Prognostic Value of the 6-Minute Walk Test in Patients With Severe Aortic Stenosis

Abstract

Background: The prognostic significance of the 6-minute walk distance (6MWD) in patients with severe aortic stenosis (AS) has not been thoroughly investigated.

Methods and Results: This study evaluated 998 patients with severe AS who underwent a 6-min walk test as part of a large multicenter prospective cohort. Patients were categorized as either fast walkers (6MWD ≥300 m; n=515) or slow walkers (6MWD <300 m; n=483). During a median follow-up of 2.3 years, 861 (86.3%) patients underwent surgical or transcatheter aortic valve replacement (AVR; 87.0% of fast walkers vs. 85.5% of slow walkers). The cumulative 3-year incidence of death was significantly lower among fast walkers than slow walkers (10.9% vs. 31.7%; P<0.001). After adjusting for confounders, slow walkers had a significantly higher risk of all-cause mortality than fast walkers (hazard ratio 2.36; 95% confidence interval 1.55–3.58; P<0.001). Stratified analysis by initial treatment strategy revealed that the cumulative 3-year incidence of all-cause death was consistently lower among fast walkers than slow walkers (initial AVR strategy: 10.1% vs. 28.1% [P<0.001]; conservative strategy: 13.4% vs. 46.7% [P<0.001]). Among asymptomatic patients managed conservatively, fast walkers demonstrated a remarkably low cumulative 3-year incidence of all-cause death (8.1%).

Conclusions: The 6MWD is a reliable prognostic marker for patients with severe AS, regardless of initial treatment strategy.

Since the introduction of transcatheter aortic valve implantation (TAVI), aortic valve replacement (AVR) can be applied in a greater number of elderly patients with severe aortic stenosis (AS).^1–4 However, elderly patients with severe AS often have multiple comorbidities, making it difficult to choose an optimal management strategy for severe AS.^5,6 In guidelines, the severity of AS and symptom status are regarded as determinants of the initial AVR strategy.^7–9 Nevertheless, recent studies suggest that assessing frailty may provide valuable prognostic insights.^10,11 One promising tool for assessing frailty is the 6-minute walk test (6MWT), which is often more easily accessible than other stress tests, such as the treadmill exercise test or cardiopulmonary exercise test.¹² The 6-minute walk distance (6MWD) could serve as a surrogate of the overall physical capacity of patients, encompassing both cardiopulmonary and musculoskeletal function.^13,14 Despite the importance of the 6MWD, relatively few studies have evaluated its prognostic impact, and it is possible that the impact of 6MWD may differ between patients undergoing an initial AVR strategy and those being treated with a conservative strategy.^15–18

The aim of this study was to evaluate the prognostic impact of the 6MWD in patients with severe AS using data from a large Japanese multicenter prospective registry that enrolled consecutive patients with severe AS.

Methods

Study Population

The design and methodology of the Contemporary Outcomes After Surgery and Medical Treatment in Patients With Severe Aortic Stenosis (CURRENT AS) Registry-2 have been described previously.⁵ Briefly, this prospective, multicenter registry included 3,369 consecutive patients with severe AS across 21 centers in Japan between April 2018 and December 2020. Patients were enrolled if they met the definition of severe AS (peak aortic jet velocity >4.0 m/s, mean aortic pressure gradient >40 mmHg, or aortic valve area <1.0 cm²) for the first time during the study period.

The study was approved by institutional review boards at all participating centers. Written informed consent was obtained from each patient at 19 centers, whereas 2 centers used an opt-out strategy, with the need for written informed consent waived, with the permission of the institutional review boards.

6MWT

In this registry, it was strongly recommended that patients underwent a 6MWT and/or treadmill exercise test. The present study population included 998 patients who actually underwent the 6MWT (Supplementary Figure 1). Patients were instructed to walk along a corridor and cover the maximum distance in 6 min under the supervision of medical staff with experience in conducting the test. Heart rate and saturation of percutaneous oxygen were measured and patients were notified how much time had elapsed every minute. After 6 min, patients were asked to stop, and the distance walked was measured in meters. Based on previous reports in patients with heart failure (HF),^19,20 as well as considering its clinical utility in identifying high-risk patients, being able to walk more than 300 m in 6 min was regarded as adequate performance in the 6MWT (fast walkers), whereas being able to walk only less than 300 m in 6 min was regarded as inadequate performance in the 6MWT (slow walkers). This cut-off value was prespecified prior to the initiation of the study.

