Transcatheter aortic valve implantation versus conservative management for severe aortic stenosis in real clinical practice.

BACKGROUND: Transcatheter aortic valve implantation (TAVI) is criticized by some as an expensive treatment in super-elder patients with limited life expectancy. However, there is a knowledge gap regarding the magnitude of clinical benefit provided by TAVI in comparison with conservative management in patients with severe aortic stenosis (AS) in real clinical practice, which would be important in the decision making for TAVI.
METHODS: We combined two independent registries, namely CURRENT AS and K-TAVI registries. CURRENT AS was a multicenter registry enrolling 3815 consecutive patients with severe AS irrespective to treatment modalities between January 2003 and December 2011. K-TAVI was a multicenter, prospective registry including 449 consecutive patients with severe AS, who underwent TAVI with SAPIEN XT balloon-expandable valves between October 2013 and June 2016. In these 2 registries, 449 patients received TAVI and 894 patients were managed with conservative strategy. We conducted propensity score matching and finally obtained a cohort of 556 patients (278 patients for each group) for the analysis. The primary outcome measures were all-cause death and heart failure (HF) hospitalization at 2-year.
RESULTS: The cumulative 2-year incidences of all-cause death and HF hospitalization were significantly lower in the TAVI group than in the conservative group (16.8% versus 36.6%, P<0.001, and 10.7% versus 37.2%, P<0.001). After adjusting the residual confounders, TAVI reduced the risks of all-cause death (HR, 0.46; 95%CI, 0.32-0.69; P = 0.0001) and HF hospitalizations (HR, 0.25; 95%CI, 0.16-0.40; P<0.0001) compared with conservative strategy. There was no difference in the cumulative incidence of non-cardiovascular death between the 2 groups.
CONCLUSIONS: TAVI in the early Japanese experience was associated with striking risk reduction for all-cause death as well as HF hospitalization as compared with the historical cohort of patients with severe AS who were managed conservatively just before introduction of TAVI in Japan.

Introduction

In symptomatic patients with severe aortic stenosis (AS), surgical aortic valve replacement (SAVR) had been the only option to improve the clinical outcomes, and has been recommended as a classⅠindication in the guidelines [1-6]. However, one of the biggest drawbacks in the management of patients with severe AS was that substantial proportion of symptomatic patients with severe AS did not receive SAVR due to advanced age, severe comorbidities, or patient rejection [7-9]. Transcatheter aortic valve implantation (TAVI) has already transformed the treatment paradigm of symptomatic patients with severe AS. In severe AS patients with high or intermediate risk for SAVR, several randomized trials clearly demonstrated that TAVI was associated with the long-term clinical outcomes at least comparable to SAVR [10-14]. Furthermore, in patients with severe AS who were not suitable for SAVR, the PARTNER (Placement of Aortic Transcatheter Valves) trial comparing TAVI with standard treatment demonstrated better outcomes for TAVI up to 5-year follow-up [15-18]. Based on these landmark clinical trials, the proportion of symptomatic severe AS patients treated with aortic valve replacement by either SAVR or TAVI clearly increased after introduction of TAVI [19].

However, there is a knowledge gap regarding how much clinical benefit could be provided by TAVI in comparison with conservative management in patients with severe AS in real clinical practice. The expected magnitude of clinical benefit would be important in the decision making for TAVI in real world patients with severe AS. Against this background, we sought to evaluate the clinical outcomes of patients who underwent TAVI in the early Japanese experience in comparison with the historical cohort of patients who were managed conservatively just before introduction of TAVI in Japan.

Materials and methods

Study population

We combined two independent registries in Japan, K-TAVI (Kyoto University-related hospital Transcatheter Aortic Valve Implantation) registry and CURRENT AS (Contemporary outcomes after sURgery and medical tREatmeNT in patients with severe Aortic Stenosis) registry, to make a historical comparison of the clinical outcomes between TAVI and conservative management in patients with severe AS.

K-TAVI registry was a multicenter and prospective registry enrolling consecutive patients with severe AS who underwent TAVI at 6 centers starting from October 2013. The selection of patients and the procedures of the K-TAVI registry were previously reported [20]. For the present analysis, we included 449 patients who underwent TAVI with SAPIEN XT (Edwards Lifesciences, CA, USA) from October 2013 to June 2016 in the K-TAVI registry (Fig 1).

Fig 1

Study flowchart.

CURRENT AS, Contemporary outcomes after sURgery and medical tREatmeNT in patients with severe Aortic Stenosis; K-TAVI, Kyoto University-related hospital Transcatheter Aortic Valve Implantation; AVR, aortic valve replacement; HD, hemodialysis; Vmax, peak aortic jet velocity; TAVI, transcatheter aortic valve implantation; LVEF, left ventricular ejection fraction.

The CURRENT AS registry was a multicenter, retrospective registry that enrolled consecutive patients with severe AS irrespective to treatment modalities from 27 centers (on-site surgical facilities: 20 centers) just before introduction of TAVI in Japan from January 2003 to December 2011. All the 6 centers that participated in the K-TAVI registry had also participated in the CURRENT AS registry. Severe AS was defined as peak aortic jet velocity (Vmax) >4.0m/s, mean aortic pressure gradient (PG) >40mmHg, or aortic valve area (AVA) <1.0cm2. The detailed design and results of the registry have been previously published [21]. Among 3815 patients enrolled in the CURRENT AS registry, conservative management was initially chosen in 2618 patients. To identify the patients with conservative management comparable to the patients in the K-TAVI registry, we excluded those patients on hemodialysis (HD) in whom TAVI has not been yet approved in Japan, and those asymptomatic patients with Vmax <5m/s and left ventricular ejection fraction (LVEF) > = 50%, who are regarded as candidates for watchful waiting according to the guidelines [4]. We also excluded those patients who were regarded as contraindicated for SAVR by the attending physicians (malnutrition, muscle weakness, cognitive impairment, and expected poor prognosis), because these patients were considered to be contraindicated for TAVI. Finally, we retrieved the data of 984 non-HD patients in the conservative group who were symptomatic or asymptomatic but with Vmax ≥5 m/s, or with LVEF of <50% (Fig 1).

The follow-up was commenced on the day of TAVI in the K-TAVI registry and on the day of index echocardiography in the conservative group from CURRENT AS registry. Follow-up was censored at 2-year in both groups considering the minimal follow-up interval in the K-TAVI registry. We obtained clinical follow-up data from the medical records and/or through mail exchanges and/or telephone interviews with the patients, families, or referring physicians.

The relevant institutional review boards at all participating hospitals approved the study protocols and were described in S3 Text. We performed the study in accordance with the Declaration of Helsinki. Written informed consent specific for the K-TAVI registry was waived because patients undergoing TAVI provided written informed consent for the compulsory national clinical database registry, and it was also waived in the CURRENT AS registry because of the retrospective study design.

