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

*Corresponding author for this work

Research output: Contribution to journalArticle

12 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)2089-2098
Number of pages10
JournalJAMA - Journal of the American Medical Association
Volume318
Issue number21
DOIs
StatePublished - Dec 5 2017

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Peripheral Arterial Disease
Granulocyte-Macrophage Colony-Stimulating Factor
Walking
Randomized Controlled Trials
Exercise
Placebos
Stem Cells

ASJC Scopus subject areas

  • Medicine(all)

Cite this

McDermott, Mary McGrae ; Ferrucci, Luigi ; Tian, Lu ; Guralnik, Jack M. ; Lloyd-Jones, Donald M ; Kibbe, Melina R. ; Polonsky, Tamar S. ; Domanchuk, Kathryn ; Stein, James H. ; Zhao, Lihui ; Taylor, Doris ; Skelly, Christopher ; Pearce, William H ; Perlman, Harris R ; McCarthy, Walter ; Li, Lingyu ; Gao, Ying ; Sufit, Robert L ; Bloomfield, Christina L. ; Criqui, Michael H. / 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. In: JAMA - Journal of the American Medical Association. 2017 ; Vol. 318, No. 21. pp. 2089-2098.
@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 McGrae} and Luigi Ferrucci and Lu Tian and Guralnik, {Jack M.} and Lloyd-Jones, {Donald M} 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 Pearce, {William H} and Perlman, {Harris R} and Walter McCarthy and Lingyu Li and Ying Gao and Sufit, {Robert L} and Bloomfield, {Christina L.} and Criqui, {Michael H.}",
year = "2017",
month = "12",
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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",
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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 McGrae; Ferrucci, Luigi; Tian, Lu; Guralnik, Jack M.; Lloyd-Jones, Donald M; Kibbe, Melina R.; Polonsky, Tamar S.; Domanchuk, Kathryn; Stein, James H.; Zhao, Lihui; Taylor, Doris; Skelly, Christopher; Pearce, William H; Perlman, Harris R; McCarthy, Walter; Li, Lingyu; Gao, Ying; Sufit, Robert L; Bloomfield, Christina L.; Criqui, Michael H.

In: JAMA - Journal of the American Medical Association, Vol. 318, No. 21, 05.12.2017, p. 2089-2098.

Research output: Contribution to journalArticle

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 McGrae

AU - Ferrucci, Luigi

AU - Tian, Lu

AU - Guralnik, Jack M.

AU - Lloyd-Jones, Donald M

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 H

AU - Perlman, Harris R

AU - McCarthy, Walter

AU - Li, Lingyu

AU - Gao, Ying

AU - Sufit, Robert L

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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DO - 10.1001/jama.2017.17437

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