Abstract
Background:
Transcatheter aortic valve replacement (TAVR) is now an approved alternative to surgical aortic valve replacement for the treatment of severe aortic stenosis. As the clinical adoption of TAVR expands, it remains important to identify predictors of mortality after TAVR. We aimed to evaluate the impact of sex differences in aortic valve calcium score (AVCS) on long term mortality following TAVR in a large patient sample.
Methods:
We included consecutive patients who successfully underwent TAVR for treatment of severe native aortic valve stenosis from June 2010 to May 2021 across all US Mayo Clinic sites with follow-up through July 2021. AVCS values were obtained from preoperative computed tomography of the chest. Additional clinical data were abstracted from medical records. Kaplan Meier curves and Cox-proportional hazard regression models were employed to evaluate the effect of aortic valve calcium score on long-term mortality.
Results:
A total of 2,543 patients were evaluated in the final analysis. Forty-one percent were women, median age was 82 years (Q1: 76, Q3: 86), 18.4% received a permanent pacemaker following TAVR and 88.5% received a balloon expandable valve. We demonstrate an increase in mortality risk with higher AVCS after multivariable adjustment (p<0.001). When stratified by sex, every 500-unit increase in AVCS was associated with a 7% increase in mortality risk among women (adjusted HR: 1.07, 95% CI: 1.02, 1.12) but not in men.
Conclusions:
We demonstrate a notable sex difference in the association between aortic valve calcium score and long-term mortality in a large TAVR patient sample. This study highlights the potential value of AVCS in pre-procedural risk stratification, specifically among women undergoing TAVR. Additional studies are needed to validate this finding.
Keywords: Aortic Stenosis, Calcium Score, Mortality, Sex differences, TAVR
Journal Subject Terms: Women, Sex and Gender, Valvular Heart Disease, Computerized Tomography, Aortic Valve Replacement/Transcatheter Aortic Valve Implantation, Disparities, Mortality/Survival
INTRODUCTION
Transcatheter aortic valve replacement (TAVR) has been approved as a safe alternative to surgical aortic valve replacement (SAVR) across multiple patient risk levels for the treatment of severe aortic stenosis.1-3 As the utilization of TAVR expands, it remains important to identify factors that influence the risk for adverse events. Historical and contemporary cardiovascular trials typically include fewer women leading to a limited evidence base for evaluating women with cardiovascular disease4, 5. The data regarding mortality after TAVR in women have produced conflicting results. Some studies have indicated worse 30-day mortality among women, largely due to increased bleeding and vascular complications. 6-8 In other studies, female sex has been demonstrated to be associated with decreased mortality following TAVR. 9-12 This underscores the importance of identifying sex dependent risk factors which impact mortality after TAVR.
The aortic valve calcium score (AVCS) measured on computed tomography scans, performed as part of the pre-TAVR evaluation, has been identified as an important contributor to the development of severe aortic stenosis and peri-prosthetic aortic regurgitation13, 14, as well as a risk factor for coronary artery disease progression15. However, women with calcific aortic stenosis are known to have lower AVCS values when compared to men at similar degrees of severity16-18. Hence, the objective of this study was to evaluate sex differences in the impact of AVCS on long-term mortality following TAVR. We hypothesize that AVCS values differentially impact mortality among women compared to men.
METHODS
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Design
This was a retrospective cohort study which included consecutive patients who underwent a TAVR procedure performed at US Mayo Clinic sites (Rochester, MN, Jacksonville, FL, Phoenix, AZ and Mayo Clinic Health Systems) from June 2010 through May 2021 with follow up for outcomes through July 2021. This study was approved by the Mayo Clinic Institutional Review Board (IRB). This study was deemed exempt by the IRB and due to the retrospective nature of the study informed consent was not required.
Study Population
We included all patients aged 18 years and older who had a TAVR procedure during the pre-specified period. Eligibility for TAVR, valve type, size, and access route were determined by the managing team. Patients with an unsuccessful procedure, missing variables, or previous aortic valve replacement (AVR) were excluded from analysis.
Measures
Our primary predictors of interest were sex and AVCS obtained from pre-procedure computed tomography (CT) of the chest reported in Agatston units (AU). All sites performed an AVCS scan prior to the CT angiography of chest, abdomen and pelvis using a standard protocol. Prospective ECG-gated noncontrast CT scans of chest were performed between 65-85% R-R interval, with tube voltage of 120 kVp, and tube current ranging between 80-150 mAs. The images were acquired from the carina through the entire heart and reconstructed at 3mm slice thickness at 1.5 - 2 mm intervals in soft tissue kernel. Imaging was performed on a range of scanners (Siemens- Edge, Definition Flash, Force; GE- Optima 660, Discovery 750HD), and the scanner specific calcium score software was used to calculate AVCS (Siemens- Syngovia; GE- Smartscore). The AVCS was measured by a trained CT technologist and further verified by the interpreting radiologist for accuracy. Caution was needed to exclude the adjacent non-valvular calcifications involving the aorta, coronary arteries, and mitral annulus. Aortic annulus measurements were calculated using multiplanar reformats at the level of most inferior points of the coronary cusp attachments to the aortic root as previously described19. The AVCS and aortic annulus measurements were obtained from the original scan report that were read by a consensus of expert cardiothoracic radiologists in conjunction with a cardiologist. Studies have shown the relationship between AVCS and the degree of aortic stenosis severity varies by sex, as such we aimed to evaluate if the effect of AVCS on long-term mortality differs by sex. The distribution of AVCS, aortic valve annulus area and AVCS density (defined as AVCS/aortic annulus area) stratified by sex is provided in Figure 1. In order to identify a clinically important cut-off value for AVCS in each sex category, we fit a spline to AVCS values for each sex and identified an inflection point occurred around the median values within each sex category, as such we also evaluated AVCS categorized by sex-based median values into high (> 1680 AU in females and >2786 AU in males) vs. low.