Initial Treatment Strategies and Follow-up

The choice of initial AVR or conservative strategy was made following discussion between the attending physician and patient, with occasional heart team consultation. The choice of surgical AVR (SAVR) or TAVI was made based on a consensus within the heart team and patient preference.

We compared baseline characteristics and 3-year clinical outcomes between fast and slow walkers, stratified according to the results of the 6MWD. Follow-up started on the day of the index echocardiography, unless specified otherwise. Patients under watchful waiting were strongly recommended to undergo regular follow-up by echocardiography and measurement of B-type natriuretic peptide (BNP) or N-terminal pro BNP (NT-proBNP) every 6 months according to current guidelines in the outpatient department of the participating center.⁸ Follow-up schedules of patients other than those under watchful waiting were left to the discretion of the attending physician. Follow-up information was collected by the attending physicians or research assistants at each participating center. If outpatient clinical follow-up was not conducted at the centers participating in the study or if additional follow-up information was needed, data were collected through contact with patients, relatives, and/or referring physicians after mailing questionnaires regarding clinical events, subsequent hospitalizations, and medication status.

Clinical Outcome Measures

The primary outcome measure in this analysis was all-cause death. Other outcome measures included cardiovascular death, non-cardiovascular death, aortic valve-related death, sudden death, HF hospitalization, and TAVI or SAVR. Aortic valve-related deaths included aortic valve procedure death, sudden death, and death due to HF possibly related to AS. HF hospitalization was defined as hospitalization due to worsening HF requiring intravenous drug therapy. Sudden death was defined as unexplained death in previously stable patients. Causes of death were classified according to the Valve Academic Research Consortium definitions, and were adjudicated by a clinical event committee.^21,22

Statistical Analysis

Continuous variables are expressed as the mean±SD or median with interquartile range (IQR). Based on their distributions, continuous variables were compared using Student’s t-test or the Wilcoxon rank-sum test. Categorical variables are presented as numbers and percentages, and were compared using the Chi-squared test. Cumulative event incidences were estimated by the Kaplan-Meier method and the significance of differences was assessed using the log-rank test. In multivariable Cox proportional hazard models, we used 23 clinically relevant factors as risk-adjusting variables (Table 1), with participating center incorporated as a stratification variable, consistent with our previous reports.^23–25 For outcome measures with fewer than 100 patients with events, parsimonious models were constructed with 7 risk-adjusting variables (Table 1) to prevent overfitting. Multivariable analysis was not conducted for outcome measures with fewer than 30 patients with events. The risks of slow walkers relative to fast walkers (reference) for the clinical outcomes were expressed as hazard ratios (HRs) with 95% confidence intervals (CIs). Subgroup analyses were stratified by initial treatment strategy, age, and sex to assess the prognostic impact of the 6MWD. A sensitivity analysis was conducted in asymptomatic patients managed with a conservative strategy.

Table 1.