Study outcomes

Valve implantation was regarded as successful, if the procedure was completed without valve delivery failure, second valve implantation, annulus rupture and conversion to open heart surgery. Device success and other procedural endpoints of TAVI was defined based on the Valve Academic Research Consortium (VARC)-2 classification [22]. The primary outcome measures of the current study were all-cause death and heart failure (HF) hospitalizations at 2-year. The secondary outcome measures included aortic valve-related death, aortic valve procedure death, cardiovascular death, sudden death, non-cardiovascular death, myocardial infarction, stroke, major bleeding, infectious endocarditis, and a composite of aortic valve-related deaths or HF hospitalization. Aortic valve-related death included aortic valve procedure death, sudden death, and death due to HF possibly related to aortic valve. HF hospitalization was defined as hospitalization due to worsening HF requiring intravenous drug therapy. Major bleeding in this study was defined as life-threatening/disabling or major bleeding in the VARC-2 classification. Definitions of other clinical events are described in S4 Text. Clinical events were adjudicated by the clinical event committee (S1 Text) in the CURRENT AS registry, while site-reported events were not adjudicated in the K-TAVI registry.

Statistical analysis

We expressed continuous variables as mean ± standard deviation or median with interquartile range (IQR), and compared them using Student’s t-test or Wilcoxon rank sum test. We expressed categorical variables as percentages and compared them using χ2 tests.

We used propensity score matching as the main analysis, because the patient characteristics were different between the TAVI and conservative groups derived from the 2 separate registries. Once we combined data of 984 patients from CURRENT AS registry and 449 patients from K-TAVI registry, we used multivariable logistic regression model to develop propensity-score for the choice of TAVI with 13 variables relevant to the choice of AVR used in our previous study (Table 1) [21]. We multiplied these variables in each patient by the coefficients in the model to calculate propensity score of each patient. The c-statistics was 0.818 and the coefficients of the independent variables were shown in S1 Table. We then calculated the propensity score by summing up all coefficients multiplies corresponding variables (S1 Fig). To make propensity-score matched cohort, patients in the TAVI group were matched to those in the conservative group using a 1:1 greedy matching technique [23]. We eliminated those patients without counterparts with corresponding propensity score, and finally constructed the propensity score-matched cohort of 556 patients (TAVI group 278 patients, and conservative group 278 patients), and used Kaplan-Meier curves to estimate cumulative incidences. Log-rank test was used to assess the differences between groups. Because some variables were not well balanced even after the propensity score matching, we performed further adjustment by using the Cox proportional hazard models incorporating the risk-adjusting variables such as Society of Thoracic Surgeons (STS)-predicted risk of mortality (PROM), Vmax, and aortic valve area (AVA). We evaluated hazard ratios (HRs) and their 95% confidence intervals (CIs) to assess the risk of the TAVI group relative to the conservative group for each outcome measure.

Table 1

Baseline patient characteristics.

	Entire cohort			Propensity score-matched cohort
	TAVI group	Conservative group	P-value	TAVI group	Conservative group	P-value
	(N = 449)	(N = 984)		(N = 278)	(N = 278)
Clinical characteristics
Age, *y	85.2±5.3	82.1±9.1	<0.0001	84.6±5.7	85.1±7.0	0.41
≥80 years†	399 (89)	644 (65)	<0.0001	233 (84)	235 (85)	0.82
Men*,†	161 (36)	288 (29)	0.01	80 (29)	81 (29)	0.93
BMI, kg/m2	22.0±3.5	21.2±3.9	0.0001	21.4±3.5	21.8±3.9	0.24
<22.0 kg/m2*,†	235 (52)	689 (70)	<0.0001	171(62)	171 (62)	1.00
BSA, m2	1.43±0.2	1.41±0.2	0.07	1.40±0.2	1.41±0.2	0.72
Hypertension*	349 (78)	717 (73)	0.05	211 (76)	211 (76)	1.00
Smoking*	82 (18)	173 (18)	0.75	46 (17)	47 (17)	0.91
Dyslipidemia	220 (49)	317 (32)	<0.0001	140 (50)	105 (38)	0.003
Diabetes mellitus	123 (27)	206 (21)	0.008	81 (29)	61 (22)	0.05
On insulin therapy*	15 (3.3)	37 (3.8)	0.69	10 (3.6)	9 (3.2)	0.82
Prior MI*	18 (4.0)	129 (13)	<0.0001	13 (4.7)	49 (18)	<0.0001
Prior PCI	126 (28)	128 (13)	<0.0001	75 (27)	46 (17)	0.003
Prior CABG	49 (11)	71 (7.2)	0.02	27 (9.7)	33 (12)	0.41
Prior heart surgery†	88 (20)	106 (11)	<0.0001	45 (16)	41 (15)	0.64
Prior symptomatic stroke*,†	55 (12)	131 (13)	0.58	30 (11)	24 (8.6)	0.39
Atrial fibrillation or flutter*	48 (11)	257 (26)	<0.0001	31 (11)	55 (20)	0.005
Aortic/peripheral vascular disease*	71 (16)	130 (13)	0.19	45 (16)	35 (13)	0.23
Serum creatinine, mg/dL*	0.9 (0.7–1.2)	0.9 (0.7–1.3)	0.90	0.9 (0.7–1.2)	1.0 (0.7–1.3)	0.32
>2mg/dL†	15 (3.4)	81 (8.2)	0.0003	12 (4.3)	11 (4.0)	0.82
Anemia*,†	344 (77)	621 (63)	<0.0001	200 (72)	206 (74)	0.61
Malignancy*,†	41 (9.1)	114 (12)	0.16	23 (8.3)	19 (6.8)	0.52
Immunosuppressive therapy†	21 (4.7)	36 (3.7)	0.37	11 (4.0)	10 (3.6)	0.82
Chronic lung disease	138 (31)	109 (11)	<0.0001	72 (26)	29 (10)	<0.0001
moderate or severe*,†	51 (11)	44 (4.5)	<0.0001	16 (5.8)	14 (5.0)	0.71
Coronary artery disease*	194 (43)	295 (30)	<0.0001	114 (41)	100 (36)	0.22
STS score (PROM), %	6.4 (4.5–9.3)	5.1 (3.1–8.6)	<0.0001	6.4 (4.5–9.2)	5.8 (4.0–9.5)	0.13
Etiology of aortic stenosis
Degenerative	445 (99)	916 (93)	<0.0001	275 (99)	268 (96)	0.22
Congenital (unicuspid, bicuspid, or quadricuspid)	2 (0.5)	21 (2.1)		1 (0.4)	3 (1.1)
Rheumatic	1 (0.2)	43 (4.4)		1 (0.4)	5 (1.8)
Infective endocarditis	0 (0)	0 (0)		0 (0)	0 (0)
Other	1 (0.2)	4 (0.4)		1 (0.4)	2 (0.7)
Echocardiographic variables
Vmax, m/s	4.7±0.7	4.1±1.0	<0.0001	4.6±0.7	4.1±1.0	<0.0001
Vmax ≥5 m/s†	154 (34)	21 (21)	<0.0001	80 (29)	67 (24)	0.23
Vmax ≥4 m/s*	385 (86)	526 (53)	<0.0001	236 (85)	151 (54)	<0.0001
Peak aortic PG, mmHg	87±28	70±33	<0.0001	84±26	72±35	<0.0001
Mean aortic PG, mmHg	52±17	40±21	<0.0001	51±17	42±22	<0.0001
AVA, cm2	0.62± 0.17	0.70±0.19	<0.0001	0.62±0.18	0.68±0.19	<0.0001
AVA index, cm2/m2	0.44±0.12	0.51±0.14	<0.0001	0.44±0.13	0.49±0.14	<0.0001
Eligibility for severe AS
Vmax >4 m/s or meanaortic PG >40 mmHg	370 (82)	505 (51)	<0.0001	225 (81)	147 (53)	<0.0001
AVA <1.0 cm2 alonewith LVEF <50%	20 (4.5)	186 (19)	<0.0001	16 (5.8)	42 (15)	0.0002
AVA <1.0 cm2 alonewith LVEF ≥50%	56 (12)	283 (29)	<0.0001	36 (13)	86 (31)	<0.0001
LVDd, mm	44±7	46 ± 7	<0.0001	44±7	44 ± 7	0.99
LVDs, mm	29±6	31 ± 8	<0.0001	29±7	30 ± 7	0.56
LVEF, %*	61±11	59 ± 15	0.005	60±12	61 ± 13	0.59
<40%†	21 (4.7)	123 (13)	<0.0001	16 (5.8)	14 (5.0)	0.70
<50%	66 (15)	259 (26)	<0.0001	50 (18)	59 (21)	0.35
IVST in diastole, mm	11±2	11 ± 2	0.13	11 ± 2	11 ± 2	0.81
PWT in diastole, mm	11±2	11 ± 2	0.46	11 ± 3	11 ± 2	0.55
Any combined valvulardisease (moderate orsevere)*,†	81 (18)	509 (52)	<0.0001	71 (26)	70 (25)	0.92
AR	33 (7.4)	234 (24)	<0.0001	29 (10)	31 (11)	0.80
MS	16 (3.6)	39 (4.0)	0.72	5 (1.8)	14 (5.1)	0.03
MR	33 (7.4)	285 (29)	<0.0001	30 (11)	43 (15)	0.11
TR	27 (6.0)	223 (23)	0.0001	24 (8.7)	34 (12)	0.17