Figure 1. Histograms showing distributions of aortic annulus area, aortic valve calcium score and aortic valve calcium score density.
AU – Agatston units
Covariates including age, pre-TAVR aortic valve hemodynamics (peak velocity, mean gradient, calculated valve area and stroke volume index) on echocardiography, left ventricular ejection fraction (LVEF), valve type, valve size, baseline ECG features, pacemaker placement, post TAVR aortic valve variables (aortic valve acceleration time, mean gradient and presence of peri-valvular leak), Society for Thoracic Surgeons (STS) predicted risk of surgical mortality score, and comorbid conditions, were extracted from medical records. The Charlson comorbidity index was calculated which has been validated for predicting mortality20. The presence of a left bundle branch block (LBBB) was categorized into 3 levels: old LBBB (present prior to TAVR), new LBBB (new following TAVR) and no LBBB. The presence of a permanent pacemaker was also categorized into 3 levels: prior pacemaker (placed prior to TAVR procedure), new pacemaker (placed following TAVR procedure) and no pacemaker. We also identified patients whose indication for a pacemaker following the procedure was believed to be TAVR related. Our primary study endpoint was all-cause mortality.
Analysis
Categorical variables were described as frequencies and percents and continuous variables as median and interquartile range (Q1, Q3). Bivariate analyses were performed stratified by sex using Wilcoxon rank sum tests for numerical variables and Pearson’s chi-square tests for categorical variables. We evaluated predictor variables for adherence to the proportional hazards (PH) assumption using Kaplan Meier curves, an extended Cox approach with time-dependent variables, and a correlation of the Schoenfeld residuals with ranked follow-up time. Kaplan Meier analysis and Cox-proportional hazard (Cox PH) regression models were employed to evaluate the sex-specific effect of AVCS on mortality. An interaction term between sex AVCS was initially evaluated and then sex-stratified analysis were generated. In order to control for multiple variables in adjusted Cox PH models as well as ensuring an effective, yet parsimonious model, a propensity score was created using a gradient boosted logistic regression model and the propensity score was then included as a covariate in the final model. Variables included in the propensity score were age, pre-TAVR peak aortic valve velocity, pre-TAVR calculated valve area, pre-TAVR stroke volume index, pre-TAVR LVEF, pacemaker implantation, LBBB, Charlson comorbidity index, STS predicted risk of surgical mortality, TAVR access type, valve type, procedure site and post-TAVR peri-valvular leak based on bivariate analysis, clinical plausibility, and prior literature showing pacemaker implantation and LBBB to be key predictors of mortality following TAVR.21. Given lower AVCS values22 and smaller aortic annulus area in women23, AVCS density and sex-specific AVCS percentiles were also evaluated in relation to mortality. All statistical analyses were performed using R version 4.0.3 (Vienna, Austria)24 and a p-value of <0.05 was considered statistically significant.
RESULTS
A total of 3,021 patients were evaluated for inclusion, 32 were excluded due to an unsuccessful or no TAVR procedure performed, 433 due to missing AVCS, 6 due to procedure being performed at a non-Mayo Clinic site and 7 due to previous aortic valve replacement. Ultimately, as demonstrated by Figure 2, 2,543 patients were included in the final analysis. The median follow-up time overall was 2.3 years (Q1: 1.0 years; Q3: 4.2 years) and 459 and 316 deaths were observed during follow up in males and females, respectively.
Figure 2. Study flow diagram.
AVCS – Aortic valve calcium score; AVR – Aortic valve replacement
Table 1 shows descriptive information for the study sample stratified by sex. The median age was 82 years and 41% were female. Three hundred and forty patients (13.4%) had a permanent pacemaker prior to the TAVR procedure and 467 (18.4%) had a new permanent pacemaker placed post-procedure, with 442 of those being related to the TAVR procedure. Women undergoing a TAVR procedure had higher rates of pre- and post-procedural LBBB, smaller valve sizes, lower AVCS, and lower rates of pre- and post-procedural pacemaker implantation (Table 1). We also provide a distribution of categorical TAVR valve sizes by sex in supplemental table 1.
Table 1.