Baseline Characteristics

	6MWD ≥300 m (n=515)	6MWD <300 m (n=483)	P value
Age* (years)	78±8	84±6	<0.001
Age ≥80 years†	257 (49.9)	404 (83.6)	<0.001
Male sex*	279 (54.2)	140 (29.0)	<0.001
BMI (kg/m2)	23.1±3.3	22.7±3.8	0.10
BMI <22 kg/m2*	205 (39.8)	233 (48.2)	0.007
Hypertension*	428 (83.1)	411 (85.1)	0.44
Current smoking*	32 (6.2)	17 (3.5)	0.06
Dyslipidemia	306 (59.4)	261 (54.0)	0.10
On statin therapy	264 (51.3)	206 (42.7)	0.008
Diabetes	137 (26.6)	122 (25.3)	0.67
On insulin therapy*	18 (3.5)	22 (4.6)	0.42
Prior myocardial infarction*	28 (5.4)	31 (6.4)	0.59
Prior PCI	69 (13.4)	60 (12.4)	0.71
Prior CABG	15 (2.9)	16 (3.3)	0.72
Prior symptomatic stroke*	57 (11.1)	83 (17.2)	0.006
Atrial fibrillation or flutter*	82 (15.9)	125 (25.9)	<0.001
Aortic/peripheral vascular disease*,†	24 (4.7)	50 (10.4)	0.001
Serum creatinine (mg/dL)	0.90 [0.73–1.13]	0.94 [0.72–1.30]	0.17
Creatinine level >2 mg/dL*	29 (5.6)	43 (8.9)	0.05
Hemodialysis*,†	16 (3.1)	25 (5.2)	0.11
Anemia*	231 (44.9)	308 (63.8)	<0.001
Liver cirrhosis (Child-Pugh B or C)*	3 (0.6)	5 (1.0)	0.49
Prior malignancy	128 (24.9)	96 (19.9)	0.07
Malignancy currently under treatment*,†	37 (7.2)	24 (5.0)	0.15
Chronic lung disease (moderate or severe)*	46 (8.9)	46 (9.5)	0.83
Coronary artery disease*	166 (32.2)	184 (38.1)	0.06
EuroSCORE II	2.5 [1.5–3.7]	3.8 [2.7–4.9]	<0.001
Logistic EuroSCORE	8.0 [5.5–12.2]	12.8 [9.5–19.2]	<0.001
STS score (PROM)	3.2 [2.0–4.6]	4.8 [3.7–6.6]	<0.001
Clinical frailty score	3.0 [2.0–3.0]	4.0 [3.0–4.5]	<0.001
1–3	411 (79.8)	174 (36.0)	<0.001
4–6	103 (20.0)	298 (61.7)
7–9	1 (0.2)	11 (2.3)
Katz index	5.97±0.25	5.46±1.26	<0.001
Symptoms	331 (64.3)	378 (78.3)	<0.001
Chest pain	63 (12.2)	46 (9.5)	0.01
Syncope	25 (4.9)	29 (6.0)	1.0
HF	279 (54.2)	342 (70.8)	0.02
NYHA Class II	227 (44.1)	207 (42.9)	<0.001
NYHA Class III	44 (8.5)	115 (23.8)
NYHA Class IV	8 (1.6)	20 (4.1)
HF hospitalization at index echocardiography*,†	24 (4.7)	34 (7.0)	0.14
BNP (pg/mL)	103 [47–236]	195 [79–422]	<0.001
NT-proBNP (pg/mL)	555 [214–1,014]	1,600 [710–3,587]	<0.001
Echocardiographic variables
Vmax (m/s)	4.3±0.7	4.3±0.8	0.97
Vmax >4 m/s*,†	366 (71.1)	331 (68.5)	0.41
Vmax >4.5 m/s	191 (37.1)	187 (38.7)	0.60
Vmax >5 m/s	76 (14.8)	104 (21.5)	0.006
Mean PG (mmHg)	44±15	46±19	0.32
Mean PG >40 mmHg	292 (56.8)	278 (57.6)	0.85
AVA (cm2)	0.76±0.18	0.69±0.17	<0.001
AVA index (cm2/m2)	0.48±0.12	0.47±0.12	0.16
LVDd (mm)	46±6	43±6	<0.001
LVDs (mm)	30±6	29±6	0.012
LVEF (%)	63±10	61±10	0.007
LVEF <60%*	138 (26.8)	150 (31.1)	0.14
IVST (mm)	10.9±1.8	11.0±1.9	0.67
PWT (mm)	10.5±1.8	10.3±1.8	0.11
Any combined valvular disease (moderate or severe)*,†	119 (23.1)	99 (20.5)	0.36
AR moderate or severe	72 (14.0)	27 (5.6)	<0.001
MR moderate or severe	45 (8.7)	55 (11.4)	0.17
MS moderate or severe	10 (1.9)	13 (2.7)	0.53
TR moderate or severe	23 (4.5)	40 (8.3)	0.02
TR PG ≥40 mmHg*	25 (4.9)	63 (13.0)	<0.001
6MWD (m)	382.0 [338.0–435.0]	189.4 [125.5–245.0]	<0.001
Initial AVR strategy*	386 (75.0)	393 (81.4)	<0.001
Conservative strategy	129 (25.0)	90 (18.6)

