Appropriateness of Transcatheter Aortic Valve Replacement
What Is Known
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Transcatheter aortic valve replacement is recognized as an established therapeutic strategy for treating severe aortic stenosis and widely performed worldwide.
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In 2017, US professional societies published joint appropriateness use criteria for the treatment of patients with severe aortic stenosis.
What the Study Adds
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Based on the current appropriateness use criteria, the proportion of rarely appropriate transcatheter aortic valve replacements ranged from 4.9% to 6.8%, with substantial variation among hospitals.
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Most procedures classified as rarely appropriate were performed for patients with dementia, bicuspid aortic valve, or anticipated life expectancy <1 year.
Introduction
See Editorial by Szpakowski and Wijeysundera
Transcatheter aortic valve replacement (TAVR) is recognized as an established therapeutic strategy for treating severe aortic stenosis (AS) in patients with intermediate, high, and prohibitive surgical risk.1,2 The number of procedures has been increasing worldwide, and in 2017, about 35 000 and 3300 procedures were performed in the United States and in Japan, respectively.3,4 Despite the technological advances, patients who undergo TAVRs are still exposed to the risk of procedure-related complications including death, stroke, newly required pacemaker, and bleeding.5 Moreover, recent studies have shown that, in ≈1/3 of patients, health status was not markedly improved after TAVR.6
To promote the appropriate and judicious implementation of TAVR, a task force of 11 US professional societies published joint appropriateness use criteria (AUC) for the treatment of patients with severe AS in 2017.7 However, no study has thus far evaluated the appropriateness of real-world TAVR based on these AUC. The granularity of the Optimized Transcatheter Valvular Intervention-Transcatheter Aortic Valve Implantation (OCEAN-TAVI) registry data collection forms enables assessment of appropriateness of TAVR performed in the real-world according to these AUC. Our aims were to (1) quantify the proportion of appropriate, maybe appropriate, and rarely appropriate TAVRs performed, (2) describe the variation in rates of rarely appropriate TAVRs among hospitals, and (3) describe the clinical scenarios leading to rarely appropriate TAVRs.
Methods
The data, analytic methods, and study materials will not be made available to other researchers for the purpose of reproducing the results or replicating the procedure.
Data Source
We analyzed the data from the OCEAN-TAVI registry, which is an ongoing, prospective, multicenter TAVR registry.8–11 In Japan, as of October 2019, a total of 172 institutes are approved as TAVR centers and allowed to perform TAVR, and of these, 20 institutes are participating in the OCEAN-TAVI program. All patients who underwent TAVR for severe AS at any of the hospitals participating in the OCEAN-TAVI registry between October 2013 and May 2017 were enrolled. During the study period, a total of 14 institutes were participating in the OCEAN-TAVI registry covers about two-thirds of all TAVRs performed in Japan (in 2016, a total of 1614 TAVRs were performed in Japan; of these, 1076 cases were included in the OCEAN-TAVI registry). The decision to perform TAVR was decided by consensus within the heart team in each center. Standardized data collection included patient demographics, medical history, echocardiographic data, procedural variables, and outcomes, which were defined in accordance of the Valve Academic Research Consortium-2 criteria.12 Clinical research coordinators specifically trained in recording TAVR procedures or experienced physicians confirmed the proper recording of data. Data reported on the internet-based system were checked via self-audit by sites. In addition, data committee members regularly audited the database for completeness and consistency and sent queries to each site if needed. The OCEAN-TAVI registry is registered with the University Hospital Medical Information Network. The medical ethics committee at each hospital approved this study protocol, and written informed consent was obtained from all patients before undergoing TAVR.
For the purpose of this analysis, we excluded (1) patients who were missing for aortic valve area or left ventricular ejection fraction, (2) patients who underwent TAVR in emergent, urgent, or salvage situations, and (3) patients who underwent TAVR via other than transfemoral approach (Figure 1). The reason why we restricted transfemoral TAVR was that, in AUC, the clinical scenarios assumed that TAVR could be performed by a transfemoral approach.
Figure 1. Study cohort creation and evaluation process. Ao indicates aorta; AS, aortic stenosis; AVA, aortic valve area; BPN, B-type natriuretic peptide; CAD, coronary artery disease; EF, ejection fraction; LAD, left anterior descending; LMT, left main trunk; MMSE, mini-mental state examination; MR, mitral regurgitation; MS, mitral stenosis; OCEAN-TAVI, Optimized Transcatheter Valvular Intervention-Transcatheter Aortic Valve Implantation; SAVR, surgical aortic valve replacement; STS-PROM, the Society of Thoracic Surgeons Predicted Risk of Mortality score; SYNTAX, the Synergy between PCI with Taxus and Cardiac Surgery score; TAVR, transcatheter aortic valve replacement; TF, transfemoral; TR, tricuspid regurgitation; and VD, vessel disease.