Patient demographic and clinical characteristics
| Characteristics | Female n= 1,041 (%) |
Male n= 1,502 (%) |
Overall n= 2,543 (%) |
p-value |
|---|---|---|---|---|
| Age* | 82.1 (76.1, 86.7) | 81.6 (75.9, 86.2) | 81.7 (76.0, 86.4) | 0.10 |
| Follow-Up Time (years)* | 2.5 (1.1, 4.3) | 2.2 (0.9, 4.1) | 2.3 (1.0, 4.2) | 0.010 |
| Conduction Disturbances Pre-procedure | ||||
| 1st degree AV block | 160 (15.4) | 336 (22.4) | 496 (19.5) | <0.001 |
| Mobitz type 1 AV block | 1 (0.1) | 4 (0.3) | 5 (0.2) | 0.34 |
| Mobitz type 2 AV block | 1 (0.1) | 0 (0.0) | 1 (0.0) | 0.23 |
| 3rd degree AV block | 1 (0.1) | 1 (0.1) | 2 (0.1) | 0.79 |
| LBBB | 78 (7.5) | 69 (4.6) | 147 (5.8) | 0.002 |
| RBBB | 87 (8.4) | 248 (16.5) | 335 (13.2) | <0.001 |
| Atrial fibrillation/flutter | 194 (18.6) | 362 (24.1) | 556 (21.9) | 0.001 |
| Conduction Disturbances Post-procedure | ||||
| 1st degree AV block | 212 (20.4) | 383 (25.5) | 595 (23.4) | 0.003 |
| Mobitz type 1 AV block | 2 (0.2) | 5 (0.3) | 7 (0.3) | 0.50 |
| Mobitz type 2 AV block | 0 (0.0) | 0 (0.0) | 0 (0.0) | |
| 3rd degree AV block | 13 (1.2) | 26 (1.7) | 39 (1.5) | 0.33 |
| LBBB | 248 (23.8) | 289 (19.2) | 537 (21.1) | 0.005 |
| RBBB | 85 (8.2) | 203 (13.5) | 288 (11.3) | <0.001 |
| Atrial fibrillation/flutter | 202 (19.4) | 375 (25.0) | 577 (22.7) | <0.001 |
| Valve Type | 0.046 | |||
| Edwards Sapien | 905 (86.9) | 1346 (89.6) | 2251 (88.5) | |
| Medtronic CoreValve | 136 (13.1) | 154 (10.3) | 290 (11.4) | |
| Other | 0 (0.0) | 2 (0.1) | 2 (0.1) | |
| Valve Size (mm)* | 23.0 (23.0, 26.0) | 26.0 (26.0, 29.0) | 26.0 (23.0, 29.0) | <0.001 |
| Annulus Size (largest diameter in mm)* | 25.5 (24.0, 27.0) | 29.0 (27.1, 31.0) | 27.7 (25.6, 29.7) | <0.001 |
| Annulus Area (cm2)* | 4.1 (3.7, 4.5) | 5.3 (4.8, 5.8) | 4.8 (4.1, 5.5) | <0.001 |
| Annulus Perimeter (mm)* | 74.0 (70.0, 78.0) | 84.0 (79.6, 88.5) | 80.0 (74.0, 86.0) | <0.001 |
| Aortic Valve Calcium Score (AU) * | 1680.0 (1166.0, 2348.3) | 2786.0 (2067.2, 3708.2) | 2312.0 (1569.0, 3201.5) | <0.001 |
| Pacemaker Status | <0.001 | |||
| No Pacemaker | 762 (73.2) | 974 (64.8) | 1736 (68.3) | |
| Prior Pacemaker | 126 (12.1) | 214 (14.2) | 340 (13.4) | |
| New Pacemaker | 153 (14.7) | 314 (20.9) | 467 (18.4) | |
| TAVR related† | 146 (95.4) | 296 (94.3) | 442 (94.6) | 0.60 |
| Pacemaker Type after TAVR | 0.68 | |||
| Single Chamber (RV only) | 21 (13.7) | 36 (11.5) | 57 (12.2) | |
| Dual Chamber | 114 (74.5) | 229 (72.9) | 343 (73.4) | |
| Biventricular (CRT) | 8 (5.2) | 22 (7.0) | 30 (6.4) | |
| Leadless (Micra) | 10 (6.5) | 27 (8.6) | 37 (7.9) | |
| Perivalvular Regurgitation or Leak prior to discharge (Yes) | 783 (75.2) | 1126 (75.0) | 1909 (75.1) | 0.89 |
| Perivalvular Regurgitation or Leak Severity | 0.78 | |||
| Trivial or Mild | 677 (86.5) | 969 (86.0) | 1646 (86.2) | |
| Moderate | 104 (13.3) | 153 (13.6) | 257 (13.5) | |
| Severe | 2 (0.3) | 5 (0.4) | 7 (0.4) | |
| Pre-TAVR Echocardiographic Measures | ||||
| Aortic valve peak velocity (m/s)* | 4.2 (4.0, 4.6) | 4.2 (3.9, 4.5) | 4.2 (3.9, 4.5) | <0.001 |
| Aortic valve mean pressure gradient (mmHg)* | 44.0 (38.0, 53.0) | 42.0 (36.0, 49.0) | 43.0 (37.0, 50.0) | <0.001 |
| Aortic valve Doppler velocity index (velocity ratio)* | 0.2 (0.2, 0.3) | 0.2 (0.2, 0.2) | 0.2 (0.2, 0.2) | <0.001 |
| Aortic valve Doppler velocity index (TVI ratio)* | 0.2 (0.2, 0.2) | 0.2 (0.2, 0.2) | 0.2 (0.2, 0.2) | <0.001 |