Unless indicated otherwise, values are expressed as n (%), mean±SD, or median [interquartile range]. *Risk-adjusting variables selected for the multivariable Cox proportional hazards models. ^†Risk-adjusting variables in the parsimonious models. Anemia was defined according to the World Health Organization criteria as hemoglobin <12.0 g/dL in women and <13.0 g/dL in men. 6MWD, 6-min walk test distance; AR, aortic regurgitation; AS, aortic stenosis; AVA, aortic valve area; AVR, aortic valve replacement; BMI, body mass index; BNP, B-type natriuretic peptide; CABG, coronary artery bypass grafting; HF, heart failure; IVST, interventricular septum thickness; LVDd, left ventricular end-diastolic diameter; LVDs, left ventricular end-systolic diameter; LVEF, left ventricular ejection fraction; MR, mitral regurgitation; MS, mitral stenosis; NT-proBNP, N-terminal pro B-type natriuretic peptide; NYHA, New York Heart Association; PCI, percutaneous coronary intervention; PG, pressure gradient; PROM, predicted risk of mortality; PWT, posterior wall thickness; STS, Society of Thoracic Surgeons; TR, tricuspid regurgitation; V_max, peak aortic jet velocity.

All statistical analyses were performed using R 3.1.1 (R Foundation for Statistical Computing, Vienna, Austria). All P values reported are 2-tailed, with P<0.05 considered significant.

Results

Of the 998 patients who performed the 6MWT at baseline, the median and mean 6MWD were 300.5 and 291.4±126.6 m, respectively. The study population was divided into 2 groups based on 6MWD: fast walkers (6MWD ≥300 m; n=515) and slow walkers (6MWD <300 m; n=483). AS-related symptoms appeared during the 6MWT in 105 of 680 patients (15.4%) who were regarded as symptomatic based on their history before the 6MWT and in 29 of 318 patients (9.1%) who were regarded as asymptomatic. Among symptomatic patients (n=709), the median 6MWD was 281.8 m; 331 (46.7%) were categorized as fast walkers and 378 (53.3%) were categorized as slow walkers. Among asymptomatic patients (n=289), the median 6MWD was 346.5 m; 184 (63.7%) were categorized fast walkers and 105 (36.3%) were categorized slow walkers (Figure 1).

Figure 1.

Number of patients with a 6-minute walk distance (6MWD) of ≥300 or <300 m according to symptom status. Aortic stenosis (AS)-related symptoms appeared during the 6-min walk test in 29 of 318 (9.1%) patients who were regarded as asymptomatic based on their history before the test.

Baseline demographic, clinical, and echocardiographic characteristics were compared between the fast and slow walkers (Table 1). Notably, compared with fast walkers, the slow walkers were older, more often women, had a lower body mass index, a higher surgical risk score, higher clinical frailty score, elevated BNP or NT-proBNP levels, and were more likely to have a history of symptomatic stroke, atrial fibrillation/flutter, aortic or peripheral vascular disease, anemia, and moderate to severe tricuspid regurgitation (TR). The severity of AS on echocardiography was similar between the fast and slow walkers (Table 1).

The median follow-up duration was 853 days (IQR 560–1,127 days) with 97% of patients completing the 1-year follow-up. During the follow-up period, 646 (64.7%) patients underwent TAVI and 215 (21.5%) underwent SAVR. The cumulative 3-year incidence of TAVI or SAVR was slightly higher among the fast walkers than among the slow walkers (89.7% vs. 87.9%; P=0.01; Figure 2).

Figure 2.

Cumulative incidence of transcatheter aortic valve implantation (TAVI) or surgical aortic valve replacement (SAVR) according to 6-minute walk distance (6MWD) of ≥300 or <300 m.

