Six-Minute Walking Distance in Women with COPD

Abstract

Background: The 6-minute walk distance (6MWD) has been useful in the evaluation of men with COPD. Little is known about 6MWD in women with the disease. Objectives: Using healthy women as a reference, to evaluate the factors that help determine 6MWD in women with COPD. To explore if the 350 meters threshold differentiates survival in women as it does in men.Methods: Healthy women (n = 164) and with COPD (n = 223) were included in the study. Age, pack-years history, smoking status, comorbidities (Charlson Index), BMI, MRC dyspnea, spirometry and 6MWD were recorded in all participants and PaO₂ and IC/TLC in COPD women. The patients were prospectively followed and deaths registered. Factors predicting 6MWD were determined by multiple regression analysis. ROC analysis was used to calculate the best threshold value for the 6MWD with mortality as gold standard. Kaplan-Meier curves compared survival of patients that walked more or less than 350 m by age categories. Results: The 6MWD is decreased in women with COPD. Values decrease with age and GOLD stages. Age, BMI, smoking status, comorbidities, MRC and FEV_1% are statistical significant predictors of 6MWD. A 350 m cut-off value has a good sensitivity and specificity to predict (73% and 80% respectively) and differentiate survival (p < 0.001 for log rank comparisons) in these patients. Conclusions: In women with COPD, the 6MWD decreases with age and GOLD stages. A 350 m distance is a valid threshold to differentiate survival. Further studies in different settings should confirm our findings.

Keywords: :

• Women
• COPD
• 6MWD
• Gender

INTRODUCTION

The 6-minute walking distance (6MWD) is a reliable, inexpensive, safe and easy to apply instrument to evaluate functional exercise capacity in patients with chronic obstructive pulmonary disease (COPD) (1, 2). The test evaluates the global and integrated responses of the pulmonary, cardiovascular and muscular component and reflects the functional exercise level for daily physical activities (1). It correlates well with other important outcomes in COPD patients such as dyspnea, airway obstruction and lung hyperinflation (3). In addition, the 6MWD has been shown to be an important prognostic factor for survival independent of the FEV₁ (4). COPD is projected to be the third cause of mortality by the year 2020 (5). According to a recent COPD disease surveillance in the United States, the absolute number of COPD cases, hospitalisations, and deaths among women have exceeded those among men (6). In the western world, the bulk of the increase in COPD-related morbidity and mortality will be driven largely by the increasing burden of disease in women. Surprisingly, very little information is available in the literature about the expression of COPD in women because most of the available data was obtained from populations of men with the disease. Even less is known about 6MWD in women with COPD.

Our group previously described that for the same degree of airway obstruction, women performed poorer in 6MWD expressed as percent of predicted using the existent predictive equations (7) and that the 6MWD is a good predictor of survival in women with COPD (8). To improve the general understanding and applicability of this test we conducted this study to:

1. Explore 6MWD in women with COPD and determine factors that determine its values.

2. Determine if the 350 m threshold predict mortality as its does in men (9).

We used a healthy female population as a reference. Part of the data of this study was included in previously published reports from our group (8, 10).

PATIENTS AND METHODS

This is an observational study with two different analyses: a cross-sectional comparative study of 6MWD between women with COPD and healthy controls, and a prospective validation of the 350 m distance threshold value to determine its capacity to differentiate survival in women with COPD as has been previously shown in men (9). This multicenter study was performed in 8 tertiary University Hospitals from 5 countries (USA, Chile, Uruguay, Venezuela and Spain). Healthy individuals and women with COPD older than 40 years old were invited to participate in the study. The COPD patients were part of the BODE observational study, recruited between January 1997 and December 2008, at several clinics in the United States (Boston and Bay Pines, Florida), Venezuela, Chile, Uruguay and Spain (Tenerife, Pamplona and Zaragoza) (11). COPD was defined by a history of smoking at least 10 pack-years and a FEV₁/FVC ratio less than 0.70 measured 20 minutes after the administration of 400 ug of inhaled albuterol. Patients were excluded if they had a history of asthma, bronchiectasis, tuberculosis or other confounding diseases like congestive heart failure, bronchiolitis. All COPD participants were in stable status (free of exacerbation for at least 6 weeks) and receiving standard medical treatment according to the ATS/ERS consensus (12).