| Aortic valve area (cm2)* | 0.8 (0.7, 0.9) | 0.9 (0.8, 1.0) | 0.8 (0.7, 0.9) | <0.001 |
| Stroke volume index (ml/m2) * | 45.0 (39.0, 51.0) | 43.0 (37.0, 49.0) | 44.0 (38.0, 50.0) | <0.001 |
| Left ventricular ejection fraction (%) * | 64.0 (57.0, 68.0) | 60.0 (50.0, 65.0) | 61.0 (53.0, 66.0) | <0.001 |
| Post-TAVR Echocardiographic Measures | ||||
| Aortic prosthetic valve acceleration time (ms)* | 86.0 (74.0, 98.0) | 85.0 (76.0, 95.0) | 85.0 (75.0, 96.8) | 0.78 |
| Aortic prosthetic valve mean pressure gradient (mmHg)* | 12.0 (10.0, 15.0) | 11.0 (9.0, 14.0) | 12.0 (9.0, 14.0) | 0.002 |
| Aortic prosthetic valve dimensionless velocity index (velocity ratio)* | 0.5 (0.4, 0.5) | 0.5 (0.4, 0.5) | 0.5 (0.4, 0.5) | 0.87 |
| Aortic prosthetic valve dimensionless velocity index (TVI ratio)* | 0.5 (0.4, 0.5) | 0.5 (0.4, 0.5) | 0.5 (0.4, 0.5) | 0.60 |
| Charlson Comorbidities | ||||
| Myocardial Infarction | 53 (5.1) | 135 (9.0) | 188 (7.4) | <0.001 |
| Congestive Heart Failure | 264 (25.4) | 438 (29.2) | 702 (27.7) | 0.037 |
| Peripheral Vascular Disease | 273 (26.3) | 480 (32.0) | 753 (29.7) | 0.002 |
| Cerebrovascular Disease | 108 (10.4) | 190 (12.7) | 298 (11.7) | 0.082 |
| Dementia | 16 (1.5) | 34 (2.3) | 50 (2.0) | 0.200 |
| Chronic Pulmonary Disease | 189 (18.2) | 288 (19.2) | 477 (18.8) | 0.530 |
| Ulcer | 11 (1.1) | 12 (0.8) | 23 (0.9) | 0.500 |
| Mild Liver Disease | 39 (3.8) | 75 (5.0) | 114 (4.5) | 0.140 |
| Diabetes | 270 (26.0) | 435 (29.0) | 705 (27.8) | 0.098 |
| Diabetes with Organ Damage | 94 (9.1) | 175 (11.7) | 269 (10.6) | 0.036 |
| Hemiplegia | 2 (0.2) | 8 (0.5) | 10 (0.4) | 0.180 |
| Moderate to Severe Renal Disease | 217 (20.9) | 365 (24.3) | 582 (22.9) | 0.043 |
| Moderate to Severe Liver Disease | 11 (1.1) | 29 (1.9) | 40 (1.6) | 0.082 |
| Metastatic Solid Tumor | 21 (2.0) | 40 (2.7) | 61 (2.4) | 0.30 |
| AIDs | 0 (0.0) | 0 (0.0) | 0 (0.0) | |
| Rheumatologic Disease | 81 (7.8) | 62 (4.1) | 143 (5.6) | <0.001 |
| Cancer (Other) | 130 (12.5) | 283 (18.9) | 413 (16.3) | <0.001 |
| Charlson Comorbidity Index* | 2.0 (0.0, 3.8) | 2.0 (0.0, 4.0) | 2.0 (0.0, 4.0) | <0.001 |
| STS Risk Score for Mortality* | 5.6 (3.6, 9.0) | 4.7 (2.9, 7.9) | 5.0 (3.2, 8.2) | <0.001 |
| Access Type | 0.96 | |||
| Transfemoral | 914 (87.8) | 1317 (87.7) | 2231 (87.8) | |
| Other | 127 (12.2) | 184 (12.3) | 311 (12.2) |
Median (Q1, Q3); AV – Atrioventricular; LBBB – Left bundle branch block; RBBB – Right bundle branch block; AU – Agatston units
Proportion of those receiving new pacemaker who had it placed due to new conduction disturbance developed post TAVR.
All-Cause Mortality
Kaplan Meier analysis in the overall sample showed a median survival of 5.75 (95% CI: 5.35, 6.20) years. This association between AVCS and mortality was different when stratified by sex-based median values (log rank p <0.001), with lower survival seen among those with high AVCS values. This difference was driven mostly by women as a sex stratified KM analysis showed a significant difference among women (log rank p<0.001) and a non-significant effect among men (log rank p=0.087) (Figure 3A, B, and C, Supplemental figure 1). The overall median survival time in women was 5.9 years and 5.5 years in men. Among women with high AVCS values, the median survival time was 4.9 years compared to 6.7 years for women with low AVCS values.
