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NEW ORLEANS – Therapy with cells known to repair ischemic damage does not improve intermittent claudication of the legs in unselected patients, according to data from the randomized, phase II PACE trial reported at the American Heart Association scientific sessions. But some patients had evidence of new vessel formation.
“Administration of ALDH [aldehyde dehydrogenase] bright cells was feasible and safe, [but] administration at this dose and in this PAD [peripheral artery disease] cohort did not change peak walking time or MRI-based anatomic and perfusion endpoints,” reported Emerson C. Perin, MD, director of Clinical Research for Cardiovascular Medicine and medical director of the Stem Cell Center, both at the Texas Heart Institute, Houston.
However, “the MRI techniques developed and applied for the first time in a multicenter PAD clinical trial are now available for application in future PAD clinical research to determine if a clinically relevant therapeutic benefit might be achieved from cells or any other promising intervention,” he noted.
“One of the things in peripheral vascular disease that’s always been true is that peak walking time is a good clinical endpoint,” said session panelist Doris A. Taylor, PhD, director of Regenerative Medicine Research at the Texas Heart Institute. “[You] proposed some MRI parameters, but those didn’t correlate with peak walking time. So is the takeaway from this trial these MRI parameters? And if they don’t necessarily correlate, why would you advocate for them?”
Dr. Perin replied: “PAD is kind of the stepchild of cardiovascular medicine, it’s very poorly understood. And I think with the PACE trial, we’ve actually taken a huge step in understanding how we can treat these patients and how to study these patients.”
“Even though intermittent claudication or PAD starts with the flow limitation, what you wind up getting later down the road is not something that just relates to flow,” he elaborated. “We were able to study flow completely in this study – we owned it. What we weren’t able to study, and at the time we couldn’t, but now we can, is the metabolic, endothelial, and mitochondrial function. That is, what’s happening at the level of the muscle that is the missing link, together with the flow, that will give us these answers. So I think PACE [Patients With Intermittent Claudication Injected With ALDH Bright Cells] was very important to give us a greater understanding of where we can go now in PAD research.”
Trial details
Between 1 and 3 million people in the United States live with claudication, Dr. Perin noted when introducing the study. “It’s a very significant problem and a problem for which we really don’t have good solutions. We have one medicine [cilostazol], revascularization surgery, and stents that have recurrence – things that are less than perfect. There are also exercise programs, which not everyone has access to.”
The ALDH bright cells tested in PACE are collected from a patient’s bone marrow and express high levels of that enzyme. They are enriched for hematopoietic, endothelial progenitor, and multipotent mesenchymal colony-forming cells, and have shown ischemic repair capacity in preclinical models, with an increase in capillary density.
The investigators enrolled 82 patients with atherosclerotic peripheral arterial disease and symptom-limiting intermittent claudication of the legs. All had a pre-exercise ankle-brachial index of less than 0.9 or a pre-exercise toe-brachial index of less than 0.7, as well as stenosis greater than 50% or occlusion of infra-inguinal arteries by advanced imaging.
The patients were treated with 10 1-mL injections of ALDH bright cells or placebo into muscles of the posterior lower thigh and calf.
Results showed that after 6 months, peak treadmill walking time had improved by 2.2 minutes in the cell therapy group and 1.2 minutes in the placebo group, but the difference was not significant, Dr. Perin reported. The groups also were statistically indistinguishable overall with respect to changes in ankle-brachial index, walking impairment, and symptoms, and in MRI-assessed collateral count, peak hyperemic flow in the popliteal artery, and capillary perfusion.
However, among the subgroup of patients having a pre-exercise ankle-brachial index of 0.6 or less at baseline, collateral count increased by 2.4 in the cell therapy group, compared with 0.5 in the placebo group (P = .021).
In addition, among patients who had occluded femoral arteries at baseline (having more collateral vessels than peers with patent femoral arteries), the number of collaterals increased by 1.5 in the cell therapy group, compared with 0.3 in the placebo group (P = .047).
