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PROPEL: Cell therapy does not boost walking performance in PAD
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ANAHEIM, Calif. — In patients with peripheral artery disease in the PROPEL trial, granulocyte-macrophage colony-stimulating factor, either alone or in combination with exercise, did not improve 6-minute walk distance.
Granulocyte-macrophage colony-stimulating factor, or GM-CSF, increases circulating endothelial progenitor cells, which have been previously associated with angiogenesis in humans, according to Mary M. McDermott, MD, the Jeremiah Stamler Professor of medicine and preventive medicine at Northwestern University Feinberg School of Medicine in Chicago.
“Because exercise-induced ischemia enhances progenitor-cell release and may also promote progenitor cell homing to ischemic calf muscle, walking exercise may augment the effects of GM-CSF in PAD. However, the effects of GM-CSF on walking performance remained unclear prior to the trial,” McDermott said at the American Heart Association Scientific Sessions.
McDermott and colleagues conducted the PROPEL trial to learn more about GM-CSF in PAD. They used a 2-by-2 factorial design in which 210 participants with PAD, with and without classic intermittent claudication, were randomly assigned between 2012 and December 2016 to one of four groups: GM-CSF plus exercise, GM-CSF plus attention control, supervised exercise plus placebo or attention control plus placebo.
Participants received GM-CSF or placebo three times per week for 2 weeks in a double blinded fashion, and supervised treadmill exercise was delivered three times a week for 6 months. The attention control intervention included weekly lectures given by clinicians for 6 months.
No benefit with GM-CSF
At 2-week follow-up, after the end of the study drug injections, both groups that received GM-CSF had statistically significant increases in circulating progenitor cells, whereas the two groups that did not receive GM-CSF had no change. By 6-week follow-up, all participants were back to baseline in terms of circulating progenitor cells.
At 12 weeks follow-up, participants assigned to supervised treadmill exercise alone had a statistically significant and clinically meaningful improvement in in the primary outcome of 6-minute walk performance compared with those who received attention control plus placebo (mean difference, 33.6 m; 95% CI, 9.4-57.7), according to the McDermott.
Participants who received GM-CSF plus exercise had greater improvement in 6-minute walk performance compared with GM-CSF alone. However, after adjustment for multiple comparisons, the difference did not reach statistical significance (mean difference, 28.7 m; 95% CI, 5.1-52.3), McDermott said.
Results also showed no differences between the GM-CSF-plus-exercise group compared with the exercise-alone group (mean difference, –6.3 m; 95% CI, –30.2 to 17.6) or between the GM-CSF-alone group compared with the attention-control-plus-placebo group (mean difference, –1.4 m; 95% CI, –25.2 to 22.4).
Additionally, at 12 weeks, participants in the exercise-plus-GM-CSF group vs. the GM-CSF-alone group had a significantly greater improvement in the secondary outcome of treadmill walking time. Similarly, participants assigned to supervised treadmill alone had significantly greater improvement in treadmill walking time than assigned attention control plus placebo. However, there was no difference between exercise plus GM-CSF compared with exercise alone and there was no difference between GM-CSF alone vs. attention control plus placebo.
There were also no significant differences for any of the four comparisons for the outcome of brachial flow-mediated dilation at 12-week follow-up, according to McDermott.
Final thoughts
During her presentation, McDermott highlighted several other interesting findings of the PROPEL trial. In response to the supervised treadmill exercise intervention, the primary outcome of the 6-minute walk distance improved more gradually compared with the secondary outcome of treadmill walking time.
“This is probably because the supervised treadmill exercise was training to the outcome measure of treadmill exercise performance,” she said.
Moreover, in contrast to previously published literature, the researchers did not see that regular supervised exercise significantly increased circulating progenitor cells over time, McDermott noted.
There were also no differences in the data according to the presence or absence of classical intermittent claudication symptoms among participants with PAD.
“The PROPEL trial confirmed previous findings regarding the fact that supervised treadmill exercise significantly improved 6-minute walk distance compared with the control group,” McDermott said. “However, GM-CSF did not significantly improve walking performance in people with PAD, either when used alone or when combined with supervised treadmill exercise.” – by Melissa Foster
References:
McDermott MM. LBS.07 – Innovative Therapies and Novel Applications. Presented at: American Heart Association Scientific Sessions; Nov. 11-15, 2017; Anaheim, California.
McDermott MM, et al. JAMA. 2017;doi:10.1001/jama.2017.17437.
Disclosure: McDermott reports no relevant financial disclosures.
Editor’s Note: This article was updated on Nov. 20, 2017 to include additional comment from the researcher and the perspective author.
Perspective
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Brian H. Annex, MD
The PAD area has been fraught with the inability to initiate and execute trials, so this study, regardless of the findings, advances our understanding of the disease.
The researchers faced many challenges in this trial, the first of which is an incomplete understanding of cell therapy as it relates to PAD and with the initial step being a mobilization strategy with GM-CSF.
I also want to highlight that there remains controversy as to the exact meaning of an endothelial progenitor cell as well as how it works. This study was also conducted 7 years ago and our understanding of endothelial progenitor cells is, if anything, more complicated now. The definition of endothelial progenitor cells in this study was different than the ones we commonly use today. Additionally, depending on how and where assessments are performed, you will come up with different measures of endothelial progenitor cells.
Finally, it is important to recognize that, although exercise time is clinically meaningful and is FDA-approvable, it is not the primary problem in PAD, which is reduced blood flow to the distal leg. There is not a one-to-one connection or correlation between changes in perfusion to changes in exercise. New imaging modalities are on the horizon that may make this easier going forward.
I agree with the definitive conclusions of Dr. McDermott and her colleagues. GM-CSF did not improve walking performance in these patients with PAD. Supervised exercise in the modern era, however, did work and worked on background therapy, whether the patients had classic claudication or not.
I would also like to go one step further and say that this trial demonstrates that there is no need for supervised exercise in these types of trials in the future. Data show the benefit of exercise training, but in a recent meta-analysis including a large number of patients showed that almost 70% will decline participation in a study involving exercise training. This is not only related to cost but both a lack of interest and inability to deal with the process. Moreover, it’s just too inconvenient. Therefore, inclusion of exercise training is going to delay trials and advances in the field of PAD.
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