Mary M McDermott1, Jack M Guralnik2, Lu Tian3, Lihui Zhao4, Tamar S Polonsky5, Melina R Kibbe6, Michael H Criqui7, Dongxue Zhang8, Michael S Conte9, Kathryn Domanchuk8, Lingyu Li8, Robert Sufit10, Christiaan Leeuwenburgh11, Luigi Ferrucci12. 1. Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Ill; Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Ill. Electronic address: mdm608@northwestern.edu. 2. Department of Epidemiology, University of Maryland, Baltimore, Md. 3. Department of Biomedical Data Science, Stanford University, Palo Alto, Calif. 4. Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Ill. 5. Department of Medicine, University of Chicago, Chicago, Ill. 6. Department of Surgery, University of North Carolina, Chapel Hill, NC. 7. Department of Family Medicine and Public Health, University of California at San Diego, San Diego, Calif. 8. Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Ill. 9. Division of Endovascular and Vascular Surgery, University of California San Francisco, San Francisco, Calif. 10. Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Ill. 11. Department of Aging and Geriatric Research, University of Florida, Gainesville, Fla. 12. Intramural Research Program, National Institute on Aging, Baltimore, Md.
Abstract
BACKGROUND: Randomized trials of people with peripheral artery disease (PAD) and intermittent claudication have traditionally used maximal treadmill walking distance as the primary outcome, but the 6-minute walk test is increasingly used as a primary outcome in randomized trials of PAD. This study compared relative changes in maximal treadmill walking distance versus 6-minute walk distance in response to a therapeutic intervention or control in randomized trials of participants with PAD. METHODS: Data from four randomized trials of therapeutic interventions in participants with PAD that measured both 6-minute walk and treadmill walking performance at baseline and the 6-month follow-up were combined. Two trials studied supervised treadmill exercise, one studied home-based walking exercise, and one studied resveratrol. RESULTS:Of 467 participants (mean age, 69.8; standard deviation, 9.7), the mean ankle-brachial index was 0.66 (standard deviation, 0.17). At the 6-month follow-up, participants with PAD randomized to control or placebo significantly declined in 6-minute walk distance (-10.2 m; 95% confidence interval, -18.2 to -2.2; P = .013), but improved maximal treadmill walking distance (+25.7 m; 95% CI, +6.0 to +45.3 m; P = .010; difference between change in 6-minute walk versus maximal treadmillwalking distance: -37.3 m; 95% CI, -56.4 to -18.2; P < .001). Home-based exercise improved the 6-minute walk distance by 43.2 m (95% CI, +28.4 to +57.9), and supervised treadmill exercise improved the 6-minute walk distance by 25.0 m (95% CI, +14.7 to +35.2; mean difference, +18.2 m favoring home-based exercise [95% CI, +0.2 to +36.2 m; P = .048]). Among all participants, the presence (vs absence) of treadmill exercise training was associated with a 141.3-m greater improvement in maximal treadmill walking distance compared to 6-minute walk distance (95% CI, 88.2-194.4; P < .001), suggesting a benefit from treadmill training on the treadmill outcome. CONCLUSIONS:Maximal treadmill walking distance and the 6-minute walk distance are not interchangeable outcomes in participants with PAD. Participants with PAD randomized to control groups improved treadmill walking distance but simultaneously meaningfully declined in 6-minute walk distance. Supervised treadmill exercise training amplified improvement in treadmill walking distance because of a training to the outcome measure phenomenon.
RCT Entities:
BACKGROUND: Randomized trials of people with peripheral artery disease (PAD) and intermittent claudication have traditionally used maximal treadmill walking distance as the primary outcome, but the 6-minute walk test is increasingly used as a primary outcome in randomized trials of PAD. This study compared relative changes in maximal treadmill walking distance versus 6-minute walk distance in response to a therapeutic intervention or control in randomized trials of participants with PAD. METHODS: Data from four randomized trials of therapeutic interventions in participants with PAD that measured both 6-minute walk and treadmill walking performance at baseline and the 6-month follow-up were combined. Two trials studied supervised treadmill exercise, one studied home-based walking exercise, and one studied resveratrol. RESULTS: Of 467 participants (mean age, 69.8; standard deviation, 9.7), the mean ankle-brachial index was 0.66 (standard deviation, 0.17). At the 6-month follow-up, participants with PAD randomized to control or placebo significantly declined in 6-minute walk distance (-10.2 m; 95% confidence interval, -18.2 to -2.2; P = .013), but improved maximal treadmill walking distance (+25.7 m; 95% CI, +6.0 to +45.3 m; P = .010; difference between change in 6-minute walk versus maximal treadmill walking distance: -37.3 m; 95% CI, -56.4 to -18.2; P < .001). Home-based exercise improved the 6-minute walk distance by 43.2 m (95% CI, +28.4 to +57.9), and supervised treadmill exercise improved the 6-minute walk distance by 25.0 m (95% CI, +14.7 to +35.2; mean difference, +18.2 m favoring home-based exercise [95% CI, +0.2 to +36.2 m; P = .048]). Among all participants, the presence (vs absence) of treadmill exercise training was associated with a 141.3-m greater improvement in maximal treadmill walking distance compared to 6-minute walk distance (95% CI, 88.2-194.4; P < .001), suggesting a benefit from treadmill training on the treadmill outcome. CONCLUSIONS: Maximal treadmill walking distance and the 6-minute walk distance are not interchangeable outcomes in participants with PAD. Participants with PAD randomized to control groups improved treadmill walking distance but simultaneously meaningfully declined in 6-minute walk distance. Supervised treadmill exercise training amplified improvement in treadmill walking distance because of a training to the outcome measure phenomenon.
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