Categorical variables were presented as number (%), and continuous variables were presented as mean ± SD, or median with interquartile range.

*Potential independent variables selected for Cox proportional hazards models in the unmatched cohort

† Potential independent variables selected for logistic regression model to develop propensity score for the choice of TAVI.

Anemia was defined as serum hemoglobin <12g/dl for women or <13g/dl for men.

TAVI, transcatheter aortic valve implantation; BMI, body mass index; BSA, body surface area; MI, myocardial infarction; PCI percutaneous coronary intervention; CABG, coronary artery bypass grafting; HD, hemodialysis; STS, society of thoracic surgeons; PROM, predicted risk of mortality; Vmax, peak aortic jet velocity; PG, pressure gradient; AVA, aortic valve area; AS, aortic stenosis; LVDd, left ventricular end-diastolic diameter; LVDs, left ventricular end-systolic diameter; LVEF, left ventricular ejection fraction; LV, left ventricular; IVST, interventricular septum thickness; PWT, posterior wall thickness; AR, aortic regurgitation; MS, mitral stenosis; MR, mitral regurgitation; TR, tricuspid regurgitation.

As a sensitivity analysis, we constructed Cox proportional hazards models incorporating 18 clinically relevant risk-adjusting variables listed in Table 1 among the entire cohort of 1433 patients (TAVI group, 449 patients, and conservative group, 984 patients). We also performed another sensitivity analysis in the propensity score-matched cohort excluding those patients who died within 30 days after the index echocardiography in the conservative group, because enrollment date of K-TAVI registry was not the index echocardiography date but the TAVI procedure date, and there was possibility that some patients scheduled for TAVI had died before actually undergoing TAVI procedure.

We also performed subgroup analyses in terms of age, sex, STS score, LVEF, and high/low gradient AS in the propensity-score matched cohort. Age and STS score were dichotomized by the median values, while LVEF was dichotomized by > = 50% and <50%.

We considered a 2-sided P-value of <0.05 to be significant for all tests. All analyses were performed using JMP 14.0.0 or SAS 9.4 software (SAS Institute, Cary, NC, USA).

Results

Patient characteristics

In the entire cohort, patients in the TAVI group were older than those in the conservative group (Table 1). The age distribution in the range of > = 85 years of age was comparable in the TAVI group and the conservative group, while the proportion of patients with <85 years of age was smaller in the TAVI group than in the conservative group (Fig 2A). Patients in the TAVI group more often had dyslipidemia, anemia, coronary artery disease, and chronic lung disease and had higher STS score, while patients in the conservative group more often had prior myocardial infarction, atrial fibrillation or flutter, and creatinine levels >2 mg/dL (Table 1). In terms of echocardiographic data, Vmax, mean aortic PG, and LVEF were greater in the TAVI group than in the conservative group. The prevalence of combined valvular disease was much higher in the conservative group than in the TAVI group (Table 1).

Fig 2

Distribution of age.

(A) Entire cohort. (B) PS matched cohort (B) PS, propensity score; TAVI, transcatheter aortic valve implantation.

In the propensity score-matched cohort, the baseline patient characteristics including STS score were much better balanced between the TAVI and conservative groups (Table 1). Mean age and the age distribution were comparable in the TAVI and conservative groups (Table 1 and Fig 2B). However, patients in the TAVI group still more often had dyslipidemia, prior percutaneous coronary intervention, and chronic lung disease, while patients in the conservative group more often had prior myocardial infarction, and atrial fibrillation or flutter (Table 1). Echocardiographic severity of AS in terms of Vmax, mean PG, and AVA was greater in the TAVI group than in the conservative group even after propensity score matching (Table 1).

Characteristics and procedural outcomes of TAVI

In terms of procedural characteristics in the TAVI group, trans-femoral approach was selected only in 63% of patients, and the vast majority of patients underwent TAVI under general anesthesia. Successful valve implantation was achieved in 97.3% and device success rate was 92.0% in the entire cohort. The major complications included annulus rupture (0.7%), conversion to open surgery (0.9%), emergency coronary intervention (0.7%), major vascular complications (4.5%), and permanent pacemaker implantation (4.5%). Median length of hospital stay after TAVI was 12 (IQR: 9–18) days (S2 Table).

Clinical outcomes in the propensity score-matched cohort

In the propensity score-matched cohort, the cumulative 30-day incidence of all-cause death was significantly lower in the TAVI group than in the conservative group (1.1% and 4.1%, log-rank P = 0.03). The cumulative 30-day incidence of stroke trended to be higher in the TAVI group than in the conservative group (1.8% and 0.4%, log-rank P = 0.11). Cumulative 30-day incidence of major bleeding was significantly higher in the TAVI group than in the conservative group (4.3%, and 0.8%, log-rank P = 0.007) (S3 Table).