Algorithm of AUC Mapping
AUC for the treatment of patients with severe AS was developed by a collaboration of 11 US professional organizations. The methodology to develop AUC for the treatment of patients with severe AS was previously described.7
In the present study, the AUC were applied to each TAVR case in the following 2 steps. The first step is to evaluate whether the decision to perform valve replacement, either TAVR or surgical aortic valve replacement, is appropriate (Figures I and II in the Data Supplement). The second step is to evaluate whether the decision to perform TAVR is appropriate (Figures III, IV, and V in the Data Supplement). Most cases were classified into more than one clinical scenario (indication); for example, low-flow low-gradient AS patients with both frailty and dementia and whose Society of Thoracic Surgeons Predicted Risk of Mortality score were ranging from 8% to 15% were eligible for any of indications number 13 to 17 or number 20 to 21 (Figure IIA and IIB in the Data Supplement), any of indications number 38 to 40 (Figure IIIB in the Data Supplement) and indication number 52 (Figure IIIH in the Data Supplement). The final appropriate rating was based on the worst rating they were assigned through the entire evaluation process. In the above-mentioned example, because indication number 52 was rated as rarely appropriate, the final appropriateness rating was rarely appropriate regardless of ratings for other indications. The evaluators were blinded from patients’ outcomes, when the appropriateness ratings were evaluated.
Despite the granularity of the OCEAN-TAVI registry data collection forms, several variables that were needed for evaluating the appropriate ratings were not captured, such as exercise test, dobutamine stress echocardiography, and the Synergy between PCI with Taxus and Cardiac Surgery score. The full list of uncaptured variables and missing values are listed in Table I in the Data Supplement. To account for the influence of these variables on the appropriate ratings, we evaluated the appropriate ratings in 2 different assumptions; the best-case scenario and the worst-case scenario. In the best-case scenario, uncaptured variables and missing values were assumed to classify a case to more appropriate clinical scenario, whereas, in the worst-case scenario, they were assumed to assign a case to less appropriate clinical scenario. In addition, several variables that were captured in the registry had >1% of missingness; mini-mental status examination (MMSE; 30.6%), the Katz Index of Independence in Activities of Daily Living (12.3%), mean pulmonary artery pressure (4.6%), stroke volume index (5.9%). Missing data were addressed using multiple imputations. Sensitivity analysis was performed using the complete-case dataset after excluding cases with missingness.
Definitions
Variables were defined according to the definitions in the AUC. However, for several variables, a definition was not clearly described in the AUC document; therefore, it needed to be generated. To assess patient’s cognitive function (dementia), in the OCEAN-TAVI registry, MMSE was systematically evaluated and captured. In the AUC, moderate to severe dementia (minimally oriented) was considered as dementia; therefore, we defined dementia as MMSE ≤17, which corresponds to moderate to severe dementia.13 The Clinical Frailty Scale, which is a semiquantitative tool to assess frailty and ranges from 1 to 9, with 9 being most severe frail, was used to determine the baseline frailty status before TAVR in the OCEAN-TAVI Registry.9,14 In this study, frail was defined as Clinical Frailty Scale ≥4, because Clinical Frailty Scale 1 to 3 is considered to be nonfrail.14 Dependence in activities of daily living was assessed using the Katz Index of Independence in Activities of Daily Living, ranging from 0 to 6, with 0 being most dependent.15 Dependent in >3 activities of daily living was defined as the Katz Index ≤3, because 1 point of the Katz Index corresponds to independence in one of daily activities; bathing, dressing, toileting, transferring, continence, and feeding.15 Anticipated life expectancy <1 year was assumed when a patient died within 1 year after TAVR owing to noncardiac causes. The full list of definitions for variables is available in Figures I through V in the Data Supplement.
Statistical Analysis
The proportion of TAVRs classified as appropriate, maybe appropriate, or rarely appropriate was determined. Algorithms for evaluating appropriate ratings are shown in Figures I through V in the Data Supplement. Patients who were unable to be assigned to any of clinical scenarios in the AUC were classified as nonmappable. Baseline characteristics and clinical variables of patients were compared by appropriateness categories. Differences were evaluated using the χ2 or Fisher exact test for categorical variables and the Wilcoxon rank-sum test for continuous variables.