Figure 3A. Kaplan Meier analysis showing survival probability of the entire cohort stratified by high vs. low AVCS category.
AVCS category is based on sex-specific median values; high AVCS category is > 1,680 Agatston units for women and > 2,786 Agatston units for men. P <0.001. AVCS – Aortic valve calcium score
Figure 3B. Kaplan Meier analysis showing survival probability among females stratified by high vs. low AVCS category.
High AVCS category is > 1,680 Agatston units. P <0.001. AVCS – Aortic valve calcium score
Figure 3C. Kaplan Meier analysis showing survival probability among males stratified by high vs. low AVCS category.
High AVCS category is > 2,786 Agatston units. P = 0.087. AVCS – Aortic valve calcium score
In unadjusted Cox-PH models, age, permanent pacemaker, Charlson comorbidity index-used as a proxy for comorbid conditions, pre-TAVR aortic valve peak velocity, pre-TAVR stroke volume index, pre-TAVR left ventricular ejection fraction, STS predicted risk of surgical mortality score, TAVR access type, procedure site and post-TAVR perivalvular leak - were associated with increased instantaneous risk of death (Supplemental table 2). Overall, men tended to have a higher mortality risk compared to women (HR: 1.11, 95% CI: 0.96, 1.28) but this did not reach statistical significance (p=0.150). We assessed for interaction between sex and AVCS and the p-value for the interaction term between sex and AVCS category was 0.086 suggesting likely effect modification by sex (at a p-value significance level of 0.10) which was also suggested by the initial Kaplan Meier analysis. As such, a sex-stratified analysis was also reported and AVCS remained significantly associated with mortality in women (Table 2). In propensity score adjusted models, AVCS remained an independent predictor of mortality in the overall patient sample and among women. Each 500 unit increase in AVCS was associated with a 7% increase in the instantaneous risk of death among women (adjusted HR: 1.07, 95% CI: 1.02, 1.12; p=0.004) but not in men (adjusted HR: 1.02, 95% CI: 0.99, 1.06; p= 0.24) (Table 2). When evaluating AVCS categories, high AVCS was associated with a 58% increase in the instantaneous risk of death among women (adjusted HR: 1.58, 95% CI: 1.22, 2.06; p<0.001) but not in men (adjusted HR: 1.13, 95% CI: 0.92, 1.39; p= 0.23) (Table 3). Hazard ratio estimates were also calculated for AVCS percentiles (for a 10% increase) and for the impact of AVCS on 30-day mortality and this showed a similar magnitude of effect and direction for men and women (Supplemental table 3 and 4).
Table 2.
Cox-proportional hazards regression model showing the impact of aortic valve calcium score on long-term mortality (for the entire cohort, stratified by sex and year of TAVR procedure)
| TAVR year | Patients | N | Deaths | Follow-Up (Years) * | cHR (95% CI) † | P-value | aHR (95% CI) ‡ | P-value |
|---|---|---|---|---|---|---|---|---|
| All Patients (2010 – 2021) | ||||||||
| All | 2543 | 801 | 2.30 (0.99, 4.17) | 1.04 (1.02, 1.06) | <0.001 | 1.06 (1.02, 1.11) | 0.004 | |
| Male | 1502 | 478 | 2.17 (0.90, 4.07) | 1.03 (1.00, 1.06) | 0.090 | 1.02 (0.99, 1.06) | 0.24 | |
| Female | 1041 | 323 | 2.51 (1.12, 4.33) | 1.07 (1.02, 1.11) | 0.002 | 1.07 (1.02, 1.12) | 0.004 | |
| 2010 - 2016 | ||||||||
| All | 956 | 549 | 4.68 (2.21, 5.89) | 1.04 (1.01, 1.07) | 0.004 | 1.04 (0.99, 1.10) | 0.14 | |
| Male | 551 | 321 | 4.66 (2.04, 5.81) | 1.03 (1.00, 1.07) | 0.059 | 1.02 (0.98, 1.06) | 0.37 | |
| Female | 405 | 228 | 4.77 (2.69, 5.96) | 1.05 (1.00, 1.10) | 0.049 | 1.07 (1.01, 1.13) | 0.030 | |
| 2017 - 2021 | ||||||||
| All | 1,587 | 252 | 1.69 (0.78, 2.84) | 1.04 (1.00, 1.08) | 0.081 | 1.10 (1.03, 1.17) | 0.006 | |
| Male | 951 | 157 | 1.60 (0.75, 2.75) | 1.00 (0.95, 1.06) | 0.93 | 1.04 (0.97, 1.10) | 0.29 | |
| Female | 636 | 95 | 1.80 (0.83, 2.94) | 1.08 (1.01, 1.16) | 0.018 | 1.08 (1.01, 1.16) | 0.034 |
Median (Q1, Q3)
Crude/unadjusted hazard ratios estimated for a 500-unit increase in aortic valve calcium score
Propensity score adjusted hazard ratios estimated for a 500-unit increase in aortic valve calcium score
Propensity score included age, pre-TAVR peak aortic valve velocity, pre-TAVR calculated valve area, pre-TAVR stroke volume index, pre-TAVR LVEF, pacemaker implantation, LBBB, Charlson comorbidity index, STS predicted risk of surgical mortality, TAVR access type, valve type, procedure site and post-TAVR peri-valvular leak.
