The 6-minute walk test distance (6MWD) has been shown to predict prognosis in selected cohorts of patients with heart failure and outcomes after surgical or transcatheter aortic valve implantation (AVI) in patients with symptomatic severe aortic stenosis (AS). Our objective was to evaluate the association between the 6MWD and outcome in patients with severe AS while remaining under medical treatment. In a prospective observational cohort study, a total of 149 patients diagnosed with severe AS by Doppler echocardiography underwent a 6-minute walk test. The single end point was a composite of all-cause death or hospitalization for heart failure. Patients receiving an AVI were censored from follow-up at the time of their AVI, so that only the events that occurred while the patients remained under medical treatment were included in the analysis. During follow-up (median 12.9 months), the end point occurred in 65 patients (43.6%). Univariate analysis showed an association between the 6MWD and the end point (p <0.001). After adjustment for symptoms, left ventricular ejection fraction, aortic valve area, Charlson co-morbidity score, and anemia, the 6MWD independently predicted the end point (adjusted hazard ratio 0.63; 95% confidence interval 0.45 to 0.89; p = 0.010). The incidence of the composite end point was 12 per 100 patient-years in patients with a 6MWD >331 m compared to 86 per 100 patient-years in those with a 6MWD ≤331 m (p <0.001). In conclusion, although patients with severe AS remain under medical treatment, the 6MWD is independently associated with all-cause death or hospitalization for heart failure.
Our current understanding of the natural history of aortic stenosis (AS) is based on studies that began nearly 50 years ago. In the light of these studies, it has been considered that although prognosis is good while patients remain asymptomatic, it becomes very poor once symptoms appear. Thus, the appearance of symptoms is the key to the treatment of patients with AS and is the main indication for aortic valve implantation (AVI). At present, however, the current clinical profile of patients with AS is different to that of the past, in that AS typically affects elderly people with other diseases. Given that AS symptoms initially become apparent with exercise, many patients remain asymptomatic because of their reduced physical capacity or slowly and gradually self-limiting activities. The clinical practice guidelines recommend exercise testing in apparently asymptomatic patients with severe AS when there is uncertainty regarding their functional capacity. The aim of the test is to check whether patients are truly asymptomatic and to obtain other data of prognostic interest. However, in the current epidemiologic setting, bicycle or treadmill exercise testing can only be administered to a reduced number of patients with AS because of their advanced age and co-morbidity. In contrast, despite its undeniable shortcomings, the 6-minute walk test (6MWT) has the advantage of providing a more realistic measure of the routine activity of the patients and reflects their true functional capacity more reliably than the bicycle or treadmill exercise test and is therefore of particular interest regarding its use in elderly patients. The prognostic value of the 6MWT has been demonstrated in patients with heart failure in that the distance walked correlates with oxygen uptake during cardiopulmonary exercise testing and survival. It has also been suggested that the 6MWT provides prognostic utility comparable to cardiopulmonary exercise testing. The 6MWT has also been shown to be feasible and safe in patients with severe symptomatic AS, and its results have been associated with the evolution of patients undergoing surgical or transcatheter AVI. However, it has not been investigated whether the 6MWT could be useful to stratify risk in patients with severe AS under conservative treatment. Thus, our aim was to analyze if the 6MWT distance (6MWD) is independently associated with the evolution of patients with severe AS while remaining under medical treatment.
Methods
Patients undergoing Doppler echocardiography in the cardiac imaging department of a single hospital from April 2012 to April 2014 were prospectively assessed for severe AS, as defined by a maximal flow velocity across the aortic valve ( V max ) >4 m/s or an aortic valve area (AVA) <1 cm 2 . All patients with severe AS who could walk without the help of another person or orthopedic aids such as crutches or walkers were included in the study. Exclusion criteria were any recent hospitalization for heart failure or acute coronary syndrome, persistent New York Heart Association functional class IV, and active infective endocarditis. The study design was approved by the Clinical Research Ethics Committee of our hospital, and all patients gave their informed consent to participate in the study.
Clinical data were collected from electronic medical records created by the patients’ physicians. Patients were considered to be symptomatic if they had presented angina, syncope, presyncope, or dyspnea. The Charlson Comorbidity Index is a method of categorizing co-morbidities of patients, which includes 17 categories (such as peripheral vascular disease, chronic pulmonary disease, renal disease, or any malignancy). Each co-morbidity category has an associated weight based on the adjusted risk of mortality, and the sum of all the weights results in a single score for a patient. The Charlson Comorbidity Index in the form of incorporating additional points depending on the age of the patient was calculated as previously reported. Anemia was defined as a hemoglobin concentration <13 g/dl in men and <12 g/dl in women.