During follow-up, 165 (16.5%) of 998 patients died; HF (16 patients) and sudden death (15 patients) were the dominant cardiac causes, whereas infection (39 patients) and malignancy (26 patients) were the dominant non-cardiac causes (Supplementary Table 1).

The cumulative 3-year incidence of death from any cause was 31.7% among the slow walkers and 10.9% among the fast walkers (P<0.001; Figure 3; Table 2). The difference in all-cause death was driven by both cardiac and non-cardiac deaths (Table 2). The cumulative incidence of aortic valve-related death, sudden death, and HF hospitalization followed the same trend as for all-cause death (Table 2). After adjusting for confounders, the excess risk of the slow walkers relative to the fast walkers remained significant for all-cause death (HR 2.36; 95% CI 1.55–3.58; P<0.001; Table 2). The risk of all-cause death increased progressively as the 6MWT distance decreased (Supplementary Figure 2). We conducted an additional analysis using 6MWD as a continuous variable. The excess risk of 6MWD as a continuous variable (per 50-m decrease) for all cause death remained significant (HR 1.27; 95% CI 1.19–1.35; P<0.001).

Figure 3.

Cumulative incidence of all-cause death according to 6-minute walk distance (6MWD) of ≥300 or <300 m.

Table 2.

Clinical Outcomes in the Entire Study Population (n=998)

	No. patients with events (cumulative 3-year incidence; %)	Log-rank P value	Unadjusted HR (95% CI)	P value	Adjusted HR (95% CI)	P value
All-cause death		<0.001
6MWD ≥300 m (n=515)	44 (10.9)		Ref.		Ref.
6MWD <300 m (n=483)	121 (31.7)		3.11 (2.2–4.39)	<0.001	2.36 (1.55–3.58)	<0.001
Cardiovascular death*		<0.001
6MWD ≥300 m	14 (3.0)		Ref.		Ref.
6MWD <300 m	52 (15.3)		4.17 (2.31–7.52)	<0.001	3.39 (1.80–6.36)	<0.001
Aortic valve-related death		0.018
6MWD ≥300 m	8 (1.9)		Ref.		Ref.
6MWD <300 m	19 (5.2)		2.61 (1.14–5.96)	0.023	N/A
Sudden death		0.039
6MWD ≥300 m	4 (0.8)		Ref.
6MWD <300 m	11 (3.6)		3.14 (1.00–9.86)	0.05	N/A
Non-cardiovascular death*		<0.001
6MWD ≥300 m	30 (8.1)		Ref.		Ref.
6MWD <300 m	69 (19.3)		2.62 (1.71–4.02)	<0.001	2.39 (1.48–3.87)	<0.001
HF hospitalization		0.027
6MWD ≥300 m	52 (11.8)		Ref.		Ref.
6MWD <300 m	70 (16.9)		1.49 (1.04–2.14)	0.028	0.97 (0.62- 1.50)	0.88
TAVI/SAVR		0.010
6MWD ≥300 m	448 (89.7)		Ref.
6MWD <300 m	413 (87.9)		1.19 (1.04–1.36)	0.013	N/A

Any death during hospitalization for AVR or TAVI was regarded as an aortic procedure-related death. Aortic valve-related deaths included aortic procedure-related death, sudden death, and death due to HF. HF hospitalization was defined as hospitalization due to worsening HF requiring intravenous drug therapy. Risk-adjusting variables included 23 clinically relevant factors (age, sex, BMI >22 kg/m², hypertension, current smoking, diabetes on insulin, coronary artery disease, prior myocardial infarction, prior symptomatic stroke, aorta/peripheral artery disease, serum creatinine >2 mg/dL, hemodialysis, anemia, liver cirrhosis, malignancy currently under treatment, chronic lung disease, any valvular disease, HF hospitalization at index echocardiography, AS severity [peak aortic jet velocity >4 m/s], LVEF <60%, atrial fibrillation or flutter, TR PG ≥40 mmHg, and initial AVR strategy). *For outcome measures with a number of patients with the event <100, we selected parsimonious models with 7 risk-adjusting variables. For outcome measures with a number of patients with the event <30, we did not perform a multivariable analysis. CI, confidence interval; HR, hazard ratio; N/A, not assessed; SAVR, surgical aortic valve replacement; TAVI, transcatheter aortic valve implantation. Other abbreviations as in Table 1.