For the long-term follow-up in the propensity score-matched cohort, median follow-up intervals of the surviving patients were 809 (IQR: 736–1118) days in the TAVI group and 1155 (IQR: 903–1590) days in the conservative group. During follow-up, 29 patients (10.4%) ultimately underwent SAVR or TAVI in the conservative group.

The cumulative 2-year incidences of the primary outcome measures (all-cause death and HF hospitalization) were significantly lower in the TAVI group than in the conservative group (16.8%, and 36.6%, log-rank P<0.0001, and 10.7% and 37.2%, log-rank P<0.0001) (Table 2, and Fig 3). The cumulative incidences of the secondary outcome measures such as cardiovascular death, aortic valve-related death, sudden death, and a composite of aortic valve-related death or HF hospitalization were also significantly lower in the TAVI group than in the conservative group (Table 2, and S2 and S3 Figs). The cumulative incidences of non-cardiovascular death, aortic valve procedure death, stroke, and myocardial infarction were not significantly different between the 2 groups (Table 2, and S3 and S4 Figs). The cumulative incidences of major bleeding and infectious endocarditis trended to be higher in the TAVI group than in the conservative group (Table 2, and S4 Fig).

Table 2

Clinical outcomes: Propensity score-matched cohort.

	TAVI group	Conservative group	Hazard Ratio (95% Confidence Interval)
	(N = 278)	(N = 278)
	N of Patients with Event	N of Patients with Event	Crude	P-value	Adjusted	P-value
	(Cumulative 2-year incidence)	(Cumulative 2-year incidence)
All-cause death	45 (16.8%)	95 (36.6%)	0.40 (0.28–0.57)	<0.0001	0.46 (0.32–0.69)	0.0001
Cardiovascular death	21 (8.2%)	69 (28.0%)	0.26 (0.16–0.42)	<0.0001	0.29 (0.17–0.48)	<0.0001
Aortic valve-related death	6 (2.3%)	54 (23.0%)	0.09 (0.04–0.20)	<0.0001	0.10 (0.04–0.22)	<0.0001
Aortic valve procedure death	5 (1.9%)	2 (1.0%)	1.45 (0.36–7.09)	0.60	N/A	-
Sudden death	7 (2.8%)	15 (6.9%)	0.40 (0.15–0.94)	0.04	N/A	-
Non-cardiovascular death	24 (9.4%)	26 (12.0%)	0.78 (0.45–1.36)	0.38	1.03 (0.55–1.97)	0.92
Heart failure hospitalization	27 (10.7%)	85 (37.2%)	0.25 (0.16–0.38)	<0.0001	0.25 (0.16–0.40)	<0.0001
Composite of aortic valve-related death or heart failure hospitalization	32 (12.4%)	103 (42.4%)	0.24 (0.16–0.36)	<0.0001	0.25 (0.16–0.37)	<0.0001
Myocardial infarction	1 (0.4%)	3 (1.5%)	0.29 (0.01–2.30)	0.25	N/A	-
Stroke	12 (4.8%)	11 (5.3%)	0.95 (0.42–2.19)	0.90	N/A	-
Major bleeding	26 (9.8%)	13 (5.7%)	1.88 (0.98–3.78)	0.06	N/A	-
Infective endocarditis	6 (2.4%)	1 (0.5%)	5.21 (0.89–98.4)	0.07	N/A	-

TAVI, transcatheter aortic valve implantation; N/A, not applicable.

Fig 3

Kaplan-Meier curves for the primary outcome measures comparing between the TAVI and conservative groups in the PS matched cohort.

(A) all-cause death. (B) heart failure hospitalization.

After adjustment for the residual confounders, TAVI as compared with conservative management was associated with highly significant risk reduction for all-cause death and HF hospitalization (HR 0.46, 95%CI, 0.32–0.69, P = 0.0001, and HR 0.25, 95%CI 0.16–0.40, P<0.0001) (Table 2). The magnitude of risk reduction with TAVI relative to conservative management for the aortic valve related outcome measure (a composite of aortic valve-related death or HF hospitalization) was comparable to that for HF hospitalization (HR, 0.25, 95%CI, 0.16–0.37; P<0.0001) (Table 2).

Sensitivity analyses

In the entire cohort, median follow-up intervals of the surviving patients were 846 (IQR: 736–1127) days in the TAVI group and 1294 (IQR: 980–1701) days in the conservative group. During follow-up, 134 patients (13.6%) ultimately underwent SAVR or TAVI in the conservative group. The adjusted risks of the TAVI group relative to the conservative group for the primary outcome measures in the entire cohort were fully consistent with those in the propensity score-matched cohort (S4 Table, and S5–S8 Figs). The results were also consistent in another sensitivity analysis in the propensity score-matched cohort excluding those patients who died within 30 days after the index echocardiography in the conservative group (S5 Table).

Subgroup analyses

In the subgroup analyses, there was no significant interaction between the subgroup factors and the effect of TAVI relative to the conservative management for the primary outcome measures, except for the positive interaction between sex and the effect for all-cause death (S9 Fig).

Discussion

The main finding of the present study was that TAVI in the early Japanese experience was associated with striking risk reduction for all-cause death as well as HF hospitalization as compared with the historical cohort of patients with severe AS who were managed conservatively just before introduction of TAVI in Japan.

TAVI is now widely accepted and has already revolutionized the treatment of severe AS. TAVI have been has been adopted rapidly for patients who are at high surgical risk in the world [24-27]. However, TAVI is criticized by some as an expensive treatment in super-elder patients with limited life expectancy. Measuring the magnitude of benefit provided by TAVI as compared with conservative management is essential to discuss the cost-effectiveness of TAVI. In the PARTNER randomized trial, TAVI as compared with standard treatment was associated with relative 44% risk reduction for all-cause death and 59% risk reduction for re-hospitalization at 2-year follow-up in patients with severe AS who were not suitable for SAVR [16]. In the real clinical practice, however, conservative management had often been selected in symptomatic severe AS patients who are high-risk but not unsuitable for SAVR, while TAVI has often been chosen in this group of patients. Therefore, the magnitude of benefit provided by TAVI as compared with conservative management could not be fully assessed in the PARTNER randomized trial. However, there was no previous study exploring how much clinical benefit could be provided by TAVI in comparison with conservative management in patients with severe AS in the real clinical practice. The 2 registries analyzed in the present study, one in the pre-TAVI era, and the other in the TAVI era, could present a unique opportunity to assess the clinical impact of TAVI relative to conservative management in the real world patients with severe AS. In the present propensity score matched analysis, TAVI as compared with conservative management was associated with striking 54% risk reduction for all-cause death and 75% risk reduction for HF hospitalization at 2-year follow-up. High rate of successful valve implantation, low complication rate and very low 30-day mortality rate were also striking, given the fact that this was the very early TAI experience using the prototype device in Japan. Initial procedural risk is usually the tax to pay for the expected long-term benefit of any invasive treatment. However, in the present study, 30-day mortality was significantly lower in the TAVI group than in the conservative group, highlighting the low procedural risk of TAVI as well as very poor prognosis of patients with severe AS when managed conservatively. Furthermore, the 2-year mortality rate after TAVI was only 16.8% in the present study as compared with 43.3% in the PARTNER trial, indicating that the life expectancy of patients undergoing TAVI in the real world was not so short as shown among the inoperable patients enrolled in the PARTNER trial. In line with the marked reduction of HF hospitalization by TAVI in the present study, TAVI is also reported to be associated with marked improvement of symptoms and quality of life [28-31]. The present study is not a formal cost-effectiveness analysis of TAVI. Nevertheless, given the substantial mortality and morbidity benefit of TAVI, the door to TAVI should not be closed due to the cost issues.

