Effect of Granulocyte-Macrophage Colony-Stimulating Factor with or Without Supervised Exercise on Walking Performance in Patients with Peripheral Artery Disease: The PROPEL Randomized Clinical Trial

Mary M. McDermott; Luigi Ferrucci; Lu Tian; Jack M. Guralnik; Donald Lloyd-Jones; Melina R. Kibbe; Tamar S. Polonsky; Kathryn Domanchuk; James H. Stein; Lihui Zhao; Doris Taylor; Christopher Skelly; William Pearce; Harris Perlman; Walter McCarthy; Lingyu Li; Ying Gao; Robert Sufit; Christina L. Bloomfield; Michael H. Criqui

doi:10.1001/jama.2017.17437

Effect of Granulocyte-Macrophage Colony-Stimulating Factor with or Without Supervised Exercise on Walking Performance in Patients with Peripheral Artery Disease: The PROPEL Randomized Clinical Trial

Mary M. McDermott^*, Luigi Ferrucci, Lu Tian, Jack M. Guralnik, Donald Lloyd-Jones, Melina R. Kibbe, Tamar S. Polonsky, Kathryn Domanchuk, James H. Stein, Lihui Zhao, Doris Taylor, Christopher Skelly, William Pearce, Harris Perlman, Walter McCarthy, Lingyu Li, Ying Gao, Robert Sufit, Christina L. Bloomfield, Michael H. Criqui

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

66 Scopus citations

Abstract

IMPORTANCE: Benefitsofgranulocyte-macrophagecolony-stimulatingfactor(GM-CSF)forimproving 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. OBJECTIVES: 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, to1 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. INTERVENTIONS: 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. RESULTS: 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, +9.4to +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.

Original language	English (US)
Pages (from-to)	2089-2098
Number of pages	10
Journal	JAMA - Journal of the American Medical Association
Volume	318
Issue number	21
DOIs	https://doi.org/10.1001/jama.2017.17437
State	Published - Dec 5 2017

Funding

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.

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General Medicine

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McDermott, M. M., Ferrucci, L., Tian, L., Guralnik, J. M., Lloyd-Jones, D., Kibbe, M. R., Polonsky, T. S., Domanchuk, K., Stein, J. H., Zhao, L., Taylor, D., Skelly, C., Pearce, W., Perlman, H., McCarthy, W., Li, L., Gao, Y., Sufit, R., Bloomfield, C. L., & Criqui, M. H. (2017). Effect of Granulocyte-Macrophage Colony-Stimulating Factor with or Without Supervised Exercise on Walking Performance in Patients with Peripheral Artery Disease: The PROPEL Randomized Clinical Trial. JAMA - Journal of the American Medical Association, 318(21), 2089-2098. https://doi.org/10.1001/jama.2017.17437

@article{ff97a29e00d04ddaa0eb2537a9a7db6c,

title = "Effect of Granulocyte-Macrophage Colony-Stimulating Factor with or Without Supervised Exercise on Walking Performance in Patients with Peripheral Artery Disease: The PROPEL Randomized Clinical Trial",

abstract = "IMPORTANCE: Benefitsofgranulocyte-macrophagecolony-stimulatingfactor(GM-CSF)forimproving 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. OBJECTIVES: 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, to1 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. INTERVENTIONS: 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. RESULTS: 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, +9.4to +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.",

author = "McDermott, {Mary M.} and Luigi Ferrucci and Lu Tian and Guralnik, {Jack M.} and Donald Lloyd-Jones and Kibbe, {Melina R.} and Polonsky, {Tamar S.} and Kathryn Domanchuk and Stein, {James H.} and Lihui Zhao and Doris Taylor and Christopher Skelly and William Pearce and Harris Perlman and Walter McCarthy and Lingyu Li and Ying Gao and Robert Sufit and Bloomfield, {Christina L.} and Criqui, {Michael H.}",

note = "Publisher Copyright: {\textcopyright} 2017 American Medical Association.",

year = "2017",

month = dec,

day = "5",

doi = "10.1001/jama.2017.17437",

language = "English (US)",

volume = "318",

pages = "2089--2098",

journal = "JAMA - Journal of the American Medical Association",

issn = "0098-7484",

publisher = "American Medical Association",

number = "21",

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McDermott, MM, Ferrucci, L, Tian, L, Guralnik, JM, Lloyd-Jones, D, Kibbe, MR, Polonsky, TS, Domanchuk, K, Stein, JH, Zhao, L, Taylor, D, Skelly, C, Pearce, W , Perlman, H, McCarthy, W, Li, L, Gao, Y, Sufit, R, Bloomfield, CL & Criqui, MH 2017, 'Effect of Granulocyte-Macrophage Colony-Stimulating Factor with or Without Supervised Exercise on Walking Performance in Patients with Peripheral Artery Disease: The PROPEL Randomized Clinical Trial', JAMA - Journal of the American Medical Association, vol. 318, no. 21, pp. 2089-2098. https://doi.org/10.1001/jama.2017.17437

Effect of Granulocyte-Macrophage Colony-Stimulating Factor with or Without Supervised Exercise on Walking Performance in Patients with Peripheral Artery Disease: The PROPEL Randomized Clinical Trial. / McDermott, Mary M.; Ferrucci, Luigi; Tian, Lu et al.
In: JAMA - Journal of the American Medical Association, Vol. 318, No. 21, 05.12.2017, p. 2089-2098.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Effect of Granulocyte-Macrophage Colony-Stimulating Factor with or Without Supervised Exercise on Walking Performance in Patients with Peripheral Artery Disease

T2 - The PROPEL Randomized Clinical Trial

AU - McDermott, Mary M.

AU - Ferrucci, Luigi

AU - Tian, Lu

AU - Guralnik, Jack M.

AU - Lloyd-Jones, Donald

AU - Kibbe, Melina R.

AU - Polonsky, Tamar S.

AU - Domanchuk, Kathryn

AU - Stein, James H.

AU - Zhao, Lihui

AU - Taylor, Doris

AU - Skelly, Christopher

AU - Pearce, William

AU - Perlman, Harris

AU - McCarthy, Walter

AU - Li, Lingyu

AU - Gao, Ying

AU - Sufit, Robert

AU - Bloomfield, Christina L.

AU - Criqui, Michael H.

PY - 2017/12/5

Y1 - 2017/12/5

N2 - IMPORTANCE: Benefitsofgranulocyte-macrophagecolony-stimulatingfactor(GM-CSF)forimproving 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. OBJECTIVES: 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, to1 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. INTERVENTIONS: 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. RESULTS: 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, +9.4to +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.

AB - IMPORTANCE: Benefitsofgranulocyte-macrophagecolony-stimulatingfactor(GM-CSF)forimproving 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. OBJECTIVES: 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, to1 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. INTERVENTIONS: 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. RESULTS: 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, +9.4to +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.

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McDermott MM, Ferrucci L, Tian L, Guralnik JM, Lloyd-Jones D, Kibbe MR et al. Effect of Granulocyte-Macrophage Colony-Stimulating Factor with or Without Supervised Exercise on Walking Performance in Patients with Peripheral Artery Disease: The PROPEL Randomized Clinical Trial. JAMA - Journal of the American Medical Association. 2017 Dec 5;318(21):2089-2098. doi: 10.1001/jama.2017.17437

Effect of Granulocyte-Macrophage Colony-Stimulating Factor with or Without Supervised Exercise on Walking Performance in Patients with Peripheral Artery Disease: The PROPEL Randomized Clinical Trial

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