Subgroup Analysis in Patients With an Initial AVR Strategy

Among patients with an initial AVR strategy, the baseline demographic, clinical, and echocardiographic characteristics were consistent with those of the entire study population, except for no differences in body mass index and prior stroke between the slow and fast walkers (Supplementary Table 2). Of the 779 patients with an initial AVR strategy, 775 (99.6%) underwent AVR (TAVI, 583 patients; SAVR, 192 patients), and 119 (15.3%) died during follow-up (42 due to cardiac causes, 77 due to non-cardiac causes; Supplementary Figure 3; Supplementary Table 3). The cumulative 3-year incidence of death from any cause was 28.1% among the slow walkers and 10.1% among the fast walkers (P<0.001; Figure 4; Supplementary Table 3). After adjusting for confounders, the excess risk of the slow walkers relative to the fast walkers remained significant for all-cause death (HR 2.32; 95% CI 1.42–3.79; P=0.001; Supplementary Table 3).

Figure 4.

Cumulative incidence of all-cause death in patients with (A) an initial aortic valve replacement strategy or (B) managed conservatively according to 6-minute walk distance (6MWD) of ≥300 or <300 m.

Subgroup Analysis in Patients Managed Conservatively

In patients managed with a conservative strategy, the baseline demographic, clinical, and echocardiographic characteristics were generally similar to those of the entire study population, except for lower peak aortic jet velocity and mean pressure gradient, and higher creatinine levels in the slow walkers than in the fast walkers (Supplementary Table 2). The reasons for choosing a conservative strategy included watchful waiting (n=172), patient refusal (n=26), and ineligible for AVR by the attending physician’s decision (n=21).

Of the 219 patients managed with a conservative strategy, 140 (63.9%) were asymptomatic. During follow-up, 86 (39.2%) patients underwent AVR (TAVI, 63 patients; SAVR, 23 patients). The cumulative 3-year incidence of AVR was lower among slow walkers than fast walkers (34.7% vs. 60.1%; P<0.001; Supplementary Figure 3). In total, 46 patients (21.0%) died during follow-up (24 due to cardiac causes, 22 due to non-cardiac causes). The cumulative 3-year incidence of death from any cause was 46.7% among the slow walkers and 13.4% among the fast walkers (P<0.001; Figure 4; Supplementary Table 4). After adjusting for confounders, the excess risk of slow walkers relative to fast walkers remained significant for all-cause death (HR 2.53; 95% CI 1.16–5.54; P=0.02; Supplementary Table 4).

Sensitivity Analysis in Asymptomatic Patients Managed Conservatively

Among asymptomatic patients managed conservatively, the cumulative 3-year incidence of AVR was lower among slow walkers than fast walkers (29.7% vs. 63.3%; P<0.001). The cumulative 3-year incidence of death from any cause was 32.3% among slow walkers and 8.1% among fast walkers (P<0.001; Supplementary Figure 4).

Subgroup Analyses Stratified by Age and Sex

In subgroup analyses stratified by age tertiles and sex, the prognostic value of 6MWD remained significant (Supplementary Figure 5).

Discussion

This study evaluated the association between physical function, as measured by 6MWD, and long-term prognosis in a multicenter prospective cohort of patients with severe AS. Our results demonstrated that the mortality rate was higher among patients with a 6MWD <300 m than among those with a 6MWD ≥300 m, regardless of the initial treatment strategy.