There were some negative aspects for TAVI in the present study. Stroke and major bleeding at 30-day were more frequent in the TAVI group than in the conservative group. The long-term risk for infective endocarditis trended to be higher in the TAVI group than in the conservative group. However, the observed mortality and morbidity benefit of TAVI far outweighed these negative aspects for TAVI. The use of newer generation devices has already reduced the incidence of peri-operative stroke and major bleeding [14,32].

There are several important limitations in this study. First, we combined 2 different registries for the present analysis. We developed the propensity-score for the choice of TAVI in the data set derived from 2 different registries, which might not be a formal way of developing propensity-score. However, the sensitivity analysis using multivariable Cox proportional hazard model in the entire cohort provided the fully consistent results with the propensity-score matched analysis. Nevertheless, we could not exclude the possibility of unmeasured confounding. Second, we conducted a comparison between the 2 registries that enrolled patients just before and after introduction of TAVI in Japan, in which the limitations associated with historical comparison were inevitable. However, we do not have good methodology other than historical comparison to estimate the impact of TAVI in the real clinical practice. The 2 multicenter observational studies conducted among the same group of investigators actually provided very unique opportunity to estimate the magnitude of benefit provided by TAVI. Third, we did not know the number of patients who were turned down for TAVI during enrollment in K-TAVI registry. However, we excluded those patients in the CURENT AS registry who were regarded as contraindicated for SAVR by the attending physicians, because some of these patients might also be contraindicated for TAVI. Fourth, we did not assess the symptomatic status of patients in the K-TAVI registry. History of acute HF hospitalization, which would have substantial prognostic impact, could not be adjusted in the comparison between TAVI and conservative management. Fifth, patients who underwent TAVI were early experience data in Japan, therefore about 37% of patients were selected alternative approach and almost all patients underwent TAVI under general anesthesia. This is quite different from current TAVI practice and this could not applicable to current TAVI practice. Finally, follow-up was commenced at different time points in the 2 registries (TAVI group: the day of TAVI, and conservative group: the day of index echocardiography). Therefore, we conducted a sensitivity analysis excluding those patients who died within 30 days after entry in the conservative group, demonstrating results that are fully consistent with those in the main analysis.

Conclusions

TAVI in the early Japanese experience was associated with striking risk reduction for all-cause death as well as HF hospitalization as compared with the historical cohort of patients with severe AS who were managed conservatively just before introduction of TAVI in Japan.

Study Organization.

(DOCX)

Click here for additional data file.

List of participating centers and investigators.

(DOCX)

Click here for additional data file.

List of relevant institutional review boards.

(DOCX)

Click here for additional data file.

Definitions of the endpoints.

(DOCX)

Click here for additional data file.

Distribution of propensity score in (A) the entire cohort and (B) PS matched cohort.

(DOCX)

Click here for additional data file.

Kaplan-Meier curves for (A) cardiovascular death and (B) composite of aortic valve-related death or heart failure hospitalization in the PS matched cohort.

(DOCX)

Click here for additional data file.

Kaplan-Meier curves for (A) aortic valve-related death, (B) aortic valve procedure death, (C) sudden death, and (D) non-cardiovascular death in the PS matched cohort.

(DOCX)

Click here for additional data file.

Kaplan-Meier curves for (A) myocardial infarction, (B) Stroke, (C) major bleeding and (D) infective endocarditis in the PS matched cohort.

(DOCX)

Click here for additional data file.

Kaplan-Meier curves for (A) all-cause death and (B) heart failure hospitalization in the entire cohort.

(DOCX)

Click here for additional data file.

Kaplan-Meier curves for (A) cardiovascular death and (B) composite of aortic valve-related death or heart failure hospitalization in the entire cohort.

(DOCX)

Click here for additional data file.

Kaplan-Meier curves for (A) aortic valve-related death, (B) aortic valve procedure death, (C) sudden death, and (D) non-cardiovascular death in the entire cohort.

(DOCX)

Click here for additional data file.

Kaplan-Meier curves for (A) myocardial infarction, (B) Stroke, (C) major bleeding and (D) infective endocarditis in the entire cohort.

(DOCX)

Click here for additional data file.

Subgroup analysis for the primary outcome measure: (A) All-cause moratality and (B) Heart failure hospitalization.

(DOCX)

Click here for additional data file.

Coefficients of the independent variables in the logistic regression function.

(DOCX)

Click here for additional data file.

Procedural characteristics and outcomes of the patients who underwent TAVI.

(DOCX)

Click here for additional data file.

Clinical outcomes at 30-day in the PS-matched cohort and in the entire cohort.

(DOCX)

Click here for additional data file.

Clinical outcomes in the entire cohort.

(DOCX)

Click here for additional data file.

Clinical outcomes in the PS-matched cohort after excluding those patients who died within 30 days after the index echocardiography in the conservative group.

(DOCX)

Click here for additional data file.

1 Aug 2019

PONE-D-19-17543

Transcatheter Aortic Valve Implantation Versus Conservative Management for Severe Aortic Stenosis in Real Clinical Practice

PLOS ONE

Dear Dr Naritatsu Saito,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

In the revised version of the manuscript, you should provide some lacking informations on patients, including inclusion/exclusion criteria. Some re-analyses should be performed in line with updated thresholds from recent studies. Satistics methods need to be adapted according to reviewer's comments.

We would appreciate receiving your revised manuscript by 31st October. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.

Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

We look forward to receiving your revised manuscript.

Kind regards,

Cécile Oury

Academic Editor

PLOS ONE

Journal Requirements:

1. When submitting your revision, we need you to address these additional requirements.

Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

http://www.journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and http://www.journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. Please provide details of the author contributions in accordance with CRediT standards https://journals.plos.org/plosone/s/authorship

*In your financial disclosure, please clearly specify whether the funders played any role in the study.

3. Please provide the names of all the ethics committees which approved this study.

*Please include the information on ethics approval and consent, given in the methods section of your manuscript, in the ethics statement on the online submission form.

4. Thank you for stating in your Funding Statement:

[Yes

CURRENT AS registry was supported by an educational grant from the Research Institute for Production Development (Kyoto, Japan).].