The association between appropriate ratings and clinical outcomes, including all-cause death and heart failure readmission within 1 year after TAVRs, was assessed. Given that TAVR appropriateness was rated on the basis of the combination of several clinical variables, the analysis evaluating the association between TAVR appropriateness and clinical outcomes was not adjusted for covariates. Kaplan-Meier plots with the log-rank tests were used for all-cause mortality. Cumulative incidence curves with the Fine and Gray’s proportional sub-distribution hazards models were used for heart failure readmission, with all-cause death as a competing risk.
Furthermore, to evaluate the association between the institutional proportion of rarely appropriate TAVR and mortality, we categorized institutes into tertiles based on the institutional proportion of rarely appropriate TAVR and compared 1-year mortality among tertiles using the Cox hazard regression models. Models were adjusted for STS risk score to account for the differences in preoperative risk among tertiles. The hazard ratios (HRs) are presented along with the 95% CIs and corresponding P values.
Data were analyzed using R software version 3.4.3 (R Foundation for Statistical Computing, Vienna, Austria). All P values were 2-sided, and significance was defined as P<0.05 for all analyses.
Results
Among a total of 2588 patients who underwent TAVR in hospitals participated in the OCEAN-TAVI registry between October 2013 and May 2017, after the exclusion criteria was applied, the remaining 2036 patients (median age [25th, 75th]: 85 years [81–88]; 70.5% female; median Society of Thoracic Surgeons Predicted Risk of Mortality score: 6.2% [4.4–8.9]) were analyzed (Figure 1).
Best-Case Scenario
In the best-case scenario, 177 (8.7%) were not successfully mapped, and 1580 (77.6%) were classified as appropriate, 180 (8.8%) as maybe appropriate, 99 (4.9%) as rarely appropriate, respectively (Figure 2). Majority of cases that were not successfully mapped were symptomatic AS patients with Vmax ≥4 m/s or mean gradient ≥40 mm Hg on resting echo whose left ventricular ejection fraction was 20% to 49%, just because there were no clinical scenarios for evaluating these patients. Compared with procedures classified as appropriate or maybe appropriate, rarely appropriate TAVRs were more likely to be performed for patients who were dependent in daily activities, and had dementia, active cancer, low surgical risk, and bicuspid valve (Tables 1 and 2). Overall, almost all of the rarely appropriate TAVRs were confined to 5 scenarios, as summarized in Table 3. Frequently encountered scenarios included TAVRs that were performed for patients with dementia, bicuspid aortic valve (low- or intermediate-surgical risk), or anticipated life expectancy <1 year due to comorbidities including active cancer.
| Appropriate |
Maybe Appropriate |
Rarely Appropriate |
Non Mappable |
P Value | |
|---|---|---|---|---|---|
| Male, n (%) | 457 (28.9) | 51 (28.3) | 30 (30.3) | 63 (35.6) | 0.313 |
| Age, median (IQR), y | 85 (82–88) | 85 (82–88) | 87 (83–89) | 83 (80–86) | <0.001 |
| BMI, median (IQR), kg/m2 | 22.3 (20.0–24.7) | 21.5 (18.8–24.3) | 20.5 (18.6–23.1) | 22.3 (19.9–24.7) | <0.001 |
| Dependent daily activity, n (%) | 46 (4.8) | 13 (12.4) | 14 (28.6) | 3 (2.7) | <0.001 |
| Frail, n (%) | 892 (56.5) | 137 (76.1) | 57 (57.6) | 108 (61.0) | <0.001 |
| MMSE, median (IQR) | 26 (23–28) | 25 (22–28) | 17 (15–24) | 25 (22–28) | <0.001 |