All patients underwent Doppler echocardiography using a standard ultrasound system (Acuson Siemens SC 2000) in all planes. All measurements and calculations were performed according to the recommendations of the echocardiography societies. The aortic annulus diameter was measured in systole, the flow time velocity integral was measured at the left ventricular outflow tract by pulsed wave Doppler, and V max and mean gradient were measured by continuous wave Doppler. The AVA was calculated as an absolute value using the continuity equation. All measurements obtained during at least 5 heartbeats were averaged in all patients with atrial fibrillation. Left ventricular ejection fraction (LVEF) was calculated using Simpson biplane method.
All patients included in the study underwent a 6MWT. The patient was instructed to walk along a 30-m corridor and cover the maximum distance in 6 minutes under the supervision of nurse with experience in conducting the test. The nurse told the patient how much time had elapsed every 2 minutes and encouraged the patient to continue at intervals of between 30 seconds and 1 minute. At the end of 6 minutes, the patient was asked to stop, and the distance walked was measured in meters. The test was repeated after a rest of at least 10 minutes, and the greatest of the 2 distances traversed was recorded.
The study end point was the time to the first of the following events: all-cause death or hospitalization for heart failure. Follow-up began on the day Doppler echocardiography was performed to assess patients for their inclusion in the study. Only the events that occurred under medical treatment were included in the analysis. Patients receiving an AVI were censored from follow-up at the time of their AVI. In patients who underwent AVI, the AVI date was used to compute the duration of follow-up, but AVI was not an end point. Data on patient outcomes were exclusively obtained by medical personnel from electronic medical records during hospitalization, physician visits, and/or telephone interviews.
Quantitative variables were expressed as mean ± standard deviation or as median and interquartile range (IQR). Two groups of continuous variables were compared using the Student t test or Mann–Whitney U test. Qualitative variables were expressed as percentages and compared using the chi-square test or Fisher exact test as needed. Kaplan–Meier curves were used to illustrate event-free survival and were compared using the Cox–Mantel log-rank test. The Spearman correlation coefficient was used to assess the association between the 6MWD and other variables (symptoms, LVEF, AVA, Charlson Comorbidity Index, anemia, body mass index, and gender) potentially related to both the 6MWD and the study end point. An unadjusted Cox proportional hazards model was used to analyze the association between the end point and the 6MWD and other variables of prognostic interest. Next, an adjusted Cox regression model was used to analyze the association between the 6MWD and the end point. The variables that have been shown to have a consistent association with the prognosis of AS in classic studies and that are crucial to the treatment of patients according to clinical practice guidelines (symptoms, LVEF, or AVA as a parameter of AS severity) and 2 other variables also associated with the 6MWD (Spearman r ) and prognosis (unadjusted Cox analysis) in our study (the Charlson Comorbidity Index and anemia) were introduced in the model. The 6MWD was converted into standard normal z -score before its inclusion in the Cox models. Harrell’s C concordance statistic was calculated, and all variables in the Cox models verified the proportional hazards assumption on the basis of visual examination of log-minus-log curves and the Schoenfeld residuals test. The receiver operating characteristic curve was used to analyze the potential of the 6MWD to predict the end point. The method of Zweig and Campbell was used to identify the optimal cut-off point for the 6MWD. The sensitivity, specificity, and positive and negative predictive values were calculated, and Wilson method was used to estimate their respective confidence intervals. All statistical analyses were performed using the SPSS statistical package version 20.0 (Chicago, Illinois) and the STATA statistical package version 14.0 (College Station, Texas).
Results
A total of 182 patients with severe AS were identified. Thirty-three patients (18%) could not perform the 6MWT: 12 were unable to walk without assistance and 21 patients were excluded for other reasons (15 patients had a recent hospitalization for heart failure or acute coronary syndrome, 5 patients had ambulatory New York Heart Association functional class IV, and 1 patient had active infective endocarditis). The patients unable to perform the 6MWT were older (81 [IQR 75.5 to 85] vs 75 years [IQR 68.7 to 81], p = 0.001), predominantly women (72.7% vs 49.7%, p = 0.016), had a higher Charlson Comorbidity Index (7 [IQR 6 to 9] vs 6 [IQR 4.75 to 8], p <0.001), and had a higher rate of atrial fibrillation (45.5% vs 9.4%, p <0.001). There was a greater proportion of symptomatic patients in this group (78.8% vs 47.7%, p = 0.001), and their AVA was smaller (0.60 [IQR 0.47 to 0.72] vs 0.71 cm 2 [IQR 0.58 to 0.85], p = 0.004). The study population comprised the 149 patients who performed the 6MWT ( Table 1 lists their clinical characteristics). These patients walked a median distance of 330 m (IQR 264 to 396, minimum 132, maximum 627). The 6MWT was inversely correlated with the Charlson Comorbidity Index, female gender, and the presence of symptoms and anemia and directly correlated with AVA and LVEF ( Table 2 ).