To appropriately compare 6MWD, we also recruited healthy women at each study site stratified by decades (I: 40–49, II: 50–59, III: 60–69 and IV: more than 70 years old).

The human-research review board at each site approved the study and all patients signed the informed consent.

A personal interview with trained personnel recorded the following information: age, smoking status, pack-years history and co-morbidities. The presence of co-morbidities was evaluated using the Charlson scale (13), where points are assigned to the presence of different co-morbidities. The score ranges from 0 to 37, with the higher score implying more co-morbidity.

Pulmonary function (i) and the 6-minute walking distance (6MWD) were performed following ATS guidelines (14). Briefly, 6MWD were measured using the better of two 6-minute walk distance tests separated by 30 minutes in a 30 m corridor, encouraging the participants each minute to do their best effort.

Dyspnea was assessed using the Modified Medical Research Council Dyspnea Scale (MMRC) (15). The body mass index (BMI) was calculated as the weight in kilograms divided by height in meters (2). In patients with COPD the inspiratory capacity (IC) was measured as previously described, determining IC/TLC from the lung volume measurements (16) COPD patients completed evaluation within 6 weeks of enrolment and continued to be followed yearly thereafter until January 2009 or until death. The patient and family were contacted if the patient failed to return for appointments. Death from any cause was recorded.

Statistical analysis

Quantitative data with a normal distribution was described using mean ± SD. Qualitative data was described using relative frequencies. ANOVA analysis was used to compare differences in 6MWD between age and GOLD stage. To calculate the 6MWD as percent predicted we divided the mean 6MWD values obtained in COPD women by the mean measured in healthy women at each age decade.

To determine the factors that best predict 6MWD in women with COPD we performed a multiple linear regression with backward step analysis including age, smoking status, Charlson comorbity index, BMI, PaO₂, MMRC, FEV₁%, and IC/TLC. A receiver operating characteristic type-II analysis with all-cause mortality as the “gold standard” reference was used to determine the C-statistic and better predictive cut-off point for the 6MWD. Kaplan–Meier analysis was used to compare survival between women with 6MWD greater or lesser than 350 m in each age category (40–60 and 60–80 years). The statistical significance was determined by the log-rank test. Significant levels for all tests were established as two-tailed p-value ≤ 0.05. Calculations were made with the statistical package SPSS version 15.0 Inc. (Chicago, IL, USA).

RESULTS

One hundred and sixty-four healthy women participated in the study. Their clinical characteristics are described in Table 1. Most of them never smoked or reported a minimal smoking history of less than 10 pack-years, with normal BMI, no dyspnea, with almost no comorbidities and normal spirometric values. Six-minute walking distance decreased by decade of age but the drop did not reach statistical significance.

Table 1  Clinical and physiological characteristics of patients

Clinical characterístics (n = 164)	Healthy	COPD patients
Age (years)	56.7±10	63±9
Co-morbidities - Charlson Index (points)	0.12±0.42	2.4±2
Pack-years history	7±14	51±29
Current/ Ex smoker/ Never smoker (%)	5/40/119	27/73
BMI (Kg/m^2)	26.4±4	25.6±5
MRC	0	2 ±1
FEV1%	101±14	53±22
FVC%	104±15	80±22
FEV1/FVC	79±4	49±11
6MWD (m)	543±78	400±104
IC/TLC (%)		29±11
IC/TLC<0.25 (%)		35%
PaO2 (mmHg)		69±12
6MWD (m) by age categories	p > 0.05 for comparison	p < 0.001 for comparison
40–49 years	575 ± 80	495 ± 85
50–59 years	547 ± 80	409 ± 100
60–69 years	534±65	402±89
more than 70 years	492±62	360±107
6MWD by GOLD stages (for COPD)		P < 0.001 for comparison
I (n = 27, 13%)		472±81
II (n = 83, 37%)		414±100
III (n = 75, 33%)		390±98
IV (n = 37, 17%)		339±107

The baseline clinical characteristics of the patients are also described in Table 1. The 223 women with COPD were followed for 49 ± 28 months and during this time, 35 patients (16%) died from any cause. On average, COPD patients were older than healthy participants (63.6 ± 9 vs 56.7 ± 10, p < 0.05), 25% were currently smoking, with normal BMI values, moderate degree of dyspnea (MRC values of 2), moderate PaO₂ (PaO₂ of 69 mmHg) and normal IC/TLC. Most of the patients were in GOLD stages II and III, included in Q1 and Q2 of the BODE classification and were equally distributed by world region and GOLD stages. The mean 6MWD was decreased compared with healthy women (p = 0.001).