| Dementia, n (%) | 54 (4.9) | 7 (6.0) | 37 (62.7) | 12 (9.3) | <0.001 |
| Symptom | <0.001 | ||||
| NYHA 3 or 4, n (%) | 734 (46.5) | 104 (57.8) | 67 (67.7) | 91 (51.4) | <0.001 |
| Angina, n (%) | 273 (17.3) | 36 (20.0) | 17 (17.2) | 31 (17.5) | 0.841 |
| Syncope, n (%) | 171 (10.8) | 22 (12.2) | 8 (8.1) | 28 (15.8) | 0.161 |
| Medical history | |||||
| Dyslipidemia, n (%) | 690 (43.7) | 67 (37.2) | 34 (34.3) | 64 (36.2) | 0.039 |
| Diabetes mellitus, n (%) | 342 (21.6) | 33 (18.3) | 23 (23.2) | 39 (22.0) | 0.73 |
| Hypertension, n (%) | 1226 (77.6) | 124 (68.9) | 76 (76.8) | 128 (72.3) | 0.037 |
| Atrial fibrillation, n (%) | 321 (20.3) | 44 (24.4) | 24 (24.2) | 27 (15.3) | 0.133 |
| Implanted device, n (%) | 91 (5.8) | 15 (8.3) | 10 (10.1) | 14 (7.9) | 0.017 |
| Coronary artery disease, n (%) | 542 (34.3) | 57 (31.7) | 32 (32.3) | 60 (33.9) | 0.891 |
| Prior PCI, n (%) | 366 (23.2) | 38 (21.1) | 23 (23.2) | 36 (20.3) | 0.794 |
| Prior CABG, n (%) | 76 (4.8) | 11 (6.1) | 7 (7.1) | 8 (4.5) | 0.668 |
| Peripheral artery disease, n (%) | 146 (9.2) | 28 (15.6) | 20 (20.2) | 10 (5.6) | <0.001 |
| Prior stroke, n (%) | 167 (10.6) | 30 (16.7) | 13 (13.1) | 20 (11.3) | 0.096 |
| COPD, n (%) | 213 (13.5) | 25 (13.9) | 24 (24.2) | 21 (11.9) | 0.021 |
| Liver cirrhosis, n (%) | 56 (3.5) | 4 (2.2) | 0 (0) | 3 (1.7) | 0.12 |
| Active cancer, n (%) | 88 (5.6) | 6 (3.3) | 5 (2.8) | 3 (3.0) | 0.196 |
| Operative risk | |||||
| STS, median (IQR) | 6.1 (4.3–8.6) | 8.3 (5.1–10.8) | 10.5 (8.1–14.0) | 5.2 (4.0–6.6) | <0.001 |
| High risk, n (%) | 1218 (77.1) | 161 (89.4) | 82 (82.8) | 119 (67.2) | <0.001 |
| Intermediate risk, n (%) | 301 (19.1) | 19 (10.6) | 7 (7.1) | 51 (28.8) | <0.001 |
| Low risk, n (%) | 61 (3.9) | 0 (0) | 10 (10.1) | 7 (4.0) | <0.001 |
| Valve type, n (%) | <0.001 | ||||
| Corevalve | 120 (7.6) | 13 (7.2) | 19 (19.2) | 15 (8.5) | |
| EvolutR | 90 (5.7) | 17 (9.4) | 6 (6.1) | 6 (3.4) | |
| Sapien S3 | 596 (37.7) | 76 (42.2) | 38 (38.4) | 61 (34.5) | |
| Sapien XT | 774 (49.0) | 74 (41.1) | 36 (36.4) | 95 (53.7) | |
| Appropriate |
Maybe Appropriate |
Rarely Appropriate |
Non Mappable |
P Value | |
|---|---|---|---|---|---|
| Laboratory data | |||||
| Hemoglobin, median (IQR), g/dL | 11.3 (10.1–12.4) | 11.3 (10.2–12.4) | 10.7 (9.8–12.0) | 11.5 (10.5–12.7) | 0.002 |
| eGFR, median (IQR), mL/(min·1.73 m2) | 51.3 (39.0–64.0) | 47.8 (37.0–61.0) | 42.7 (31.1–55.7) | 56.2 (45.0–66.0) | <0.001 |
| Albumin, median (IQR), g/dL | 3.9 (3.5–4.1) | 3.8 (3.4–4.0) | 3.5 (3.1–3.9) | 3.8 (3.5–4.1) | <0.001 |
| Echocardiographical data | |||||
| LVEF, median (IQR), % | 64.0 (58.0–69.0) | 60.0 (50.0–68.3) | 57.0 (46.0–65.0) | 43.0 (39.0–48.0) | <0.001 |
| LVEF ≥50, n (%) | 1430 (90.5) | 138 (76.7) | 68 (68.7) | 17 (9.6) | <0.001 |
| LVEF 20–49, n (%) | 146 (9.2) | 41 (22.8) | 31 (31.3) | 159 (89.8) | <0.001 |
| LVEF <20, n (%) | 4 (0.3) | 1 (0.6) | 0 (0) | 1 (0.6) | 0.743 |
| Low flow, n (%) | 282 (9.6) | 37 (22.4) | 28 (29.5) | 33 (20.0) | 0.117 |
| Low gradient, n (%) | 444 (28.1) | 49 (27.2) | 28 (28.3) | 62 (35.0) | 0.268 |
| AV Vmax, median (IQR) | 4.5 (4.1–5.1) | 4.6 (4.1–5.1) | 4.6 (4.1–5.3) | 4.4 (4.0–4.8) | 0.035 |
| AV mean PG, median (IQR), mm Hg | 48.0 (39.0, 62.0) | 48.3 (39.0–62.5) | 50.2 (39.0–67.2) | 45.9 (37.7–57.0) | 0.09 |
| Bicuspid valve, n (%) | 1 (0.1) | 32 (17.8) | 22 (22.2) | 0 (0) | <0.001 |
| AUC Table* | AUC Indication† | Clinical Scenario | Surgical Risk | No. of Cases (%) |
