.8, 37.0) | 0.027 |
| Mean STJ diameter (mm), median (IQR) | 31.0 (27.6, 33.8) | 30.6 (27.3, 33.2) | 0.48 |
| Ascending aorta diameter at 4 cm (mm), median (IQR) | 37.5 (34.6, 41.0) | 36.8 (33.6, 40.0) | 0.20 |
| Ascending aorta diameter ≥45 mm, % | 11 (7.8%) | 64 (8.3%) | 0.84 |
| LMCA height (mm), median (IQR) | 15.0 (12.7, 17.5) | 14.4 (12.5, 16.6) | 0.093 |
| RCA height (mm), mean (SD) | 17.5 (3.8) | 17.3 (3.6) | 0.54 |
| Aortic angle (°), median (IQR) | 55.0 (47.0, 65.0) | 53.0 (46.0, 60.0) | 0.030 |
| AV calcium scoring (mm 3), median (IQR) | 802.0 (451.3, 1356.0) | 773.6 (417.0, 1365.0) | 0.59 |
| Pattern of calcium of the nonfused cusp | 0.12 | ||
| Restricted | 36 (25.5%) | 157 (20.4%) | |
| Unrestricted | 71 (50.4%) | 366 (47.5%) | |
| Intermedium | 34 (24.1%) | 248 (32.2%) | |
| Annular/LVOT calcification | 0.81 | ||
| Mild | 31 (22.0%) | 163 (21.1%) | |
| Moderate | 16 (11.3%) | 70 (9.1%) | |
| Severe | 6 (4.3%) | 39 (5.1%) | |
| Membranous septum length (mm), median (IQR) | 4.2 (3.0, 5.7) | 4.1 (3.0, 5.8) | 0.64 |
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