Long‐term outcomes in Japanese nonagenarians undergoing transcatheter aortic valve implantation: A multi‐center analysis

Abstract Background and Hypothesis Japan is an aging society, and the number of nonagenarians with severe aortic stenosis undergoing transcatheter aortic valve implantation (TAVI) is increasing, but their outcomes have not been determined fully. Methods We prospectively enrolled 767 consecutive patients who underwent TAVI in three Japanese institutions. Clinical characteristics and outcomes of nonagenarians (n = 94) were evaluated and compared with those of patients aged <90 years (n = 673). Results Prevalence of New York Heart Association (NYHA) class III/IV was not different between the two groups. Preoperative risk scores were significantly higher in nonagenarians compared with those in non‐nonagenarians, whereas the Clinical Frailty Scale was not different. Thirty‐day mortality tended to be higher (P = .06) and major vascular complication was significantly higher in nonagenarians than in non‐nonagenarians (P < .05), but 3‐year mortality was equivalent between the two groups. Even after adjustment for covariates, female sex (hazard ratio, 0.41; 95% confidence interval: 0.25‐0.67), body mass index (0.87, 0.80‐0.94), and NYHA class III/IV (1.84, 1.06‐3.29) were associated with all‐cause mortality. Age ≥ 90 years was not associated with all‐cause mortality. Conclusions TAVI could be undertaken safely and effectively in nonagenarians, who had acceptable long‐term results compared with those for younger patients, although careful attention should be paid to major vascular complication.

Transcatheter aortic valve implantation (TAVI) has emerged as a less invasive alternative to SAVR in patients with severe AS who cannot undergo surgery, or who are at intermediate/high surgical risk, resulting in acceptable clinical outcomes. [3][4][5][6][7][8] Japan is an aging society, and the number of nonagenarians with severe AS undergoing TAVI is increasing, but their outcomes have not been determined fully.
Vendrik et al 9 reported the 5-year outcomes of European nonagenarians who underwent TAVI. Moreover, Miura et al 10 reported on the early outcomes of Japanese nonagenarians who underwent TAVI, but they did not evaluate long-term outcomes. In this study, we evaluated the long-term outcomes of Japanese nonagenarians who underwent TAVI. The decision to undertake TAVI was made by the Cardiac Teams (cardiologists, cardiac surgeons, radiologists, and anesthesiologists) of each institution. All patients were considered to be "high-risk" cases and not suitable for SAVR by the Cardiac Teams. The Society of Thoracic Surgeons predictive risk of mortality, the logistic European System for Cardiac Operative Risk Evaluation (Logistic EuroScore), and Euro II Score were evaluated for preoperative risk. Moreover, the Clinical Frailty Scale (CFS), major organ dysfunction (including the respiratory system) and procedure-specific impediments were evaluated to confirm patient status not reflected in preoperative risk scores according to the 2014 American Heart Association/American College of Cardiology guidelines for the management of valvular heart disease. 11 The transfemoral approach was the primary procedure. Selection and sizing of the device were based on multi-slice computed tomography by each Cardiac Team. Other access sites (eg, transapical or transsubclavian artery) were considered if the transfemoral approach was not suitable for advancing the large sheath.

| Endpoints
The primary endpoint of our study was all-cause mortality after TAVI.
Moreover, we evaluated early safety endpoints (all-cause mortality, stroke, life-threatening bleeding, acute kidney injury, coronary artery obstruction, major vascular complications, and valve-related dysfunction requiring repeat procedure) according to Valve Academic Research Consortium 2 (VARC-2) criteria. 12 Information regarding patient survival was obtained from each institution where TAVI was done or through telephone calls directly to patients/patients' families according to the criteria of the ethics committee of each participating institution.