| Variables | |
|---|---|
| Age (years) | 75 (68.7-81) |
| Charlson Score Index | 6 (4.75-8) |
| Women | 74 (49.7%) |
| Body Mass Index (kg/m 2 ) | 29.2±4.4 |
| Hypertension | 121 (81.2%) |
| Diabetes mellitus | 60 (40.3%) |
| Ischemic Heart Disease | 33 (22.1%) |
| Chronic kidney disease (Filtration Rate <60 mL/min/1.73 cm 2 ) | 60 (40.3%) |
| Anemia (hemoglobin >13g/dL in men, >12g/dL in women) | 54 (36.2%) |
| Symptoms | 71 (47.7%) |
| Left ventricular hypertrophy | 104 (69.8%) |
| Atrial fibrillation | 14 (9.4%) |
| Left ventricular end diastolic diameter (mm) | 47.9±6.05 |
| Left ventricular end-systolic diameter (mm) | 30.8±7.7 |
| Interventricular septum thickness in diastole (mm) | 13.1±2.6 |
| Posterior wall thickness in diastole (mm) | 12.7±2.4 |
| Peak aortic jet velocity (m/s) | 4.30 (4.11-4.61) |
| Mean gradient (mmHg) | 49.9±13.1 |
| Aortic valve area (cm 2 ) | 0.71 (0.58-0.85) |
| Left ventricular ejection fraction (%) | 65 (57.7-71) |
| Variables | Category | n | 6-minutes Walking Test distance Median (IQR 25°-75°) | Spearman Correlation | P |
|---|---|---|---|---|---|
| Charlson Score Index | ≤6 | 87 | 345 (289-429) | -0.49 | <0.001 |
| >6 | 62 | 287 (198-361) | |||
| Gender | Male | 75 | 363 (285-440) | -0.32 | <0.001 |
| Female | 74 | 297 (234-345) | |||
| Body Mass Index (kg/m 2 ) | ≤29 | 77 | 330 (264-396) | 0.05 | 0.546 |
| >29 | 72 | 330 (249-396) | |||
| Anemia (hemoglobin <13g/dL in men, <12g/dL in women) | Absent | 95 | 340 (270-429) | -0.21 | 0.012 |
| Present | 54 | 297 (229-365) | |||
| Symptoms | Absent | 78 | 371 (330-432) | -0.56 | <0.001 |
| Present | 71 | 264 (190-330) | |||
| Aortic valve area (cm 2 ) | ≤0,70 | 73 | 297 (230-363) | 0.26 | 0.001 |
| >0,70 | 76 | 345 (281-429) | |||
| Left ventricular ejection fraction (%) | ≤65 | 71 | 297 (220-363) | 0.27 | 0.001 |
| >65 | 69 | 345 (284-429) |
After a median follow-up of 12.9 months, 65 patients (43.6%) of the study population who performed the 6MWT reached the study end point. The first event was hospitalization (49 patients) and death (16 patients). Surgical or percutaneous AVI was performed in 47 patients (31.5%) at a median of 8.2 months after inclusion. Of the 47 patients who underwent intervention, 22 (46.8%) patients reached the end point (i.e., hospitalization admission) before AVI. An inverse correlation was found between the 6MWD and the end point (hazard ratio 0.39, 95% confidence interval [CI] 0.29 to 0.52; p <0.001). Although the 6MWD was less in women than in men ( Table 2 ), no association was found between gender and the study end point. Finally, associations between the 6MWD and the end point were analyzed in a Cox regression model adjusted for the variables symptoms, LVEF, AVA, Charlson Comorbidity Index, and anemia. Together with symptoms and AVA, the 6MWD maintained its independent association with prognosis ( Table 3 and Figure 1 ). Harrell’s C index in the adjusted Cox model was 0.81.
