ANAHEIM, CA — Injections of investigational granulocyte-macrophage colony-stimulating factor (GM-CSF) progenitor cells did not help patients with peripheral artery disease (PAD) walk further in the 6-minute-walk test, in a new trial[1].
However, supervised treadmill training, the control therapy, did result in a moderate, clinically meaningful improvement in walking.
Dr Mary M McDermott (Northwestern University Feinberg School of Medicine, Chicago, Illinois) presented these findings of the Progenitor Cell Release Plus Exercise to Improve Functional Performance in PAD (PROPEL) trial November 15, 2017 at the American Heart Association 2017 Scientific Sessions, and the study was simultaneously published online in the Journal of the American Medical Association.
"These results confirm the benefits of exercise but do not support using GM-CSF to treat walking impairment in patients with PAD," she reported.
"I agree completely," said the discussant, Dr Brian Annex (University of Virginia, Charlottesville). However, he added, "I'd also like to go perhaps a step further and say that the trial demonstrates that there's really no need for supervised exercise in these types of future trials," since this "is going to delay trials and advances in the field of PAD."
A recent meta-analysis[2] showed that 50% of potential PAD-trial participants were not interested in participating and a further 19% said the supervised exercise program was too inconvenient.
"On that controversial note, we'll move on," said session comoderator Dr Robert Califf (Duke university, Durham, North Carolina) after Annex concluded.
Invited to comment further, Califf told theheart.org | Medscape Cardiology that "there are a lot of things in medicine where usual care is not optimal care. It's always an interesting, worthwhile debate as to which strategy you should take in the control group."
This provocative statement by Annex "should rev people up who can help people with exercise programs," Califf said.
Supervised exercise is still first-line therapy, McDermott told theheart.org | Medscape Cardiology, and "should be offered to all patients with PAD. . . . There may be some who are unable or don't find it too convenient, but it should be offered, and I think many people take it up."
Exercise or Lectures, Cell Therapy or Placebo Injections
GM-CSF increases circulating endothelial progenitor cells, and early evidence suggested that "if you inject those cells into humans, they incorporate into developing new blood vessels," McDermott explained.
"We thought that if we could increase the circulating progenitor cells, it might promote angiogenesis" in the calf muscle in patients with PAD.
From 2012 to 2016, the researchers recruited patients in Chicago with PAD with or without symptoms who were 55 and older through ads and by contacting patients who had participated in their earlier research.
They assessed 827 patients and excluded 75%, mainly because individuals did not have PAD (439). Another 89 patients were not interested or unable to attend the exercise sessions.
They randomized 210 patients in a 2x2 factorial design into 4 groups:
GM-CSF plus exercise (53 patients).
GM-CSF plus lectures (53 patients).
Exercise plus placebo (53 patients).
Lectures ("attention control") plus placebo (51 patients).
The GM-CSF was given as injections of 250 μg/m2/day, three times a week for 2 weeks. Placebo injections were given at the same frequency.
Exercise consisted of supervised treadmill training sessions given three times a week for 6 months, where walking time was increased by 5 minutes per session each week to reach 40 to 50 minutes a session, and treadmill speed and grade were such that patients had symptoms of leg ischemia.
The lectures were an hour long and given every week for 6 months, and they covered health-related topics such as cancer screening, immunizations, nutritional supplements, and hypertension.
The patients had a mean age of 67, and 39% were women. Two-thirds (67%) were black and 38% had diabetes.
Fewer than a third (30%) had intermittent claudication; 65% had other ischemic leg symptoms; and 4% had no exertional leg symptoms—which reflects patients seen in clinical practice, the researchers note.
They measured outcomes at 6 weeks, 12 weeks, and 6 months, and 92% of the patients completed 12-weeks of follow-up.
The primary outcome was change in 6-minute-walk distance after 12 weeks of therapy compared with baseline.
At 12 weeks, exercise plus GM-CSF did not significantly improve results on the 6-minute-walk distance more than exercise alone (mean difference −6.3 m [95% CI −30.2 to 17.6; P=0.61]) or more than GM-CSF alone (mean difference 28.7 m [95% CI 5.1–52.3; Hochberg-adjusted P=0.052]).
GM-CSF alone did not improve 6-minute-walk distance over the lectures plus placebo (mean difference −1.4 m [95% CI −25.2 to 22.4; P=0.91]).
However, exercise alone did significantly improve the 6-minute-walk distance compared with lectures plus placebo (mean difference +33.6 m [95% CI 9.4–57.7; Hochberg-adjusted P=0.02]).
There was also no significant difference in brachial artery flow-mediated dilation with exercise or GM-CSF treatment.
New Imaging for Perfusion on the Horizon
PAD trials are challenging, Annex said. First, it's still not completely clear how cell therapies relate to PAD, and there is still controversy about what an endothelial progenitor cell is and how it works. Second, the nomenclature[3] is complex and inconsistent, making it difficult to compare studies.
Last, "while exercise over time is clinically meaningful and is FDA approvable, it is not actually the primary problem," Annex said. "The primary problem in PAD is reduced blood flow to the distal leg, and there is not a 1:1 correlation between changes in perfusion to changes in exercise.
"New imaging methods for muscle perfusion[4] are on the horizon that may make this easier going forward," he said.
Future studies could look at direct injection of stem cells into the calf muscle, McDermott suggested.
"Unfortunately, we don't have great drugs available, which is why we need more trials testing novel therapies, but always supervised exercise, and if the patient is not willing, trying to get them to do any walking at home really is a good idea."
This study was funded by the National Heart, Lung, and Blood Institute and the National Institute on Aging. McDermott receives research funding from Novartis and received study drug for another PAD study from ReserveAge. Disclosures for the coauthors are listed in the paper. Annex and Califf have no relevant financial relationships.
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Medscape Medical News © 2017
Cite this: Treadmill Training, Not Cell Therapy, Aids Walking in PAD: PROPEL - Medscape - Nov 22, 2017.
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