The 6-Minute-Walk Distance Test as a Chronic Obstructive Pulmonary Disease Stratification Tool. Insights from the COPD Biomarker Qualification Consortium

Abstract

Rationale: The 6-minute-walk distance (6MWD) test predicts mortality in chronic obstructive pulmonary disease (COPD). Whether variability in study type (observational vs. interventional) or region performed limits use of the test as a stratification tool or outcome measure for therapeutic trials is unclear.

Objectives: To analyze the original data from several large observational studies and from randomized clinical trials with bronchodilators to support the qualification of the 6MWD test as a drug development tool in COPD.

Methods: Original data from 14,497 patients with COPD from six observational (n = 9,641) and five interventional (n = 4,856) studies larger than 100 patients and longer than 6 months in duration were included. The geographical, anthropometrics, FEV1, dyspnea, comorbidities, and health status scores were measured. Associations between 6MWD and mortality, hospitalizations, and exacerbations adjusted by study type, age, and sex were evaluated. Thresholds for outcome prediction were calculated using receiver operating curves. The change in 6MWD after inhaled bronchodilator treatment and surgical lung volume reduction were analyzed to evaluate the responsiveness of the test as an outcome measure.

Measurements and main results: The 6MWD was significantly lower in nonsurvivors, those hospitalized, or who exacerbated compared with those without events at 6, 12, and greater than 12 months. At these time points, the 6MWD receiver operating characteristic curve-area under the curve to predict mortality was 0.71, 0.70, and 0.68 and for hospitalizations was 0.61, 0.60, and 0.59, respectively. After treatment, the 6MWD was not different between placebo and bronchodilators but increased after surgical lung volume reduction compared with medical therapy. Variation across study types (observational or therapeutic) or regions did not confound the ability of 6MWD to predict outcome.

Conclusions: The 6MWD test can be used to stratify patients with COPD for clinical trials and interventions aimed at modifying exacerbations, hospitalizations, or death.

Keywords: 6-minute-walk distance; chronic obstructive pulmonary disease; outcomes.

Figures

Figure 1.

Flow diagram of the patients included in the analyses. For details on each of the studies, see Table E1. *NETT evaluated effectiveness of LVRS and will be analyzed separately in selected analyses. 6MWT = 6-minute-walk distance test; BODE = Body mass index, Obstruction, Dyspnea, and Exercise index; CHS = Cardiovascular Health Study; COPD = chronic obstructive pulmonary disease; ECLIPSE = Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints; GOLD = Global Initiative for Chronic Obstructive Lung Disease; LVRS = lung volume reduction surgery; NETT = National Emphysema Therapy Trial; VATS = video-assisted thoracoscopic surgery.

Figure 2.

The distribution of baseline 6-minute-walk distance (6MWD) was similar in the observational and interventional studies as shown in A and B, respectively. (A) Histogram of the 6MWD distribution in observational studies (n = 8,423). (B) Histogram of the 6MWD distribution in interventional studies (n = 4,856).

Figure 3.

Proportion of subjects who did (dark bars) or did not (light bars) have the outcome of interest for each category of 6-minute-walk distance (6MWD) at 12 months. Vertical axis: Proportion of total subjects who did or did not have the outcome of interest in each 6MWD category. (A–C) Distribution of baseline 6MWD by mortality (A), hospitalization (B), and exacerbation (C) at 12 months. (A) The proportion of subjects who died (light bars) was larger than that of survivors for shorter baseline 6MWDs. The same was true for hospitalizations (B) and exacerbations (C). Above the threshold of 350 m, the proportion of patients who had the outcome of interest was less than those who did not. The numbers of subjects are given inside the bars.

Figure 4.

Response in the 6-minute-walk distance (6MWD) to pharmacologic therapy (bronchodilator [Bronch]) or placebo in the randomized controlled clinical trials. The change in the 6MWD in interventional studies after the administration of either placebo (solid dark line) or active treatment (dashed red line) was similar at 6 and 12 months, which were the end times for the trials included in this analysis.

Figure 5.

Effect of controlled trials of inhaled pharmacotherapy (CT) and lung volume reduction (NETT) on the 6-minute-walk distance (6MWD) and FEV1. The 6MWD, expressed on the horizontal axis as percentage change from baseline (top) or as absolute distance in meters (bottom), increased proportionally to the improvement in FEV1 (vertical axis) in patients included in the National Emphysema Therapy Trial (NETT). The decrease in FEV1 shown in the lower portion of the graphs shows that overall, there was a decrease in lung function and there was no relation between change in 6MWD and lung function in the pharmacologic trials (CT).