* Please provide an amended statement that declares *all* the funding or sources of support (whether external or internal to your organization) received during this study, as detailed online in our guide for authors at http://journals.plos.org/plosone/s/submit-now.  Please also include the statement “There was no additional external funding received for this study.” in your updated Funding Statement.

* Please include your amended Funding Statement within your cover letter. We will change the online submission form on your behalf.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: No

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: No

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This is a nice study combining two prospective registries. The study is providing new and valuable data.

The references are perhaps missing European registries’data.

The paper is nicely written and very informative, the discussion is really nice and the figures are clean.

Perhaps the text is a bit too long? It could be shorten to provide more data on subgroups with figures.

It appears that the study is not including patients with any low gradient, low flow AS? That is a pity and adding a specific analysis on this group of patients could be even more original and valuable as no strong data are available yet.

The EF is looked according to cut-off of 40 and 50% but the recent literature is underscoring the difference between 60 or 55% versus below: could the authors provide these data and the Kaplan Meier curves according to EF above of below 55% when the patients are treated or not?

The COPD is strikingly different between groups: comments.

The ischemic heart disease: comments?

Is it expected to have such a low rate of AF in such elderly patients? This is strikingly different for USA and Europe.

Reviewer #2: General comments:

In this observational retrospective study authors aimed at comparing TAVI to medical treatment using historical cohort data. The study is not timely since the question asked has been previously answered in much more robust studies. However, it could still be interesting regarding the long-term differences between the two groups. But authors should provide a more robust methodological and statistical approach and would benefit from simplification (the sensitivity and subgroup analyses provide little new insight).

Specific comments:

• Not a timely study, as attested by the use of Sapien XT valves, 37% of alternative access, with probably transapical as first alternative (Results page 22 “trans-femoral approach was selected only in 63% of patients”) with a comparator based on a historical pre-TAVI era cohort. Must be clearly stated that comparison is not applicable to current clinical practice

• Method page 15 “We also excluded those patients … might also be contraindicated for TAVI” Authors should clarify what patients were excluded here and reformulate this statement because TAVI is a clear indication for a large proportion of patients which are contraindicated to SAVR. Please also clarify the flow chart figure 1 with regard to the box “conservative group with formal indication of AVR …”

• Statistical analysis page 17 “Because some variables were not well balanced … further adjustment by using the Cox proportional hazard models” In case of PS matching failure please consider removing PS matching step and apply multivariable Cox upfront.

• Statistical analysis “We also performed subgroup analyses in terms of age, sex, STS score, LVEF, and high/low gradient AS in the propensity-score matched cohort” As reported by authors, the PS matching failed, therefore building subgroups for this cohort is likely to provide biased results.

• Please consider separating all-cause mortality and HR rehospitalization all over the manuscript. Those 2 outcomes have little in common and the database is likely able to provide these data.

• Please provide information regarding TAVI procedural characteristics in a Table: valves used, labels/generations, pathways, TEE use, general versus local anaesthesia, complications, etc

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: Yes: Thomas Modine, Pavel Overtchouk

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step.

12 Aug 2019

Reply to the comments of the editors and reviewers

We truly appreciate the time and effort invested by the editors and reviewers in providing us with a critical assessment on our manuscript. We revised our manuscript according to the comments and suggestions of the editors and reviewers.

We showed all of the response to editors and reviewers with reference tables and figures in "Response to reviewer file" added on the end of "revised file".

1. When submitting your revision, we need you to address these additional requirements.

Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming.

Thank you for your guidance. We confirmed our script meet PLOS ONE's style requirements.

2. Please provide details of the author contributions in accordance with CRediT standards

*In your financial disclosure, please clearly specify whether the funders played any role in the study.

Thank you for your guidance. We confirmed and describe the author contributions in accordance with CRediT standards as follows.

Author Contributions (Page 23, Line 16- Page 24, Line 12)

Conceptualization: Takeshi Morimoto, Takeshi Kimura.

Data curation: Yasuaki Takeji, Tomohiko Taniguchi

Methodology: Takeshi Morimoto, Takeshi Kimura.

Formal analysis: Yasuaki Takeji, Takeshi Morimoto.

Project administration: Tomohiko Taniguchi, Takeshi Morimoto, Naritatsu Saito, Kenji Ando, Shinichi Shirai, Genichi Sakaguchi, Yoshio Arai, Yasushi Fuku, Yuichi Kawase, Tatsuhiko Komiya, Natsuhiko Ehara, Takeshi Kitai, Tadaaki Koyama, Shin Watanabe, Hirotoshi Watanabe, Hiroki Shiomi, Eri Minamino-Muta, Shintaro Matsuda, Hidenori Yaku, Yusuke Yoshikawa, Kazuhiro Yamazaki, Masahide Kawatou, Kazuhisa Sakamoto, Toshihiro Tamura, Makoto Miyake, Hisashi Sakaguchi, Koichiro Murata, Masanao Nakai, Norio Kanamori, Chisato Izumi, Hirokazu Mitsuoka, Masashi Kato, Yutaka Hirano, Tsukasa Inada, Kazuya Nagao, Hiroshi Mabuchi, Yasuyo Takeuchi, Keiichiro Yamane, Takashi Tamura, Mamoru Toyofuku, Mitsuru Ishii, Moriaki Inoko, Tomoyuki Ikeda, Katsuhisa Ishii, Kozo Hotta, Toshikazu Jinnai, Nobuya Higashitani, Yoshihiro Kato, Yasutaka Inuzuka, Yuko Morikami, Kenji Minatoya, Takeshi Kimura.

Software: Takeshi Morimoto.

Supervision: Naritatsu Saito, Tomohiko Taniguchi, Takeshi Morimoto, Takeshi Kimura.

Validation: Yasuaki Takeji, Takeshi Morimoto.

Writing – original draft: Yasuaki Takeji.

Writing – review & editing: Naritatsu Saito, Takeshi Morimoto, Takeshi Kimura

3. Please provide the names of all the ethics committees which approved this study.

*Please include the information on ethics approval and consent, given in the methods section of your manuscript, in the ethics statement on the online submission form.

We appreciate your guidance.

The following sentence was placed in the Materials and Methods section of our manuscript and The relevant institutional review boards at all participating hospitals were described in S3 Text.

Materials and Methods (Page 8, Line 21- Page 9, Line 2)

The relevant institutional review boards at all participating hospitals approved the study protocols and were described in S3 text. We performed the study in accordance with the Declaration of Helsinki. Written informed consent specific for the K-TAVI registry was waived because patients undergoing TAVI provided written informed consent for the compulsory national clinical database registry, and it was also waived in the CURRENT AS registry because of the retrospective study design.

4. Thank you for stating in your Funding Statement:

[Yes

CURRENT AS registry was supported by an educational grant from the Research Institute for Production Development (Kyoto, Japan).].

* Please provide an amended statement that declares *all* the funding or sources of support (whether external or internal to your organization) received during this study, as detailed online in our guide for authors at http://journals.plos.org/plosone/s/submit-now. Please also include the statement “There was no additional external funding received for this study.” in your updated Funding Statement.