|---|---|---|---|---|
| Best-case scenario | 99 | |||
| Table 3 | 52 | Severe symptomatic AS; moderate to severe dementia (minimally oriented) | STS-PROM 8%–15% | 57 (57.6) |
| Table 3 | 37 | Severe symptomatic AS; health status seems to be influenced more by AS than by comorbidities; anticipated life expectancy <1 y | STS-PROM >15% | 18 (18.2) |
| Table 5 | 80, 81 | Severe symptomatic AS; bicuspid aortic valve (regardless of ascending aorta diameter) | Intermediate | 13 (13.1) |
| Table 5 | 82, 83 | Severe symptomatic AS; bicuspid aortic valve (regardless of ascending aorta diameter) | Low | 8 (8.1) |
| Table 3 | 54 | Severe symptomatic AS; malignancy; anticipated life expectancy <1 y | STS-PROM 8%–15% | 3 (3.0) |
| Worst-case scenario | 138 | |||
| Table 3 | 52 | Severe symptomatic AS; moderate to severe dementia (minimally oriented) | STS-PROM 8%–15% | 57 (41.3) |
| Table 3 | 32 | Severe symptomatic AS; health status seems to be influenced more by comorbidities than by AS; anticipated life expectancy <1 y | STS-PROM 8%–15% | 28 (20.3) |
| Table 2 | 15, 17 | Low-flow, low-gradient AS; LVEF 20%–49%; flow reserve on low-dose dobutamine echo but pseudosevere AS or no reserve on low-dose dobutamine echo | High or intermediate | 18 (13.0) |
| Table 3 | 36 | Severe symptomatic AS; health status seems to be influenced more by comorbidities than by AS; anticipated life expectancy <1 y | STS-PROM >15% | 18 (13.0) |
| Table 5 | 80, 81 | Severe symptomatic AS; bicuspid aortic valve (regardless of ascending aorta diameter) | Intermediate | 12 (8.7) |
Figure 2. Appropriate ratings and typical clinical scenarios that were assigned to rarely appropriate transcatheter aortic valve replacements (TAVRs). Appropriate ratings and typical rarely appropriate TAVRs in the best-case scenario (A) and worst-case scenario (B). LFLG AS indicates low-flow low-gradient aortic stenosis.
Worst-Case Scenario
In the worst-case scenario, the rate of rarely appropriate increased to 6.8% (Figure 2). Similar to the best-case scenario, rarely appropriate TAVRs were more likely to be performed for patients with dementia, bicuspid valve, or anticipated life expectancy <1 year due to comorbidities, compared with TAVRs that were assigned to appropriate or maybe appropriate. In the worst-case scenario, lower left ventricular ejection fraction and higher proportion of low-flow AS were noted in rarely appropriate TAVRs than in procedures classified as appropriate or maybe appropriate (Table II in the Data Supplement). In addition to the clinical scenarios that were listed as common to rarely appropriate TAVRs in the best-case scenario, TAVRs for pseudo-severe AS or low-flow low-gradient AS without flow reserve on dobutamine stress echocardiography appeared as common clinical scenarios assigned to rarely appropriate in the worst-case scenario (Table 3).
Variation in the Proportion of Rarely Appropriate TAVR Among Sites
There was a substantial variation in the proportion of rarely appropriate TAVR across hospitals (Figure 3). In the best-case scenario, median (interquartile range) rate for rarely appropriate TAVR was 4.9% (3.8%–6.6%, P<0.001); in the worst-case scenario, that was 6.5% (5.6%–8.6%, P<0.001).
Figure 3. Variability of rarely appropriate ratings among hospitals. Variability of rarely appropriate TAVR among hospitals in the best-case scenario (A) and worst-case scenario (B). TAVR indicates transcatheter aortic valve replacement.