To better analyze the interaction between age and disease severity we divided the patients in two groups. Those with FEV₁% > or ≤50% and expressed the 6MWD as percent of healthy values by decades of age. Figure 1 shows that the 6MWD fall to were less than 80% of the control values only in those patients with COPD GOLD stages I+II when they are older than 70 years. In contrast, the 6MWD were less than 80% of the control values in patients with GOLD stages III+IV at a younger age (50 years).

Table 2 shows the sensitivity and specificity of the different cut-off values for 6MWD to better predict survival in women with COPD. A cut-off value of 362 m has the best balance between both values (76% and 75%, respectively). However, the 350 m threshold also has good sensitivity and specificity values (73% and 80% respectively). Figure 2 shows the ROC value for 350 m value to predict survival in women. The area under the curve (AUC) of 0.81 confirms the excellent predictive power of this value.

Table 2  Sensitivity and specificity values for the different 6MWD values to predict survival

6MWD (m) less than	Sensitivity	Specificity
500	100	15
450	93	43
400	80	62
350	73	80
300	50	90

Table 3 shows the factors independently associated to the 6MWD in a multiple linear regression analysis. Degree of dyspnea, age, co-morbidities, FEV₁%, BMI and smoking status are the most important predictors of the distance walked in women with COPD. Figure 3 shows the Kaplan-Meier survival curves of COPD. Those patients able to walk more than 350 m have a significantly better survival independently of the age category. Figure 4 shows the percentage of women with COPD with 6MWD <350 m by GOLD stages. The percentage increases with disease severity from 3.7% in stage I up to 55% in Stage IV.

DISCUSSION

This observational study, the first comparing a population of women with COPD with healthy controls, had two major findings. First, the 6MWD is decreased in women with COPD and its value is determined by multiple clinical and physiological factors and not only by the degree of airway obstruction. Second, the threshold value of 350 m is valid to differentiate survival in women with COPD, just as it has been shown for men.

Figure 1  6MWD values shown as percentage of healthy values for each age category.

Figure 2  Receiving operating curve for 350 m to predict survival in women with COPD.

Figure 3  Kaplan-Meier Survival curves for COPD women that walked > or < 350 m divided in two age categories: 40–60 years old and 60–80 years old.

The 6MWD is a simple, inexpensive, well validated test used to evaluate functional capacity in patients with COPD (i). It has shown to be associated with other important outcomes in COPD such as dyspnea, airway obstruction and lung hyperinflation (iii), as well as an independent prognostic factor for survival in patients with the disease (iv). Most of the available information about 6MWD in COPD patients comes from cohorts of men with very little female representation.

Very scarce information is available in the literature about 6MWD in women with COPD. Carter et al. (17) were the first to describe the 6MWD characteristics in a small sample (only 30 women with severe COPD: FEV₁% 48 ± 12). They found that the 6MWD was 367 ± 78 m, 78% of the predicted values, similar to the values we found in our GOLD stages III patients. Our group also previously described in a small cohort (54 women with GOLD stages II and III), that the 6MWD was within the normal predicted values (86%) using the existing reference equation for the European population (vii). Cote et al. (18) also reported that in a matched population of severe COPD, women had higher 6MWD values (expressed as% predicted) than the men (12 to 15% more according to reference equations or 35 m higher). She suggested that a lower 6MWD might have an even greater meaning in the prognosis of women with COPD. This finding was then proven in an observational study with 245 women with COPD and a wide range of disease severity (viii).

