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In people with lower extremity peripheral artery disease (PAD), do granulocyte-macrophage colony-stimulating factor (GM-CSF) and supervised treadmill exercise improve 6-minute walk performance when the 2 interventions are combined and when each is used alone?
In a randomized clinical trial of 210 participants with PAD, supervised treadmill exercise significantly improved the 6-minute walk by 34 m at 12-week follow-up, compared with control. The combination of treadmill exercise with GM-CSF did not significantly improve the 6-minute walk distance more than exercise alone or more than GM-CSF alone, and GM-CSF alone did not improve the 6-minute walk distance more than placebo at 12-week follow-up.
These results confirm the benefits of exercise but do not support using GM-CSF either alone or with exercise to treat walking impairment in PAD.
Benefits of granulocyte-macrophage colony-stimulating factor (GM-CSF) for improving walking ability in people with lower extremity peripheral artery disease (PAD) are unclear. Walking exercise may augment the effects of GM-CSF in PAD, since exercise-induced ischemia enhances progenitor cell release and may promote progenitor cell homing to ischemic calf muscle.
To determine whether GM-CSF combined with supervised treadmill exercise improves 6-minute walk distance, compared with exercise alone and compared with GM-CSF alone; to determine whether GM-CSF alone improves 6-minute walk more than placebo and whether exercise improves 6-minute walk more than an attention control intervention.
Design, Setting, and Participants
Randomized clinical trial with 2 × 2 factorial design. Participants were identified from the Chicago metropolitan area and randomized between January 6, 2012, and December 22, 2016, to 1 of 4 groups: supervised exercise + GM-CSF (exercise + GM-CSF) (n = 53), supervised exercise + placebo (exercise alone) (n = 53), attention control + GM-CSF (GM-CSF alone) (n = 53), attention control + placebo (n = 51). The final follow-up visit was on August 15, 2017.
Supervised exercise consisted of treadmill exercise 3 times weekly for 6 months. The attention control consisted of weekly educational lectures by clinicians for 6 months. GM-CSF (250 μg/m2/d) or placebo were administered subcutaneously (double-blinded) 3 times/wk for the first 2 weeks of the intervention.
Main Outcomes and Measures
The primary outcome was change in 6-minute walk distance at 12-week follow-up (minimum clinically important difference, 20 m). P values were adjusted based on the Hochberg step-up method.
Of 827 persons evaluated, 210 participants with PAD were randomized (mean age, 67.0 [SD, 8.6] years; 141 [67%] black, 82 [39%] women). One hundred ninety-five (93%) completed 12-week follow-up. At 12-week follow-up, exercise + GM-CSF did not significantly improve 6-minute walk distance more than exercise alone (mean difference, −6.3 m [95% CI, −30.2 to +17.6]; P = .61) or more than GM-CSF alone (mean difference, +28.7 m [95% CI, +5.1 to +52.3]; Hochberg-adjusted P = .052). GM-CSF alone did not improve 6-minute walk more than attention control + placebo (mean difference, −1.4 m [95% CI, −25.2 to +22.4]; P = .91). Exercise alone improved 6-minute walk compared with attention control + placebo (mean difference, +33.6 m [95% CI, +9.4 to +57.7]; Hochberg-adjusted P = .02).
Conclusions and Relevance
Among patients with PAD, supervised treadmill exercise significantly improved 6-minute walk distance compared with attention control + placebo, whereas GM-CSF did not significantly improve walking performance, either when used alone or when combined with supervised treadmill exercise. These results confirm the benefits of exercise but do not support using GM-CSF to treat walking impairment in patients with PAD.
clinicaltrials.gov Identifier: NCT01408901
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Corresponding Author: Mary M. McDermott, MD, Division of General Internal Medicine and Geriatrics, Northwestern University Feinberg School of Medicine, 750 N Lake Shore Dr, 10th Floor, Chicago, IL 60611 (firstname.lastname@example.org).
Accepted for Publication: October 20, 2017.
Published Online: November 15, 2017. doi:10.1001/jama.2017.17437
Author Contributions: Dr Tian had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: McDermott, Ferrucci, Tian, Guralnik, Lloyd-Jones, Kibbe, Taylor, Perlman, Criqui.
Acquisition, analysis, or interpretation of data: McDermott, Ferrucci, Tian, Guralnik, Lloyd-Jones, Kibbe, Polonsky, Domanchuk, Stein, Zhao, Taylor, Skelly, Pearce, Perlman, McCarthy, Li, Gao, Sufit, Bloomfield, Criqui.
Drafting of the manuscript: McDermott, Li.
Critical revision of the manuscript for important intellectual content: McDermott, Ferrucci, Tian, Guralnik, Lloyd-Jones, Kibbe, Polonsky, Domanchuk, Stein, Zhao, Taylor, Skelly, Pearce, Perlman, McCarthy, Li, Gao, Sufit, Bloomfield, Criqui.
Statistical analysis: Tian, Guralnik, Zhao, Li, Gao, Bloomfield.
Obtained funding: McDermott, Criqui.
Administrative, technical, or material support: McDermott, Lloyd-Jones, Kibbe, Polonsky, Domanchuk, Stein, Skelly, Perlman, McCarthy.
Supervision: McDermott, Domanchuk, Taylor, Perlman.
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr McDermott reported receiving research funding from Novartis and receipt of study drug for another peripheral artery disease study from ReserveAge. Dr Stein reported receiving royalties from the Wisconsin Alumni Research Foundation for intellectual property related to carotid ultrasound and arterial age and serving on a data and safety monitoring board for Lily. Dr Taylor reported that she is cofounder of, but receives no compensation from, Stem Cell Security. Dr Skelly reported having editor royalty agreements with Springer and Inside Ultrasound and that he is cofounder of Maji Therapeutics. No other authors reported disclosures.
Funding/Support: This study was funded by the National Heart, Lung, and Blood Institute (NHLBI) (R01-HL107510) and the National Institute on Aging. The material reported in this article is in part the result of work supported with resources and the use of facilities at the Jesse Brown VA Medical Center in Chicago, Illinois.
Role of the Funders/Sponsors: A representative from the NHLBI was a nonvoting member of the data and safety monitoring board. The study sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Disclaimer: Dr McDermott, senior editor for JAMA, and Dr Kibbe, editor of JAMA Surgery, had no role in the evaluation of or decision to publish this article.
Meeting Presentation: Material in this article was presented at the American Heart Association Scientific Sessions; November 15, 2017; Anaheim, California.
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