Sensitivity Analysis With Complete-Case Data Set
Sensitivity analysis was performed with the complete-case data set (N=939) after excluding cases with missingness. Baseline characteristics were not clinically different between main study cohort (N=2036) and complete-case data set (N=939; Table III in the Data Supplement). The results were consistent with the main analysis. In the best-case scenario, 83 (8.8%) were not successfully mapped, and 725 (77.2%) were classified as appropriate, 88 (9.4%) as maybe appropriate, 43 (4.6%) as rarely appropriate, respectively (Figure VI in the Data Supplement). In the worst-case scenario, the rate of rarely appropriate increased to 7.7%. Substantial variation among hospitals was also confirmed in both best- and worst-case scenarios (Figure VII in the Data Supplement).
Appropriate Ratings and Clinical Outcomes
The occurrences of all-cause death are illustrated in Kaplan-Meier curves in Figure 4. In both best-case and worst-case scenarios, 1-year all-cause mortality in rarely appropriate TAVR was significantly higher than that in appropriate and maybe appropriate TAVR (Figure 4). Similar trend was observed in the association of appropriate ratings and heart failure readmission, although it did not reach statistical significance in the best-case scenario (Figure VIII in the Data Supplement).
Figure 4. All-cause mortality by appropriate ratings. Probability of survival by appropriate ratings in best-case (A) and worst-case scenarios (B). TAVR indicates transcatheter aortic valve replacement.
Table 4 summarizes 1-year mortality rates according to institutional rate of rarely appropriate TAVRs. When institutes were categorized into tertiles based on their proportion of rarely appropriate TAVRs, 1-year all-cause mortality in highest tertile institutes (higher proportion of rarely appropriate TAVR) was significantly higher than that in lowest tertile institutes (HR, 1.48 [95% CI, 1.03–2.12] in best-case scenario; HR, 1.49 [95% CI, 1.02–2.17] in worst-case scenario).
| No. of Institutes | No. of Cases | No. of Deaths at 1 y | Mortality Rate at 1 y | HR (95% CI) | P Value | |
|---|---|---|---|---|---|---|
| Best-case scenario | ||||||
| Lowest tertile | 5 | 820 | 59 | 7.2% | Reference | |
| Middle tertile | 4 | 661 | 51 | 7.7% | 1.07 (0.73–1.55) | 0.732 |
| Highest tertile* | 5 | 555 | 64 | 11.5% | 1.48 (1.03–2.12) | 0.032 |
| Worst-case scenario | ||||||
| Lowest tertile | 5 | 898 | 64 | 7.1% | Reference | |
| Middle tertile | 4 | 712 | 61 | 8.6% | 1.18 (0.83–1.68) | 0.352 |
| Highest tertile* | 5 | 426 | 49 | 11.5% | 1.49 (1.02–2.17) | 0.041 |
Discussion
We applied the US multisociety AUC for the treatment of patients with severe AS to our multicenter Japanese TAVR registry to evaluate the appropriateness of TAVRs in daily clinical practice. We found that the proportion of rarely appropriate TAVRs ranged from 4.9% to 6.8%, with substantial variation among hospitals. Most procedures classified as rarely appropriate were performed for patients with dementia, bicuspid aortic valve with low- or intermediate-surgical risk, or anticipated life expectancy <1 year. Procedures for low-flow low- gradient AS may also have a potential to be assigned to rarely appropriate TAVRs. The institutional higher rate of rarely appropriate TAVR was associated with higher 1-year mortality.
Appropriate Ratings of TAVRs and Its Institutional Variation
To the best of our knowledge, this is the first study to evaluate the appropriateness of TAVRs in daily clinical practice. The detailed clinical scenarios in the AUC document for the treatment of patients with severe AS has made it difficult for TAVR registries to evaluate their appropriateness. In our study, about 70% of TAVRs were rated as appropriate, whereas a small but significant minority was deemed to be rarely appropriate (4.9% in the best-case scenario and 6.8% in the worst-case scenario) with substantial variation among hospitals. Given the higher 1-year adjusted mortality rates in institutes with higher (versus lower) rarely appropriate cases, which underscores the importance and validity of AUC in TAVR, continued efforts towards minimizing hospital variation in AUC performance should be implemented.
In the field of percutaneous coronary intervention (PCI), assessment of PCI appropriateness led to the awareness of elective PCI overuse,16 achieving standardization of PCI indication and decrease in rarely appropriate PCIs through feedback in each hospital and financial incentives.17–19 We believe that our findings serve as a benchmark of future investigations, clarify potential targets for improving procedural indications, and provide a baseline for the design and implementation of measures to improve hospital variation in AUC performance.