LBBB – Left bundle branch block; LVEF – Left ventricular ejection fraction; TAVR – Transcatheter aortic valve replacement; STS – Society for thoracic surgeons
Table 3.
Cox-proportional hazards regression model showing the impact of aortic valve calcium score category (high vs. low) on long-term mortality (for the entire cohort, stratified by sex and year of TAVR procedure)
| TAVR year | Patients | N | Deaths | Follow-Up (Years) * | cHR (95% CI) † | P-value | aHR (95% CI) ‡ | P-value |
|---|---|---|---|---|---|---|---|---|
| All Patients (2010 – 2021) | ||||||||
| All | 2543 | 801 | 2.30 (0.99, 4.17) | 1.29 (1.13, 1.49) | <0.001 | 1.51 (1.18, 1.92) | <0.001 | |
| Male | 1502 | 478 | 2.17 (0.90, 4.07) | 1.17 (0.98, 1.40) | 0.088 | 1.13 (0.92, 1.39) | 0.23 | |
| Female | 1041 | 323 | 2.51 (1.12, 4.33) | 1.50 (1.20, 1.87) | <0.001 | 1.58 (1.22, 2.06) | <0.001 | |
| 2010 - 2016 | ||||||||
| All | 956 | 549 | 4.68 (2.21, 5.89) | 1.32 (1.11, 1.56) | 0.001 | 1.42 (1.06, 1.91) | 0.018 | |
| Male | 551 | 321 | 4.66 (2.04, 5.81) | 1.24 (0.99, 1.54) | 0.060 | 1.12 (0.87, 1.43) | 0.37 | |
| Female | 405 | 228 | 4.77 (2.69, 5.96) | 1.44 (1.11, 1.88) | 0.007 | 1.67 (1.21, 2.30) | 0.002 | |
| 2017 - 2021 | ||||||||
| All | 1,587 | 252 | 1.69 (0.78, 2.84) | 1.21 (0.94, 1.55) | 0.13 | 1.69 (1.11, 2.59) | 0.016 | |
| Male | 951 | 157 | 1.60 (0.75, 2.75) | 1.04 (0.76, 1.42) | 0.82 | 1.26 (0.88, 1.81) | 0.21 | |
| Female | 636 | 95 | 1.80 (0.83, 2.94) | 1.53 (1.02, 2.30) | 0.040 | 1.51 (0.96, 2.39) | 0.073 | |
Median (Q1,Q3)
Crude/unadjusted hazard ratios estimated for aortic valve calcium score category (high vs. low)
Propensity score adjusted hazard ratios estimated for aortic valve calcium score category (high vs. low)
Propensity score included age, pre-TAVR peak aortic valve velocity, pre-TAVR calculated valve area, pre-TAVR stroke volume index, pre-TAVR LVEF, pacemaker implantation, LBBB, Charlson comorbidity index, STS predicted risk of surgical mortality, TAVR access type, valve type, procedure site and post-TAVR peri-valvular leak.
LBBB – Left bundle branch block; LVEF – Left ventricular ejection fraction; TAVR – Transcatheter aortic valve replacement; STS – Society for thoracic surgeons
Year of TAVR Valve Implantation
A temporal analysis was performed for the years 2010 – 2016 compared to 2017 – 2021 in order to indirectly account for older vs. newer generation valves. In the 2010 – 2016 cohort, we showed that a 500-unit increase in AVCS remained associated with mortality among women but not in men. In the 2017 – 2021 cohort, we noticed a similar trend with a significant increase in mortality for each 500-unit change in AVCS among women (p=0.034) (Table 2). However, the increased mortality seen did not reach statistical significance when AVCS category was evaluated for the 2017 – 2021 time-period (p=0.073) (Table 3). This may be due to the reduced follow up time in the 2017 - 2021 cohort. The median follow-up time for the 2010 – 2016 cohort was 4.68 years compared to 1.69 years in the 2017 – 2021 cohort.
AVCS Density
Given lower AVCS for a given degree of aortic stenosis in addition to small aortic valve annulus in women additional analyses were performed to evaluate the impact of AVCS density on mortality. We demonstrated AVCS density to also be significantly associated with mortality in a similar fashion as described above. A higher mortality risk was seen with every 100-unit increase in AVCS density among women (adjusted HR: 1.06, 95% CI: 1.01, 1.11; p=0.011) with a non-significant increase in risk among men (adjusted HR: 1.03, 95% CI: 0.99, 1.08; p=0.17). (Table 4). When stratified by year of TAVR procedure, the direction of effect was similar but this did not reach statistical significance.
Table 4.
