Validation and comparison of reference equations for the 6-min walk distance test

Patients

A total of 1,379 patients with a wide range of COPD stages, as accepted by the American Thoracic Society (ATS) 18, were recruited into an observational study between January 1997 and September 2004, and followed until July 2007 at several of the BODE (Body mass index, airflow Obstruction, Dyspnoea and Exercise capacity index) study sites. Inclusion/exclusion criteria have been previously published 19. The protocol was approved by the institutional review board of each institution and all patients signed a consent form. Patients completed an evaluation within 6 weeks of enrolment and continued to be followed thereafter at 6-month intervals until July 2007 or until death. Data for mortality was confirmed by reviewing the medical records and by contacting patients’ next of kin in every site.

Measurements

Demographic information and smoking history were collected. Pulmonary function tests were obtained according to ATS guidelines 20. Spirometry, lung volumes and diffusing capacity were also measured. The 6MWD was performed following ATS guidelines 14 and the 6MWD % pred was calculated by using the reference equations provided by Enright and Sherrill 15 and Troosters et al. 16 for males and females. In order to calculate the 6MWDW, the distance walked by the patient in metres was multiplied by the weight of the patient in kg 17. Dyspnoea was assessed using the Modified Medical Research Council (MMRC) dyspnoea scale 21. To determine the degree of comorbidity the validated Charlson's index 22 was used.

Reference equations

The reference equations for males (1) and females (2), respectively, provided by Enright and Sherill 15 are:

6MWD = (7.57×height(cm))-(5.02×age(yrs))-(1.76×weight(kg))-309m (1)

6MWD = (2.11×height(cm))-(5.78×age(yrs))-(2.29×weight(kg))-667m (2)

and the reference equation for males and females by Troosters et al. 16 is:

6MWD pred = 218+(5.14×height(cm)-5.32×age(yrs))-(1.8×height(cm))+(51.31×sex) (3)

where sex = 1 for males and 0 for females.

Statistical analysis

Normally distributed variables are reported as mean±sd. The differences in physical characteristics, pulmonary function test and exercise parameters were evaluated using unpaired t-tests. Comparison of 6MWD between patients with terminal COPD and those dying from other terminal diseases was performed using ANOVA. Pearson's correlation coefficients were obtained between different variables and mortality and between 6MWD, and 6MWDW and % pred by Enright and Sherrill 15 and Troosters et al. 16. For diagnostic analysis of the different modalities of testing, receiver operating characteristic (ROC) curves were used in order to assess the thresholds with the best sensitivity and specificity to predict mortality.

Mortality

There were 623 deaths. In total 316 (51%) of deaths were directly related to COPD, 40 (6.4%) were of respiratory origin other than COPD, 92 (14.7%) were due to lung cancer, 56 (8.9%) to cardiovascular disease, 44 (7%) to malignancies other than lung cancer, 27 (4.3%) to various medical illnesses and in 48 (7.7%) cases, the cause of death could not be determined. The mortality rates and the different causes of death are shown in table 2⇓ with patients classified into two groups according to 6MWD > or <350 m. COPD mortality was much higher for patients walking <350 m. Non-COPD causes of death were higher among patients with preserved exercise capacity. Using ANOVA for inter-group comparisons, the mean 6MWD of patients who died as a result of COPD (268±136 m) was significantly different from that of patients dying from any other cause (348±121 m) as shown in figure 1⇓.

• Download figure
• Open in new tab
• Download powerpoint

Fig. 1—

Mortality outcomes over the study period. COPD: chronic obstructive pulmonary disease. The 6-min walk distance (6MWD; mean±sd) at entry into the study for each cause of death were: 353±109 m for medical illness; 359±129 m for respiratory disease other than COPD; 349±124 m for cancer other than lung; 326±116 m for unknown reasons; 328±106 m for cardiovascular disease; 366±130 m for lung cancer; and 268±136 m for COPD. ^#: 6MWD was significantly different (p<0.00005) to other causes of death.

Receiver operating characteristic curves

Using ROCs, the threshold values with the best specificity and sensitivity to predict mortality were determined for the reference equations, 6MWDW and 6MWD test. The results are shown in table 3⇓. The area under the curve was very similar for all four modalities of testing. Values below the thresholds were considered as abnormal.

Enright's reference equation

The threshold value for the Enright's equation was 67%. A total of 560 (40.6%) patients were below this threshold, 612 (44.3%) fell between 67–100% of normal and 206 (15%) patients exceeded 100% of their predicted walk. Overall mortality of patients below the critical threshold was 64.2% (n = 360). A total of 212 (37.7%) deaths were due to COPD. Conversely, 263 (31.7%) deaths were seen in patients above the critical threshold and, of these, 103 (12.4%) deaths were due to COPD.