* Please include your amended Funding Statement within your cover letter. We will change the online submission form on your behalf.

We appreciate your guidance.

We included my amended Funding Statement within your cover letter and manuscript as follows.

CURRENT AS registry was supported by an educational grant from the Research Institute for Production Development (Kyoto, Japan). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. There was no additional external funding received for this study.

Reviewer #1:

#1.This is a nice study combining two prospective registries. The study is providing new and valuable data. The references are perhaps missing European registries’data.

The paper is nicely written and very informative, the discussion is really nice and the figures are clean.

We appreciate your comment. As we mentioned in text, to evaluate the clinical benefit of TAVI compared with conservative therapy have been still important for clinical decision. Not only randomized control trials but also real-world data was important regarding about this problem.

We added the following description and reference from European registries’ reference in the Discussion section.

Discussion (Page 18, Line 25 to Page 19, Line 1)

TAVI have been has been adopted rapidly for patients who are at high surgical risk in the world [24-27].

[24] Gilard M, Eltchaninoff H, Iung B, Donzeau-Gouge P, Chevreul K, Fajadet J, et al. Registry of transcatheter aortic-valve implantation in high-risk patients. The New England journal of medicine. 2012;366(18):1705-15.

[25] Ludman PF, Moat N, de Belder MA, Blackman DJ, Duncan A, Banya W, et al. Transcatheter aortic valve implantation in the United Kingdom: temporal trends, predictors of outcome, and 6-year follow-up: a report from the UK Transcatheter Aortic Valve Implantation (TAVI) Registry, 2007 to 2012. Circulation. 2015;131(13):1181-90.

[26] Krasopoulos G, Falconieri F, Benedetto U, Newton J, Sayeed R, Kharbanda R, et al. European real world trans-catheter aortic valve implantation: systematic review and meta-analysis of European national registries. Journal of cardiothoracic surgery. 2016;11(1):159.

[27] Auffret V, Lefevre T, Van Belle E, Eltchaninoff H, Iung B, Koning R, et al. Temporal Trends in Transcatheter Aortic Valve Replacement in France: FRANCE 2 to FRANCE TAVI. Journal of the American College of Cardiology. 2017;70(1):42-55.

#2.Perhaps the text is a bit too long? It could be shorten to provide more data on subgroups with figures.

Thank you for your comment. In my text, we described introduction, materials and methods, results and discussion. We described details of the materials and methods because of this complex methodology, and both results and discussion had important message in our study.

On the other hand, in subgroup analysis, we only wanted to demonstrate consistency about primary outcomes, and we did not aim to obtain new finding from subgroup analysis.

#3.It appears that the study is not including patients with any low gradient, low flow AS? That is a pity and adding a specific analysis on this group of patients could be even more original and valuable as no strong data are available yet.

Thank you for your valuable comment. In this study, we also included patients with low gradient AS. However, we did not have data of stroke volume , so we could not identify patients with low flow, low gradient severe AS.

#4.The EF is looked according to cut-off of 40 and 50% but the recent literature is underscoring the difference between 60 or 55% versus below: could the authors provide these data and the Kaplan Meier curves according to EF above of below 55% when the patients are treated or not?.

Thank you very much for your valuable suggestion. Cut-off of 40 and 50% were used in prior our study and we adopted the same value. These days, in the field of heart failure, heart failure with mid- range ejection fraction was hot topic and this was defined as EF 40-49%. We set also heart failure hospitalization as one of primary endpoint in this study. Regarding this point, our group consider that the cut-off point 40 and 50 were reasonable. However, for post-hoc analysis, we conducted Kaplan Meier curves according to EF above or below 55% and cumulative incidence and adjusted hazard ratio divided by EF 55 and 60% in "Response to reviewer file" added on the end of "revised file".

The results of both cut-off points were consistent with cut-off of 50%.

#5.The COPD is strikingly different between groups: comments..

Thank you for your valuable comments.

As you pointed out, much more patients had chronic lung disease in the TAVI group than in the conservative group. We consider this was because TAVI procedure in this study was at the early experience after introduction of TAVI in Japan. In this era, Japanese physicians selected TAVI when patients have high risk of surgical aortic valve replacement because of comorbidities like chronic lung disease. This is proof that 29.5% of the patients who underwent TAVI had moderate and severe COPD in Japanese National TAVI registry [1]. However, after propensity score matched cohort, the difference of rate of moderate or severe chronic lung disease was set off.

#6.The ischemic heart disease: comments?

Thank you for your valuable comments.

As you pointed out, patients in the TAVI group had more coronary artery disease than in the conservative group. We consider this is because before TAVI procedure, cardiologist in Japan usually underwent coronary angiography, therefore coronary artery disease more tended to detect. However, after propensity score matched cohort, the difference of rate of coronary artery disease was set off.

#7.Is it expected to have such a low rate of AF in such elderly patients? This is strikingly different for USA and Europe.

Thank you for your valuable comments.

In studies of USA and Europe country regarding TAVI procedure, the prevalence of AF in patients with severe AS who underwent TAVI was about 40%, and this is strikingly different for our data. There was a study that prevalence of atrial fibrillation in the general population of Japan was lower than USA [2]. In addition, another TAVI registry in Japan showed that only 20% of the patients who underwent TAVI had atrial fibrillation [3]. We consider that the prevalence of AF was lower than US data even in such elderly patients.

Reference:

[1] Handa N, Kumamaru H, Torikai K, Kohsaka S, Takayama M, Kobayashi J, et al. Learning Curve for Transcatheter Aortic Valve Implantation Under a Controlled Introduction System- Initial Analysis of a Japanese Nationwide Registry. Circulation journal : official journal of the Japanese Circulation Society. 2018;82(7):1951-8.

[2] Inoue H, Fujiki A, Origasa H, Ogawa S, Okumura K, Kubota I, et al. Prevalence of atrial fibrillation in the general population of Japan: an analysis based on periodic health examination. International journal of cardiology. 2009;137(2):102-7.

[3] Hioki H, Watanabe Y, Kozuma K, Kawashima H, Nagura F, Nakashima M, et al. The MAGGIC risk score predicts mortality in patients undergoing transcatheter aortic valve replacement: sub-analysis of the OCEAN-TAVI registry. Heart and vessels. 2019.

Reviewer #2:

In this observational retrospective study authors aimed at comparing TAVI to medical treatment using historical cohort data. The study is not timely since the question asked has been previously answered in much more robust studies. However, it could still be interesting regarding the long-term differences between the two groups. But authors should provide a more robust methodological and statistical approach and would benefit from simplification (the sensitivity and subgroup analyses provide little new insight).