Table 3  Multiple linear regression analysis of factors that significantly predict 6MWD

			95% CI for B
Clinical Parameter	B coefficient	β coefficient	Lower limit	Upper Limit	p-value
MRC	-38.7	-0.32	-59.6	-17.7	0.001
Age	-3.4	-0.27	-6.1	-0.7	0.014
Charlson	-12.6	-0.27	-20.1	-2.9	0.001
FEV1%	1.21	0.20	0.15	2.27	0.025
BMI	-3.4	-0.19	-6.07	-0.69	0.014
Smoking Status	-73.6	-0.19	-129.3	-17.9	0.010

The present study expands on our previous observations by showing that the 6MWD is affected differently in different COPD stages. As is shown in Figure 1, patients in GOLD stages I+II have 6MWD values above 80% of predicted up to age 70 when the values fall below that threshold. Interestingly, in patients with more severe disease (GOLD stages III+IV) the 6MWD values fall below 80% of predicted at much younger age (50 years average). This suggests a different behaviour in mild to moderate disease compared with that of women with more advanced stages of the disease. This is an interesting finding not yet described in men. This implies that decreased exercise capacity is highly prevalent in COPD women of younger age and severe disease.

Among the factors associated with the 6MWD, the degree of functional dyspnea, age and comorbidities had the strongest statistical power with less strong but still significant associations between 6MWD and BMI, smoking status and as expected degree of airway obstruction. Data from previous work indicated that a poor 6MWD (<350 m) is predicted by degree of dyspnea, extent of emphysema, severe GOLD stages and the presence of depressive symptoms. The novel finding of the current study is that IC/TLC did not remain in the predictive equation for 6MWD in women.

Figure 4  Percentage of women with COPD that walked <350 m in each GOLD stage.

This could be partially explained by the fact that women with COPD women have shown a lesser degree of emphysema compared with males and therefore exhibit less lung hyperinflation. Previous work form our group ⁽20) indicated that the degree of lung hyperinflation significantly correlated with the degree of dyspnea developed after a 6MWD. In fact in the present study, a good proportion of women (36%) had an IC/TLC<0.25, a proven independent predictor of survival in COPD. One possible explanation could be that there are sex differences in breathing strategies that allowed a lesser impact of lung hyperinflation on 6MWD in women.

Several previous studies, completed primarily in men validated a distance of 350m as an excellent a cut-off value to differentiate survival in patients with COPD (ix). As is shown in Table 3 the best balance between sensitivity and specificity was established at 362 m, not that different as previously described for men (ix). However, we also found that the commonly used threshold value of 350 m, has excellent sensitivity and specificity values and a good AUC (Figure 2). Given the practicality associated with the 350 meters, we believe that it may be appropriate to continue using this as the threshold of significance for men and women with COPD. Indeed, Figure 3 shows that in our population of women, 350 m is still an excellent cut-off value to evaluate survival in all age categories: 40–60 years old and 60–80 years old. Interestingly, when we determined the percentage of patients that walked <350 m by GOLD stages, we found that already in GOLD stage II, 20% of the women walked below that distance and the percentage increased with disease severity. Again, this implies that 6MWD can be useful to identify a phenotype of patients with impaired exercise capacity of particularly poor prognosis independent of their age. This finding also demonstrated that this cut-off value could be appropriately used to categorized female patients in the different multidimensional scores that have been recently described (xi, 21).

There are some limitations in this study. Although this is the largest study evaluating 6MWD in women with COPD, we could not recruit enough number of women to represent each GOLD stage to then allow for a more robust analysis. On the other hand, there were women from 5 different countries and 3 different continents followed for close to 5 years, rendering our findings more applicable to the general population than single center studies. It can be argued that the women enrolled in this study are mainly women attending pulmonary clinics at tertiary university hospitals and therefore may not represent the population of women with COPD at large.

However, it is in the clinic where tests such as the 6MWD have the greatest value, as it can help select high-risk patients that the health care provider may want to further evaluate. In conclusion the present study shows that in women with COPD, 6MWD is affected even in those with milder stage of the disease. Like in men, 6MWD constitutes an integrative test that is influenced by pulmonary and extrapulmonary factors, including co-morbidity. A 350 m distance is an excellent cut-off value to differentiate survival behavior in women independently of age. Further studies in a different setting should confirm our findings.

DECLARATION OF INTEREST

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.