Association of Dementia With Poor Outcomes
In our analysis, the main reason to be assigned to rarely appropriate was moderate to severe dementia. Several studies have demonstrated that cognitive impairment was associated with increased risks of mortality and postoperative complications after cardiac surgery including TAVR.20,21 Arnold et al22 showed that, in patients with TAVR, lower MMSE score was an important factor in predicting poor outcome, a composite of death and poor improvement in quality of life scale. A report from the OCEAN-TAVI registry also showed that, in patients undergoing TAVR, even mild cognitive impairment was associated with higher mortality at 1 year after TAVR and the association was more apparent in patients with severe dementia.11 Given the accumulating evidence regarding the association of dementia and poor outcomes after TAVR in terms of patient-centered outcomes as well as hard end points, standardized assessment of cognitive function should be included in the screening process before TAVR. Moreover, in the evaluation process of appropriate ratings, frailty and dependence in activities of daily living are also emphasized. To account for these issues properly when we judge procedural indications, multidimensional geriatric assessment should be further encouraged.23
TAVRs for Severe AS due to Bicuspid Aortic Valve
In the current AUC, regardless of ascending aorta dilatation, TAVR for bicuspid aortic valve in patients with low- or intermediate-surgical risk is deemed rarely appropriate. However, several observational findings support the safety and effectiveness of TAVR for bicuspid aortic valve.24–26 A recent study demonstrated similar prognosis in patients undergoing TAVR in bicuspid valve compared with tricuspid valve.26 Although the device success was lower in bicuspid valve than in tricuspid valve, the difference was no longer observed when confined to the new-generation devices, such as Sapien 3, Lotus, and Evolut R.26 Given mean STS scores ranging from 4.6% to 4.9% in patients with bicuspid valve in these studies,24–26 the use of TAVR in bicuspid valve in patients with intermediate-, and potentially low-, surgical risk may be justified. However, further evidences are required to determine if TAVRs for severe AS with bicuspid valve are appropriate or not. Ongoing trials, such as Medtronic Transcatheter Aortic Valve Replacement Low Risk Bicuspid Study (NCT03635424) and The Safety and Effectiveness of Transcatheter Aortic Valve Replacemet in Intermediate Risk Patients With Bicuspid Aortic Stenosis (NCT03163329), may provide some answers.
Role and Limitation of Dobutamine Stress Echocardiography in Low-flow Low-Gradient AS
In the worst-case scenario, the cases related to low-flow low-gradient AS appeared as common clinical scenarios assigned to the rarely appropriate category. This is not because TAVR was actually performed for patients with pseudosevere AS or no reserve on dobutamine stress echocardiography, but because dobutamine stress echocardiography was not captured in the registry; therefore, it was assumed to classify a case to the least appropriate clinical scenario (rarely appropriate). Dobutamine stress echocardiography was not included in the data collection form in our database, but Kataoka et al10 reported that, among a total of 109 consecutive patients with symptomatic low-flow, low-gradient AS who underwent TAVR in hospitals participating in the OCEAN-TAVI Registry, dobutamine stress echocardiography was performed for only 24 patients (22%). However, we should also recognize the limitations of dobutamine stress echocardiography for low-flow low-gradient AS, especially in the era of TAVR. First, among patients with low-flow low-gradient AS who underwent TAVR, mortality at 1 year after TAVR and change in LVEF from baseline to 1-year follow-up were not different between patients with versus without flow reserve on dobutamine stress echocardiography.27,28 Second, in patients with low-flow low- gradient AS, dobutamine stress echocardiography criteria of the composite of a peak stress mean gradient ≥40 mm Hg and a peak stress aortic valve area ≤1 cm2 proposed in the guidelines to identify true-severe AS have limited value to predict actual stenosis severity.29 Given these recent findings, confirmation of flow reserve by dobutamine stress echocardiography before TAVRs in patients with low-flow low-gradient AS may not be mandatory.
Gaps in the Current AUC
Our findings also pointed out a few challenges in the current AUC. For instance, many symptomatic AS patients with Vmax ≥4 m/s or mean gradient ≥40 mm Hg on resting echo whose left ventricular ejection fraction was 20% to 49% were classified as nonmappable, due to lack of clinical scenarios in the current AUC for evaluating these patients. Under otherwise identical conditions, if patients had left ventricular ejection fraction ≥50%, TAVR would be considered appropriate (indications number 22 or number 23 in Figure IIC in the Data Supplement). Similarly, if patients were asymptomatic, they were also classified as appropriate (indications number 10 or number 11 in Figure I in the Data Supplement). However, aortic valve replacement for symptomatic high-flow high-gradient AS with left ventricular ejection fraction of 20% to 49% is apparently appropriate based on the current US guideline with class I recommendation.30 Furthermore, in the current AUC, comorbidities and disability, such as lung disease, renal disease, liver disease, malignancy, and dementia, are taken into account to assess appropriate ratings only for patients with high- or extreme-surgical risk (Figure III in the Data Supplement). In other words, for evaluating the appropriateness of TAVRs in patients with low- or intermediate-surgical risk, these factors were not taken into account at all. Given the expanding indications of TAVR, the AUC may need to be updated to reflect the current daily practice.