#1.Not a timely study, as attested by the use of Sapien XT valves, 37% of alternative access, with probably transapical as first alternative (Results page 22 “trans-femoral approach was selected only in 63% of patients”) with a comparator based on a historical pre-TAVI era cohort. Must be clearly stated that comparison is not applicable to current clinical practice

Thank you very much for your valuable suggestion. As you pointed out, this study compared TAVI with early experience in Japan and conservative therapy in before introduction TAVI. About 37% of patients who underwent TAVI were selected alternative approach and almost all patients were undergone TAVI under general anesthesia. This is not applicable to current TAVI practice ,although we consider that the data of early experience was important to evaluate long-term results over 2 years.

We added the following statement regarding the difference from current clinical practice in the limitations section.

Limitations (Page 21, Line 9 to Page 21, Line 12)

Fifth, patients who underwent TAVI were early experience data in Japan, therefore about 37% of patients were selected alternative approach and almost all patients underwent TAVI under general anesthesia. This is quite different from current TAVI practice and this could not applicable to current TAVI practice.

#2.Method page 15 “We also excluded those patients … might also be contraindicated for TAVI” Authors should clarify what patients were excluded here and reformulate this statement because TAVI is a clear indication for a large proportion of patients which are contraindicated to SAVR. Please also clarify the flow chart figure 1 with regard to the box “conservative group with formal indication of AVR …”

Thank you for your valuable suggestion. We excluded patients who were considered to be contraindicated aortic valve replacement (TAVI or SAVR) because of malnutrition, muscle weakness, cognitive impairment, and expected poor prognosis due to morbidities other than heart disease.

For detail, 146 patients excluded contraindicated because of malnutrition (61 patients) , muscle weakness (26 patients), cognitive impairment (101 patients), and 46 patients excluded because of expected poor prognosis due to morbidities other than heart disease.

We added this details of exclusion you suggested to method, and modified Fig 1 in "Response to reviewer file" added on the end of "revised file".

Materials and Methods (Page 8, Line 10 to Page 8, Line 12)

We also excluded those patients who were regarded as contraindicated for SAVR by the attending physicians (malnutrition, muscle weakness, cognitive impairment, and expected poor prognosis), because these patients were considered to be contraindicated for TAVI.

The detail of “conservative group with formal indication of AVR” was written below in the same box in Figure 1.

The formal indication of AVR were symptomatic patients, asymptomatic patients with Vmax>=5m/, or asymptomatic patient with LVEF<50% mentioned in AHA/ACC Guideline [1].

We clearly described as below.

Materials and Methods (Page 8, Line 6 to Page 8, Line 9)

we excluded those patients on hemodialysis (HD) in whom TAVI has not been yet approved in Japan, and those asymptomatic patients with Vmax <5m/s and left ventricular ejection fraction (LVEF) >=50%, who are regarded as candidates for watchful waiting according to the guidelines

#3.Statistical analysis page 17 “Because some variables were not well balanced … further adjustment by using the Cox proportional hazard models” In case of PS matching failure please consider removing PS matching step and apply multivariable Cox upfront.

Thank you for your valuable suggestion.

In this study, we combined two different studies and the difference of baseline characteristics between two groups was significant. Regarding this problem, we discussed with statistician and decided to use PS matching. The statistical method of using cox proportional hazard model with residual variables to adjust after PS matching have been conducted in prior studies [2][3][4].

To confirm robustness of PS matching method, we also conducted cox proportional hazard models as sensitivity analysis, and the results were consistent with PS matching.

#4.Statistical analysis “We also performed subgroup analyses in terms of age, sex, STS score, LVEF, and high/low gradient AS in the propensity-score matched cohort” As reported by authors, the PS matching failed, therefore building subgroups for this cohort is likely to provide biased results.

Thank you for your valuable suggestion.

To adjust residual confounders, we also conducted cox proportional hazard model after PS matching for subgroup analyses. As you pointed out, there were not new finding in subgroup analysis. Our aim to conduct subgroup analysis was to confirm consistency of results about primary outcomes.

#5 Please consider separating all-cause mortality and HR rehospitalization all over the manuscript. Those 2 outcomes have little in common and the database is likely able to provide these data.

Thank you very much for your suggestion. In the study, primary outcomes were all-cause mortality and HF hospitalization, but these were not composite endpoint. In our study, these two outcomes described respectively.

#6.Please provide information regarding TAVI procedural characteristics in a Table: valves used, labels/generations, pathways, TEE use, general versus local anaesthesia, complications, etc

Thank you very much for your comment. We described TAVI procedural characteristics in S2 Table below. We show reference table in "Response to reviewer file" added on the end of "revised file".

We described approach site, procedure time, valve size, type of anesthesia, ECMO and complications. However, we did not have data about TEE use.

Reference:

[1] Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin JP, 3rd, Fleisher LA, et al. 2017 AHA/ACC Focused Update of the 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Journal of the American College of Cardiology. 2017;70(2):252-89.

[2] Taniguchi T, Morimoto T, Shiomi H, Ando K, Kanamori N, Murata K, et al. Initial Surgical Versus Conservative Strategies in Patients With Asymptomatic Severe Aortic Stenosis. Journal of the American College of Cardiology. 2015;66(25):2827-38.

[3] Birkhead JS, Weston CF, Chen R. Determinants and outcomes of coronary angiography after non-ST-segment elevation myocardial infarction. A cohort study of the Myocardial Ischaemia National Audit Project (MINAP). Heart (British Cardiac Society). 2009;95(19):1593-9.

[4] Bajaj JS, Ratliff SM, Heuman DM, Lapane KL. Proton pump inhibitors are associated with a high rate of serious infections in veterans with decompensated cirrhosis. Aliment Pharmacol Ther. 2012;36(9):866-74.

Submitted filename: Rebuttal Letter.docx

Click here for additional data file.

12 Sep 2019

[EXSCINDED]

Transcatheter Aortic Valve Implantation Versus Conservative Management for Severe Aortic Stenosis in Real Clinical Practice

PONE-D-19-17543R1

Dear Dr. Naritatsu Saito,

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication.

Shortly after the formal acceptance letter is sent, an invoice for payment will follow. To ensure an efficient production and billing process, please log into Editorial Manager at https://www.editorialmanager.com/pone/, click the "Update My Information" link at the top of the page, and update your user information. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, you must inform our press team as soon as possible and no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

With kind regards,

Cécile Oury

Academic Editor

PLOS ONE

Additional Editor Comments:

The reviewer 1 and myself considered that the authors have adequately addressed the issues that were raised. The reason why the study is not a timely study according to current clinical practices has been well justified by the authors, missing patient informations have been provided, and statistical analyses have been adapted as requested.

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Thanks for having worked on the manuscript according to the comments we previously did.

The paper is OK and is providing data that are insteresting.

No major comment remains about the form and,

the content is OK.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: DONAL Erwan

18 Sep 2019

PONE-D-19-17543R1

Transcatheter Aortic Valve Implantation Versus Conservative Management for Severe Aortic Stenosis in Real Clinical Practice

Dear Dr. Saito:

I am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

For any other questions or concerns, please email plosone@plos.org.

Thank you for submitting your work to PLOS ONE.

With kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Cécile Oury

Academic Editor

PLOS ONE