Cox-proportional hazards regression model showing the impact of aortic valve calcium score density on long-term mortality (for the entire cohort, stratified by sex and year of TAVR procedure)
| TAVR year | All patients | N | Deaths | Follow-Up (Years) * | cHR (95% CI) † | P-value | aHR (95% CI) ‡ | P-value |
|---|---|---|---|---|---|---|---|---|
| All Patients (2010 – 2021) | ||||||||
| Overall | 2400 | 689 | 2.25 (0.97, 4.06) | 1.05 (1.02, 1.07) | 0.001 | 1.06 (1.01, 1.11) | 0.009 | |
| Male | 1419 | 413 | 2.15 (0.92, 4.02) | 1.03 (0.99, 1.07) | 0.099 | 1.03 (0.99, 1.08) | 0.17 | |
| Female | 981 | 276 | 2.44 (1.10, 4.11) | 1.06 (1.02, 1.10) | 0.006 | 1.06 (1.01, 1.11) | 0.011 | |
| 2010 - 2016 | ||||||||
| Overall | 823 | 440 | 4.78 (2.39, 5.83) | 1.05 (1.02, 1.09) | 0.003 | 1.04 (0.98, 1.11) | 0.16 | |
| Male | 475 | 258 | 4.79 (2.20, 5.76) | 1.06 (1.01, 1.10) | 0.015 | 1.04 (0.99, 1.10) | 0.12 | |
| Female | 348 | 182 | 4.78 (2.71, 5.89) | 1.05 (0.99, 1.11) | 0.095 | 1.07 (1.00, 1.14) | 0.055 | |
| 2017 - 2021 | ||||||||
| Overall | 1577 | 249 | 1.69 (0.79, 2.84) | 1.03 (0.98, 1.08) | 0.27 | 1.08 (1.01, 1.15) | 0.017 | |
| Male | 944 | 155 | 1.62 (0.75, 2.76) | 0.98 (0.91, 1.05) | 0.51 | 1.01 (0.93, 1.09) | 0.90 | |
| Female | 633 | 94 | 1.80 (0.83, 2.94) | 1.07 (1.01, 1.14) | 0.034 | 1.07 (1.00, 1.14) | 0.060 | |
Median (Q1,Q3)
Crude/unadjusted hazard ratios estimated for a 100-unit increase in aortic valve calcium score density
Propensity score adjusted hazard ratios estimated for a 100-unit increase in aortic valve calcium score density
Propensity score included age, pre-TAVR peak aortic valve velocity, pre-TAVR calculated valve area, pre-TAVR stroke volume index, pre-TAVR LVEF, pacemaker implantation, LBBB, Charlson comorbidity index, STS predicted risk of surgical mortality, TAVR access type, valve type, procedure site and post-TAVR peri-valvular leak.
LBBB – Left bundle branch block; LVEF – Left ventricular ejection fraction; TAVR – Transcatheter aortic valve replacement; STS – Society for thoracic surgeons
DISCUSSION
This study demonstrates that the impact of AVCS on mortality after TAVR differs by sex. (1) A stronger and statistically significant association was seen with increasing AVCS and higher mortality risk in women but not in men; (2) after adjusting for multiple covariates, the relationship between AVCS and mortality remained significant in women; (3) the median survival following TAVR was 5.8 years overall (5.9 years in women and 5.5 years in men). When stratified by AVCS categories (high vs. low), the median survival was 4.9 years vs. 6.7 years, respectively, among women (p<0.001) and 5.3 years vs. 6.4 years among men (p=0.087). No prior studies have evaluated sex-specific differences in the relationship between AVCS (measured on CT) and long-term mortality following TAVR.
Prior studies evaluating AVCS and 30-day mortality following TAVR have been conflicting. Small studies with first-generation balloon-expandable and self-expanding valves demonstrated an association between AVCS and 30-day mortality, while studies evaluating newer valve generations showed no association25-28. These studies were limited by a small sample size with no long-term follow-up. Thomassen et al. evaluated visually assessed aortic valve calcification with echocardiography among patients with asymptomatic AS and found an association with increased mortality only in men but not in women29, which is the opposite of the findings from our study. This was however based on a qualitative assessment of aortic valve calcification and their findings may be related to lower aortic valve calcium load in women, likely leading to underestimation of valve calcification by visual assessment. A higher degree of aortic valve calcification is known be associated with greater severity of AS30, 31 and women have lower AVCS than men at equivalent degrees of AS severity16. Furthermore, recent work has shown that the main predictor of aortic valve calcification progression is baseline AVCS22; however, the authors also demonstrated sex-specific differences in the progression of aortic valve calcification, with hypertension being associated with increased progression in women while dyslipidemia was associated with increased progression in men.
Sex-specific differences in AVCS and AS severity have been previously described, with severe AS corresponding with AVCS greater than 1,274 AU in women, and greater than 2,065 AU in men.32 These AVCS cut-off values representing severe AS were also shown to be associated with increased mortality among those who were managed medically (i.e. without AVR) in both men and women32. More recently, sex-specific cut-off values (1,377 AU in women; 2,062 AU in men) were shown to predict AVR and death in an international registry of 918 patients33. However, Mendes et al. analyzed sex-specific AVCS values in a group of patients evaluated for TAVR and found that its discriminative ability for ruling out severe AS (values <800 AU) was poor in women, with a negative predictive value of 43%34. As such, we performed a sex-stratified analysis and generated separate effect estimates for men and women.