Troosters' reference equation

The threshold value for Troosters’ equation was 54%. In total, 563 (40.5%) patients were below this level, 612 (58%) patients fell between 54–100% pred and only 10 (0.7%) patients exceeded 100% of their predicted walk. The mortality in patients below the critical threshold was 65.7% (n = 370). A total of 218 (38.7%) patients died from COPD. Among the 816 (58.7%) patients with normal exercise capacity there were 253 (31%) deaths and 98 (12%) were due to COPD.

6MWD work

The threshold valued identified for the 6MWD work was 25,000 kg·m⁻¹. Using this value, 545 (39.2%) patients were below the critical threshold. All cause mortality among these patients was 65.5% (n = 357) and COPD mortality was 40.5% (n = 221). Overall mortality among the 844 patients with values above the threshold was 31.5% (n = 266). A total of 95 (11.2%) patients died from COPD.

6MWD test

The threshold value for the 6MWD test was 350 m. A total of 559 (40.2%) patients were below this threshold and the observed mortality among these patients was 66% (n = 369). COPD mortality was 39.7% (n = 222). Mortality in patients above the critical threshold was 30.6% (n = 254), and 94 (11.3%) patients died from COPD.

Comparison of patients above and below the different thresholds are shown in table 2⇑. An exponential increase was noted in all-cause mortality for every 100 m decrease in the 6MWD test. The results are shown in figure 2⇓.

• Download figure
• Open in new tab
• Download powerpoint

Fig. 2—

All-cause and chronic obstructive pulmonary disease (COPD) mortality in COPD patients stratified by 100 m in the performance of the 6-min walk distance (6MWD). ▓: all-cause mortality; ░: COPD mortality. *: p<0.05.

Correlations with mortality

Pearson's correlation coefficients were used to investigate the relationship between all-cause mortality and COPD mortality with exercise performance in all patients and according to sex. When all patients were included in the analysis, similar correlations between all-cause mortality and COPD mortality were found, with all type of evaluations. Higher correlations were seen between all-cause mortality and female sex for all modalities of testing. The results are shown in table 4⇓.

Kaplan–Meier survival analysis is shown in figure 3⇓. No significant differences between the tests was found. The best Chi-squared value was seen with the 6MWD work.

• Download figure
• Open in new tab
• Download powerpoint

Fig. 3—

Kaplan–Meier survival analysis for a) 6-min walk distance (6MWD) test; b) 6MWD work; c) Enright % predicted; and d) Troosters % pred. Survival curves are shown for patients above (······) and below (–––) threshold values. Threshold values were: a) 350 m; b) 25,000 m·kg⁻¹; c) 67%; and d) 54%. Chi-squared values were 168.262, 181.233, 127.025 and 147.744 for 6MWD, 6MWD work, Enright % pred and Troosters % pred, respectively. Number of patients at months 0, 12, 24, 36, 48, 60, 72, 84 and 96 for: a) 6MWD <350 m were 559, 495, 415, 356, 293, 252, 221, 209, 199, and >350 m were 820, 797, 745, 712, 663, 621, 597, 579, 570; b) 6MWD work <25,000 m·kg⁻¹ were 545, 485, 402, 340, 289, 247, 217, 205, 197, and >25,000m·kg⁻¹ were 834, 808, 759, 729, 668, 627, 602, 584, 573; c) Enright % pred <67% were 560, 495, 416, 357, 302, 265, 232, 218, 209, and >67% were 819, 797, 744, 711, 654, 608, 586, 570, 560; and d) Troosters % pred <54% were 563, 497, 416, 355, 298, 259, 225, 211, 202, and >54% were 816, 795, 744, 713, 658, 614, 593, 577 and 567; respectively. ^#: p<0.00005.

Pearson's correlation coefficients revealed an excellent correlation between the 6MWD, Troosters % pred (r = 0.96), Enright % pred (r = 0.93), and a slightly less significant correlation with 6MWD work (r = 0.83). ROC curves (fig. 4⇓) showed all tests to have a similar discriminatory diagnostic capability for mortality in COPD patients. The area under the curve (AUC) for: 6MWD was 0.75; for 6MWD work, 0.77; for Enright % pred, 0.74; and for Troosters % pred, 0.75. The differences between groups were not statistically significant.

• Download figure
• Open in new tab
• Download powerpoint

Fig. 4—

Receiver operating characteristic curves show great similarity between all modalities of testing. The best area under the curve was found with the 6-min walk distance (6MWD) test work, although there was no statistical significant difference between the groups. –––: Troosters % predicted; ----: Enright % pred; ······: 6MWD work; — — —: 6MWD.

Discussion

The present study has several important findings. First, it has been found that the absolute value of 6MWD is as good a predictor of mortality in patients with COPD as values normalised by reference equations. Secondly, a 6MWD value of <350 m can be used as a threshold for poor prognosis. ROCs are considered the optimal method to determine the best performance for a diagnostic test, based on their best sensitivity and specificity. Threshold values of clinically significant abnormality were identified for published reference equations and for the 6MWD work and the 6MWD test and it was found that they predicted mortality in COPD in almost an identical way (table 3⇑).