| Statistical analyses
Continuous variables are the mean ± SD or median (interquartile range). Categorical variables are expressed as numbers and percentages. An unpaired t test or χ 2 test was used to compare differences between the two groups. The Mann-Whitney U test was used for nonparametric variables. The chi-square test was used to compare categorical variables. Mortality was estimated using the Kaplan-Meier method and compared using the log-rank test. Multivariate analysis for the predictors of all-cause mortality 3 years after TAVI was undertaken using Cox proportional hazards regres-

| Baseline characteristics of the study cohort
We evaluated 767 patients (543 females [71%]; mean age, 84 ± 5 years) and they were divided into two groups according to their age at TAVI: nonagenarians (age ≥ 90 years, n = 94) and nonnonagenarians (age < 90 years, n = 673). The baseline characteristics of study patients are summarized in Table 1. There was no significant difference in sex between the two groups. Nonagenarians were shorter and lighter, and had a lower BMI than non-nonagenarians. A history of stroke, coronary artery disease, peripheral arterial disease, and atrial arrhythmia were not significantly different between the two groups. Prevalence of NYHA class III/IV was not significantly different between the two groups. EuroScore II (5. We also assessed transthoracic echo parameters before TAVI. The area of the aortic valve was smaller in nonagenarians compared with non-nonagenarians (0.60 ± 0.17 vs 0.65 ± 0.16 cm 2 , P < .05), but there was no significant difference in LVEF or the prevalence of aortic valve regurgitation. The level of N-terminal prohormone of brain natriuretic peptide (NT-proBNP) was higher, and eGFR lower, in nonagenarians than in non-nonagenarians.

| TAVI
The procedural characteristics of TAVI are summarized in Table 2. A transfemoral approach was taken in 678 (88%) patients, and there were no significant differences in approach between the two groups.

| Long-term mortality
Long-term mortality was evaluated by the log-rank test ( Figure 1C).
Freedom from any cause of death 3 years after TAVI was not significantly different between the two groups (77.9% in nonagenarians vs 82.5% in non-nonagenarians, P = .25), and the cause of death (cardiovascular death or non-cardiovascular death) was mentioned in Table 3.

| Predictors of all-cause mortality
We performed multivariate Cox proportional hazard analyses to evaluate the predictors of all-cause mortality 3 years after TAVI ( Note. "Early safety" was defined as the composite endpoint according to VARC-2 criteria.

| DISCUSSION
In this three-center study, we evaluated the long-term outcomes of Japanese nonagenarians who underwent TAVI. Main findings were that: (a) patients aged ≥90 years tended to have higher 30-day mortality in comparison with those with aged <90 years; (b) early safety was similar between patients aged ≥90 years and those aged <90 years; (c) there was no significant difference in 3-year outcomes between patients aged ≥90 years and those aged <90 years; (d) age ≥ 90 years was not a predictor for all-cause mortality. Nonagenarians had a slightly higher prevalence of short-term mortality, but there was not significantly different in longterm mortality between nonagenarians and non-nonagenarians. Hence, caution in selecting TAVI for nonagenarians might be unwarranted.
There were few differences in preoperative comorbidities as evaluated by the CFS between nonagenarians and non-nonagenarians.
Considering these results, it appears that the nonagenarians in this study are self-selected patient populations who have selecting bias.
Age is an important prognostic factor and should be taken into consideration, but comorbidities or functional status have been shown to be better predictors of mortality. 13 We think that careful evaluation of patients and their risk factors before TAVI is very important for preventing postoperative complications, morbidity and mortality.
Several researchers have reported worse short-term mortality in nonagenarians who underwent TAVI compared with that in non- In the present study, about half of all patients were treated by local anesthesia with mild sedation and without intubation. Benefits of local anesthesia include early recovery and risk reduction of hemodynamic instability during TAVI. Local anesthesia with mild sedation is favored, especially in nonagenarians, because they need a shorter stay in hospital to recover early after TAVI. It is thought that local anesthesia with mild sedation will aid better outcomes for nonagenarians who undergo TAVI.
Our study had two main limitations. First, there was selection bias among nonagenarians. No data were available among nonagenarians who did not undergo TAVI. Second, our study cohort was small, so further large-scale studies are clearly warranted.

| CONCLUSIONS
TAVI could be carried out safely and effectively in nonagenarians, and they had acceptable long-term results compared with non-nonagenarians, although careful attention should be paid to major vascular complication.

CONFLICT OF INTEREST
The authors declare no potential conflict of interests.