Sex differences in mortality following TAVR have varied in the literature. A large study from a German registry of over 25,000 patients who underwent TAVR between 2011-2014 found that women who underwent transfemoral TAVR had lower in-hospital mortality compared to men (odds ratio: 0.87, CI: 0.77-1.00)7. In contrast to these findings, a study of the National Inpatient Sample database from 2012-2015 with 61,239 patients found that women had increased in-hospital mortality following TAVR compared to men (adjusted odds ratio: 1.25, 95% CI: 1.01-1.54)6. With regard to long-term mortality, data from the Transcatheter Valve Therapy Registry included 23,652 patients and demonstrated lower one-year mortality among women (adjusted hazard ratio: 0.73; 95% CI: 0.63, 0.85) compared to men12 whereas a cohort of 683 patients in Australia who underwent TAVR showed that long term mortality (up to ten years) was similar between men and women35. In our study, we found no statistically significant difference in overall mortality for women compared to men in our study, although the direction of this effect was lower for women (p=0.15). Additionally, the analysis of TAVR procedures done between 2010-2016 and 2017-2021, suggests that the use of newer generation valves may not clearly impact the differential mortality between the sexes related to increasing AVCS. However, subsequent analyses allowing for a longer follow up time among patients with newer generation valves is needed to confirm or refute these findings. One hypothesis to explain the sex-specific impact of AVCS on mortality observed in our study is the differences in left ventricular adaptation to aortic stenosis and pressure overload with increasing AVCS in women compared to men36, 37. Additional studies are needed to further evaluate mechanistic factors that explain this association.
Conclusion
Our study contributes to the existing body of literature further highlighting sex-specific differences in outcomes following TAVR and suggests that identifying sex-specific risk factors can better guide pre-procedural risk stratification and potentially pre-procedure planning. Whether the decreased mortality among women noted in prior studies is related to lower AVCS remains unclear. Our results suggest consideration of AVCS values as an important risk factor for mortality, particularly among women undergoing TAVR. We also highlight the need to develop a composite risk assessment tool (similar to the STS risk score) that evaluates multiple metrics known to predict mortality following TAVR including AVCS, which would be extremely useful as part of pre-TAVR procedure planning. Previously identified risk factors for mortality in the TAVR population include age38, atrial fibrillation39, COPD40 coronary disease41, frailty42, low body weight41, poor functional status41, renal failure39 and left ventricular dysfunction39.
A major strength of our study is a fairly large patient sample with longer follow-up times which adds essential information to the literature regarding long-term mortality after TAVR. Limitations of this study include its observational nature within a singular health system, as such mortality occurring outside of these hospitals may have been missed. We evaluated all-cause mortality and are unable to ascertain if the differences seen hold true for death from cardiovascular causes alone. We also acknowledge that our sample (patients undergoing TAVR only) comprises only a subset of aortic stenosis patients, leading to some selection bias as surgical patients are excluded. Unfortunately, the aortic valve calcium burden among surgically treated AS patients is not frequently assessed. As such, the literature regarding its impact on survival is limited in the surgical population. In addition, data on bleeding events following TAVR was not assessed which may potentially contribute to differences in short-term mortality, however, this effect is likely to be attenuated by the longer duration of follow-up.
In conclusion, we demonstrate that the impact of AVCS on mortality is modified by sex with increasing AVCS values being more strongly associated with higher mortality risk among women following TAVR.
Supplementary Material
Clinical Perspective:
The purpose of this study was to evaluate the effect of sex on the relationship between aortic valve calcium score and long-term mortality among adult patients undergoing transcatheter aortic valve replacement (TAVR). Among 2,543 patients evaluated, 41% were women and median age was 82 years. We demonstrate for the first time, a sex-specific difference in long term mortality where a higher aortic valve calcium score prior to TAVR was associated with increased mortality risk in women but not in men. This suggests that aortic valve calcium score should be considered as a sex-specific risk factor for mortality among patients undergoing TAVR and highlights the need to develop risk assessment tools incorporating sex-specific variables prior to TAVR.
SOURCES OF FUNDING
This study was made possible using resources supported by the Mayo Clinic Women's Health Research Center and the Mayo Clinic Building Interdisciplinary Research Careers in Women’s Health (BIRCWH) Program funded by the National Institutes of Health (NIH) [grant number K12 HD065987]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
ABBREVIATIONS
- AVCS
Aortic valve calcium score
- AVR
Aortic valve replacement
- AU
Agatston units
- BIRCWH
Building Interdisciplinary Research Careers in Women’s Health
- COPD
Chronic obstructive pulmonary disease
- CT
Computed tomography
- KM
Kaplan Meier
- LBBB
Left bundle branch block
- LVEF
Left ventricular ejection fraction
- TAVR
Transcatheter aortic valve replacement
- NIH
National Institutes of Health
- SAVR
Surgical aortic valve replacement
- STS
Society for thoracic surgeons
Footnotes
DISCLOSURES
None
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