Previous studies have also indicated that physical function, as assessed by the 6MWD, was a predictor of outcome in severe AS. In the Aortic Stentless Versus Stented Valve Assessed by Echocardiography Randomised Trial (ASSERT), de Arenaza et al. reported that baseline 6MWD (300 m) was an independent predictor of a composite endpoint of death, myocardial infarction, and stroke among 208 patients who underwent SAVR.¹⁵ Similarly, in a retrospective analysis of the Placement of Aortic Transcatheter Valves (PARTER) trial, Green et al. revealed that of the 1,057 patients who underwent TAVI, 484 attempted the 6MWT, 218 of whom were unable to walk.¹⁶ For the 266 patients who completed the 6MWT, baseline 6MWD (128.5 m) was associated with all-cause death, primarily due to an increased risk of non-cardiac death.¹⁶ Furthermore, Castillo-Moreno et al. reported that, in a prospective observational cohort study in 149 patients with severe AS who received continued medical management, 6MWD (331 m) was independently associated with all-cause death or HF hospitalization over a median follow-up period of 12.9 months.¹⁷ Thus, although our findings confirm those of previous studies, the present study expanded this association to the largest sample size to date, spanning multiple centers. Although age and sex may influence the prognostic value of the 6MWD, our findings suggest that the 6MWD remains a consistent predictor across these subgroups. Despite potential ethnic differences, previous studies in diverse populations have also demonstrated the prognostic value of the 6MWD. However, variations in patient characteristics, age, intervention methods, and cut-off values across studies warrant further investigation (Supplementary Table 5).

In the present study, 6MWD was shown to be a robust prognostic tool for stratifying both cardiovascular and non-cardiovascular mortality, suggesting that it serves as a simple marker capable of evaluating both cardiopulmonary function and musculoskeletal activity in patients with severe AS. Frailty is highly prevalent in AS and has emerged as a critical predictor of outcomes following aortic valve intervention.^10,11 In the present analysis, 6MWD was correlated with other frailty measures, such as the clinical frailty score and Katz index. The clinical frailty score and Katz index are straightforward, but they are subjective. In contrast, the advantages of the 6MWD are that it is easy to perform, provides objective results, and yields valuable prognostic information. van Mourik et al. conducted a meta-analysis and reported that among various frailty parameters used in TAVI studies, chronic lung disease, chronic kidney disease, low body weight, hypoalbuminemia, low frailty score, anemia, slow gait speed, and deficits in activities of daily living were all associated with worse 1-year outcomes.¹⁰ Further research into combining these factors may enable more precise identification of high-risk patients undergoing aortic valve intervention. Given that a 6MWD <300 m was associated with an increased risk of both cardiovascular and non-cardiovascular death following aortic valve intervention, careful follow-up would be warranted for these patients. A meta-analysis of observational studies involving 2,365 patients reported that cardiac rehabilitation following TAVI significantly improved 6MWD and Barthel index scores, leading to meaningful benefits in exercise tolerance and functional independence.²⁶ However, further research is needed to determine optimal management strategies after aortic valve intervention to improve prognosis in this population.

In the initial conservative therapy group, many patients with a 6MWD <300 m were considered asymptomatic based on clinical history. However, these patients often had elevated BNP or NT-proBNP levels, suggesting a higher risk of HF or elevated BNP due to conditions such as chronic kidney disease or atrial fibrillation. These patients are at high risk with a poor prognosis. To ensure that aortic valve intervention could provide meaningful survival benefits in such patients, it may be crucial to confirm that AS is truly severe.

Conversely, among the 129 patients managed conservatively with a 6MWD ≥300 m, the cumulative 3-year incidence of all-cause death was 13.4%, which is comparable to the 10.1% among the 386 patients managed with initial AVR with a 6MWD ≥300 m. These findings are consistent with our sensitivity analysis of asymptomatic patients managed conservatively, in whom the cumulative 3-year incidence of all-cause death was only 8.1% if their 6MWD was ≥300 m. Therefore, the clinical utility of the 6MWT may be particularly high in seemingly asymptomatic patients with severe AS for whom conservative management is planned, especially in cases where a treadmill exercise test or cardiopulmonary exercise test cannot be performed. Symptom assessment in elderly patients with severe AS is often challenging, and an objective measure like the 6MWD could complement traditional symptom-based decision-making. Although current guidelines emphasize symptom status, our findings suggest that 6MWD may provide additional prognostic information, potentially aiding in AVR decision-making. Patients who can walk more >300 m may be able to manage safely, whereas patients who cannot walk >300 m need to be carefully evaluated to determine whether their inability to walk is due to AS and whether AVR is indicated. Furthermore, the clinical utility of the 6MWT may be particularly high in patients with severe AS who appear asymptomatic. However, because the present study is an observational study, further prospective research is needed to formally establish the role of the 6MWT in guiding AVR indications.

