For patients with IPF, the 6MWT appears to be a valid reflection of global functional capacity;8
it is frequently used clinically to assess changes in IPF disease status over time but with few data to support this practice. More importantly, the 6MWT—either the 6MWT itself, variations thereof, or data collected during the 6MWT (e.g., measures of oxygenation) —has been used as an outcome measure in trials enrolling subjects with IPF.23–25
However, there are large knowledge gaps regarding certain important aspects of this test in IPF.
In this study, for a select group of well-defined subjects with IPF who were able to walk no less than 150m and no more than 499m during a baseline 6MWT, and who performed follow-up testing, we found no significant change from baseline in 6MWD at six or twelve months. These data are supported by studies from Tomioka and Raghu who also found no significant change over time frames ranging from about 12–14 months.9,10
Our study estimates the MID for 6MWD in patients with IPF, which we found to be in the range of 28 meters. To our knowledge, only two other groups of investigators have assessed the MID for the 6MWD in patients with IPF. In a study published only in abstract form, Mathai and colleagues divided into two subgroups 20 IPF patients who were participating in a one-day support group. Each patient performed a 6MWT, and then each subgroup of 10 patients spent the day together at a support group meeting (details not provided). At the end of the day, each patient was asked to rate his ability to walk relative to the other members in his subgroup. These investigators found that 6MWD needed to differ by a mean 17.9±103.6m for patients to stop rating themselves as “the same” as other members in their group. Redelmeier and colleagues developed this method, and used it to show that the MID for 6MWD in patients with COPD is 54m (95% confidence interval 37–71m); that is, the mean difference in 6MWD between subjects who rated themselves as being able to walk either “a little bit better” or “a little bit worse,” compared with those who rated themselves as being able to walk “about the same” as other patients, was 54m. In that study, patients who rated themselves as “a little worse” on average walked 80m less than other patients in their group, whereas subjects who rated themselves as “a little better” walked only 30m more than other patients in their group—yielding a weighted average of 54m among subjects who rated themselves as minimally (or “a little…”) different from other patients.
Another method commonly used to determine the MID for an outcome measure involves asking subjects to provide a so-called transition assessment at the time of follow-up testing. For example, at six months, subjects (blinded to baseline and follow-up data) might be asked to report whether they perceived their 6MWD to be “the same as,” “a little bit less,” “a lot less,” “a little bit greater,” or “a lot greater” than their baseline walk. The mean 6MWD for subjects reporting a minimal change in perceived 6MWD (i.e., “a little bit less” or “a little bit greater”) would be the estimate of the MID. Singh and co-investigators used this method to estimate the MID for the incremental shuttle walk test to be 47.5m in patients with COPD.26
In the only study of the 6MWD MID in IPF published in manuscript format, Holland and her colleagues used global change ratings, receiver operating characteristic (ROC) curves, and a distribution-based approach to derive their estimate.27
Among 24 subjects with IPF who completed a 6MWT before and after an 8-week exercise program, the MID was found to be between 29 and 34 meters
No transition assessment was used in the BUILD-1 trial, but we employed a related (and perhaps the most common) method of determining the MID—an anchor-based method. Although any variable can be an anchor, each should meet three criteria: (1) it should be related to the outcome variable, (2) it must possess face validity, and (3) it must be able to be divided into at least three categories: no change, minimal, and other.12
As one anchor, we selected the SGRQ Total for several reasons: (1) it is a patient-oriented or patient-assessed outcome measure, and as such, it asks specifically about patients’ perceptions28
—a notion viewed by many investigators as paramount to deriving the MID for an outcome variable;12
(2) IPF impairs—and patients value—the quality of their lives, so the SGRQ and other health status questionnaires provide meaningful data in this population;29,30
and (3) we have shown previously that a 7-point change in SGRQ Total score is its MID among patients with IPF (paper accepted for publication: Swigris et al. The SF-36 and SGRQ: validity and first look at minimum important differences in IPF. Respir Med 2009). As the second anchor we chose the FVC because it is perhaps the most widely used physiologic measurement to assess IPF severity, and cut-off values for its clinical and prognostic meaningfulness have been established in a number of studies.31–35
We elected to use FVC rather than DLCO because of the greater intrinsic variability in DLCO measures as well as our inability to confidently define the clinically significant range for its minimum change.
There are a number of limitations to this study. As is often the case, the distribution-based method yielded higher estimates for the MID than the anchor-based methods.36
The selected population included only IPF patients who could walk more than 150 but less than 499m during a 6MWT at baseline—and the overwhelming majority could walk at least 350m. Furthermore, data from subjects who died, or who were unable to complete the 6MWT for other reasons, was not included in our analyses; this could introduce bias. Thus, inferences drawn here may not be applicable to extremely debilitated IPF patients in the latter stages of the disease or to more fit IPF patients in the earlier stages of disease. However, the results of this study may have important implications for both IPF investigators who plan to power future IPF studies for change in 6MWD as well as clinicians who prognosticate future changes in functional status. While the pattern of decline in 6MWD over time is unclear, if a linear decline were assumed, one might expect a 30 meter decline in 6MWD to occur, on average, at 31 months of follow-up (data not shown). It has been recommended that multiple anchors (in multiple studies) be used to generate a range for the MID for any outcome variable.12
Although this is but one study, we derived the MID for 6MWD by using two clinically meaningful anchors as well as by employing distribution-based methods. Furthermore, our estimate is nearly identical to the estimate from the only other published study to examine the 6MWD MID in IPF. Finally, it must be recognized that the MID estimate here is to be used at the population level; that is, the mean change in 6MWD that is considered clinically important in a population is “often much less” than the change in 6MWD that would allow a practitioner to be confident that a change within an individual patient is outside of inter-test variability.36
In conclusion, data from this study provide the first systematic examination of 12-month longitudinal changes in 6MWD as a prospectively acquired, primary outcome variable in a well-defined subset of patients with IPF, as well as an estimate of the MID for 6MWD in patients with this disease. It appears as though the MID for 6MWD is smaller for IPF than for COPD, but future confirmatory studies should be performed to estimate the MID for 6MWD in IPF.