Thirdly, the present study has shown that there is an increased correlation between mortality and female sex for all tests, which suggests that poor exercise performance in females might carry an ominous prognosis. As seen in table 4⇑, the correlation between 6MWD and mortality in females was r =  -0.49, p<0.0001 versus r =  −0.38, p<0.0001 in males. Sex-related differences in patients with COPD need closer consideration.

COPD is a disease that impairs functional capacity. However, the degree of exercise intolerance as measured by the 6MWD test varies widely even among patients with similar airflow limitation. This was evident in large clinical trials such as that of patients enrolled for lung volume reduction surgery 23, who by design had a narrow range of airflow limitation but a wide range of exercise performance. The exact reason for exercise limitation in COPD is not fully understood but appears to be somewhat independent of FEV₁. In the majority of patients with COPD, dyspnoea is a main limiting factor 24, likely related to hyperinflation 25, 26, airflow limitation 27 and impairment in diffusing capacity 28. In addition, skeletal muscle dysfunction has also been implicated in the genesis of exercise limitation among patients with COPD 29. The muscle of COPD patients shows structural and metabolic abnormalities, not seen in normal patients of similar age 30–32. Whatever the exact reasons for exercise limitation, the evaluation of exercise capacity using the 6MWD in patients with COPD helps assess disease severity. Furthermore, identifying levels of exercise impairment helps with the characterisation of these patients and assists with the referral to programmes such as pulmonary rehabilitation, lung reduction surgery or lung transplantation.

Most authors agree that 6MWD is a practical field test but its correct interpretation is more debatable 33. Studies have used the absolute value in metres to determine its prognostic ability or its responsiveness to pulmonary rehabilitation 7 or lung reduction surgery 23. However, it is well known that the 6MWD is influenced by age, sex and height. Indeed, the two studies validated herein, have provided reference equations based on the testing of normal individuals and then expressed the observed results as a percentage of predicted normal 15, 16. Interestingly, both reference values, although obtained through different methodologies, performed similarly at predicting mortality in COPD, indicating that at least for males, the equations have similar behaviour. Although the number of female patients in the present study was relatively small (n = 158), they were found to have a higher 6MWD compared with males. The female patients were compared to an equal number of male patients (n = 160), matched by FEV₁% (50±12) and age. Females walked 12–15% more according to reference equations and ∼35 m more according to the 6MWD. This finding is similar to that found in the unmatched analysis (females n = 158, males n = 1221) but needs to be tested in a larger population of female patients with COPD. This finding may explain the lower mortality observed among females compared with males (all-cause mortality 22 versus 48%, p<0.002; COPD mortality 12 versus 24%, p<0.007). Conversely, the walking distance of males dying from COPD (252±131 m) was very similar to that of females dying from COPD (264±118 m). However, the observed per cent predicted by reference equations for males (Enright = 48%, Troosters = 38%) was significantly lower than the observed per cent predicted among females who died (Enright = 54%, Troosters = 45%). Taken together, these findings suggest that a lower 6MWD in females might confer a worse prognosis than in males.

The present authors believe that, this is the first large study of a well characterised population of patients with COPD that applies and validates reference equations, determines values of clinical significance and describes the association between the performance on these tests and mortality over a long observational period. Previous reports included a smaller number of patients and a shorter time of follow-up. In the present study, the value of the 6MWD as a surrogate for survival has been further demonstrated. The present study confirms the threshold of clinical relevance for the 6MWD, as described in the original BODE study 19. As shown in table 3⇑, this threshold has similar sensitivity and specificity for mortality as reference equations and 6MWD work, and an almost linear increase in mortality as the walking distance decreases by 100 m (fig. 2⇑).

The present study has several limitations; the most important is the small number of females included in the study. Thus, the generalisation of these results to female patients with COPD may not fully apply and remains to be validated in studies including a much larger number of females. Additionally, the population included is primarily that of patients attending pulmonary clinics. This may bias toward patients with more symptomatic disease and it remains to be proven that the conclusions are extensive to the COPD population at large. Conversely, the long-term follow-up and the relatively large population included do suggest that the conclusions may be applicable to the majority of patients in whom an evaluation of exercise capacity may be of clinical value.

In summary, the present study shows that the distance walked during a 6-min walk distance test by patients with chronic obstructive pulmonary disease is as good a predictor of mortality as values normalised by reference equations and by the 6-min walk distance work. The present authors believe that the application of reference equations may be justified for the scientific interpretation of exercise performance. However, they add complexity to a test that remains grossly underutilised. Facilitating the interpretation of the test could influence implementation by the practitioner. The present authors believe that a 6-min walking distance test adds important independent information to the routine evaluation of patients with symptomatic chronic obstructive pulmonary disease and should be incorporated in the regular evaluation of these patients. If the value is >350 m, there is less need for close observation. Conversely, a value lower than this threshold identifies patients at higher risk for death and therefore candidates for closer observation and for possible therapies, such as pulmonary rehabilitation or lung volume reduction.