The relationship between 6MWD and symptoms was weak. Among 709 symptomatic patients who were able to perform the test (median distance 281.8 m), 378 (53.3%) could not walk 300 m. In contrast, of the 289 asymptomatic patients (median distance 346.5 m), 184 (63.7%) were able to walk more than 300 m. The shorter 6MWD may reflect the severity of exercise intolerance caused by a combination of factors, such as severe AS, age, and multiple comorbidities. The prognostic value of the 6MWD may be attributed to its association with decreased cardiopulmonary reserve, multiorgan dysfunction, frailty, or a combination of these factors. Thus, the 6MWD may not be a definitive indicator of the presence of symptoms. However, approximately 10% of asymptomatic patients were reclassified as symptomatic based on the findings of the 6MWT (Figure 1). Because symptom assessment through medical history alone has inherent uncertainties, the 6MWT can partially complement clinical evaluations in this regard.

This study has several limitations. Despite recommendation of the 6MWT by the protocol, it was not conducted for all patients in the cohort. We performed multivariable analyses; however, unmeasured confounding factors may have influenced the risk of the primary endpoint. In addition, changes in 6MWD over time and after treatment were not investigated. This study included only Japanese patients, which may limit its generalizability. Ethnic differences in cardiovascular risk factors, treatment strategies (TAVI/SAVR), and responses to treatment may influence the outcomes.

Conclusions

The 6MWD is a reliable prognostic marker for patients with severe AS, regardless of the initial treatment strategy. Patients with a 6MWD <300 m have a high risk of mortality, even after AVR, highlighting the need for careful follow-up and appropriate management. In contrast, patients with a 6MWD ≥300 m may be safely managed with conservative therapy based on initial assessments.

Acknowledgments

The authors extend their appreciation to coinvestigators participating in the CURRENT AS Registry-2 for their support and collaboration.

Sources of Funding

This work was supported by an educational grant from the Research Institute for Production Development (Kyoto, Japan).

Disclosures

H.S. reports personal fees from Abbott Vascular, Boston Scientific, and Daiichi Sankyo. T.M. reports lecturer fees from Bristol-Myers Squibb, Daiichi Sankyo, Japan Lifeline, Kowa, Kyocera, Novartis, and Toray; manuscript fees from Bristol-Myers Squibb and Kowa; and being on an advisory board for Sanofi. T. Kimura reports being on an advisory board for Abbott Vascular; grants from Edwards Lifesciences, Daiichi Sankyo, Takeda Pharmaceutical, Bayer, Otsuka Pharmaceutical, Boehringer Ingelheim, Mitsubishi Tanabe Pharma, Sumitomo Dainippon Pharma, Kowa, Abiomed, Japan Academic Research Forum, NIPRO, W. L. Gore & Associates G.K., RPM Co., Ltd., CSL Behring, Pfizer R&D Japan G.K., EP-CRSU Co., Ltd; and honoraria from MSD, Eisai, Edwards Lifesciences, Ono Pharmaceutical, Tsumura, Medical Review, Kowa, Sanofi, Pharmaceuticals and Medical Devices Agency, Bristol-Myers Squibb, Boston Scientific, Lifescience, Toray, Astellas Amgen Biopharma, Astellas, AstraZeneca, OrbusNeich, MSD Life Science Foundation, Public Health Research Foundation, Chugai Pharmaceutical, Japan Society for the Promotion of Science, Interscience, Philips, Kowa Pharmaceutical, Mitsubishi Tanabe Pharma, Terumo, Novartis Pharma, HeartFlow Japan G.K., and CROSSCO Co.

K. Minatoya and K. Ono are members of Circulation Journal’s Editorial Team. The remaining authors have no conflicts of interest to declare.

IRB Information

The present study was approved by Kyoto University Graduate School and the Faculty of Medicine Ethics Committee (Reference no. R1501).

Data Availability

The deidentified participant data will not be shared.

Supplementary Files

Please find supplementary file(s);

https://doi.org/10.1253/circj.CJ-25-0056

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