Limitations
There are several limitations in our study. First, not all hospitals that perform TAVR in Japan participate in our registry. However, the OCEAN-TAVI registry covers about two-thirds of all TAVRs performed in Japan (in 2016, a total of 1614 TAVRs were performed in Japan, of these, 1076 cases were included in the OCEAN-TAVI registry).4 In addition, when compared with the J-TVT registry, which is a Japanese nationwide TAVR registry and captures all TAVR cases performed in Japan,31 baseline characteristics of the OCEAN-TAVI registry were not clinically different (Table IV in the Data Supplement), suggesting our registry is representative of the Japanese TAVR experience and reflects current practice patterns throughout Japan. External validation using other databases, especially in the US, is required to corroborate our results, yet we believe our findings serve as benchmarks for future assessments of TAVR appropriateness. Second, the food and drug administration approved TAVR for severe AS patients with intermediate-surgical risk in August 2016 for Edwards Sapien valves and in July 2017 for Medtronic CoreValves, respectively. Furthermore, the Food and Drug Administration opened use of TAVR to severe AS patients with low surgical risk in August 2019 for both devices. These changes in indications of TAVR have not been incorporated in the current AUC. However, in Japan, TAVR was approved only for high- and prohibitive-surgical risk patients with severe AS during the study period and therefore the expanded indication in the US may not affect the appropriate ratings in Japan. In addition, rarely appropriate was mainly determined by factors other than surgical risk, such as dementia, bicuspid aortic valve, and anticipated life expectancy less than 1 year; therefore, we believe our findings could be applicable in the current clinical practice. Third, uncaptured variables may also affect the appropriate ratings; however, our approach using 2 different assumptions (the best-case scenario and the worst-case scenario) enabled us to assess the range of possible impacts. In addition, sensitivity analysis with complete-case dataset showed the consistent results and confirmed the robustness of our findings. Fourth, the final appropriate rating was based on the worst rating they were assigned through the entire evaluation process. If the cases were rated on the basis of the best rating, the proportion of rarely appropriate TAVRs might decrease. However, given that rarely appropriate procedures should be a focus of interest to highlight potential targets for quality improvement in terms of patient selection, we believe our approach that prioritized the worst rating is reasonable.
Conclusions
In this representative Japanese registry, the proportion of rarely appropriate TAVRs ranged from 4.9% to 6.8%, with substantial variation between sites. The majority of rarely appropriate procedures were performed for patients with moderate to severe dementia, bicuspid aortic valve with low or intermediate-surgical risk, or anticipated life expectancy <1 year. This study provides a better understanding of the clinical situations where the procedures were deemed rarely appropriate and clarifies the potential targets of quality improvement.
Acknowledgments
We appreciate the contributions of all the investigators and clinical coordinators involved in the optimized transcatheter valvular intervention-transcatheter aortic valve implantation registry.
Sources of Funding
This study was funded in part by Edwards Lifesciences and Daiichi Sankyo. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the article for publication.
Disclosures
Dr Inohara receives research grant from Boston Scientific. Dr Vemulapalli receives grant support from American College of Cardiology, Society of Thoracic Surgeons, Boston Scientific, Abbott Vascular, Patient Centered Outcomes Research Institute, National Institutes of Health and consultant fees/advisory board from Boston Scientific, Janssen, Zafgen and Premiere Inc. Dr Kohsaka receives grant support from Japan Society for Promotion of Science (16H05215 and 16KK0186), Bayer, Daiichi Sankyo and consultant/lecture fees from Bayer, Bristol Meier Squibb, Pfizer and AstraZeneka. Dr Yamamoto, Dr Tada, Dr Naganuma, Dr Shirai, Dr Mizutani, and Dr Watanabe are clinical proctors for Edwards Lifesciences and Medtronic. Dr Araki, Dr Tabata, Dr Takagi, Dr Higashimori, Dr Shimizu, and Dr Hayashida are clinical proctors of Edwards Lifesciences. Dr Ueno is a clinical proctor for Edwards Lifesciences and Medtronic. The other authors report no conflicts.
Footnotes
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