“This suggests an arteriogenic effect of cell therapy in patients with an occluded femoral artery substrate,” said Dr. Perin, who disclosed that he received a research grant from the National Heart, Lung, and Blood Institute.
NEW ORLEANS – Therapy with cells known to repair ischemic damage does not improve intermittent claudication of the legs in unselected patients, according to data from the randomized, phase II PACE trial reported at the American Heart Association scientific sessions. But some patients had evidence of new vessel formation.
“Administration of ALDH [aldehyde dehydrogenase] bright cells was feasible and safe, [but] administration at this dose and in this PAD [peripheral artery disease] cohort did not change peak walking time or MRI-based anatomic and perfusion endpoints,” reported Emerson C. Perin, MD, director of Clinical Research for Cardiovascular Medicine and medical director of the Stem Cell Center, both at the Texas Heart Institute, Houston.
However, “the MRI techniques developed and applied for the first time in a multicenter PAD clinical trial are now available for application in future PAD clinical research to determine if a clinically relevant therapeutic benefit might be achieved from cells or any other promising intervention,” he noted.
“One of the things in peripheral vascular disease that’s always been true is that peak walking time is a good clinical endpoint,” said session panelist Doris A. Taylor, PhD, director of Regenerative Medicine Research at the Texas Heart Institute. “[You] proposed some MRI parameters, but those didn’t correlate with peak walking time. So is the takeaway from this trial these MRI parameters? And if they don’t necessarily correlate, why would you advocate for them?”
Dr. Perin replied: “PAD is kind of the stepchild of cardiovascular medicine, it’s very poorly understood. And I think with the PACE trial, we’ve actually taken a huge step in understanding how we can treat these patients and how to study these patients.”
“Even though intermittent claudication or PAD starts with the flow limitation, what you wind up getting later down the road is not something that just relates to flow,” he elaborated. “We were able to study flow completely in this study – we owned it. What we weren’t able to study, and at the time we couldn’t, but now we can, is the metabolic, endothelial, and mitochondrial function. That is, what’s happening at the level of the muscle that is the missing link, together with the flow, that will give us these answers. So I think PACE [Patients With Intermittent Claudication Injected With ALDH Bright Cells] was very important to give us a greater understanding of where we can go now in PAD research.”
Trial details
Between 1 and 3 million people in the United States live with claudication, Dr. Perin noted when introducing the study. “It’s a very significant problem and a problem for which we really don’t have good solutions. We have one medicine [cilostazol], revascularization surgery, and stents that have recurrence – things that are less than perfect. There are also exercise programs, which not everyone has access to.”
The ALDH bright cells tested in PACE are collected from a patient’s bone marrow and express high levels of that enzyme. They are enriched for hematopoietic, endothelial progenitor, and multipotent mesenchymal colony-forming cells, and have shown ischemic repair capacity in preclinical models, with an increase in capillary density.
The investigators enrolled 82 patients with atherosclerotic peripheral arterial disease and symptom-limiting intermittent claudication of the legs. All had a pre-exercise ankle-brachial index of less than 0.9 or a pre-exercise toe-brachial index of less than 0.7, as well as stenosis greater than 50% or occlusion of infra-inguinal arteries by advanced imaging.
The patients were treated with 10 1-mL injections of ALDH bright cells or placebo into muscles of the posterior lower thigh and calf.
Results showed that after 6 months, peak treadmill walking time had improved by 2.2 minutes in the cell therapy group and 1.2 minutes in the placebo group, but the difference was not significant, Dr. Perin reported. The groups also were statistically indistinguishable overall with respect to changes in ankle-brachial index, walking impairment, and symptoms, and in MRI-assessed collateral count, peak hyperemic flow in the popliteal artery, and capillary perfusion.
However, among the subgroup of patients having a pre-exercise ankle-brachial index of 0.6 or less at baseline, collateral count increased by 2.4 in the cell therapy group, compared with 0.5 in the placebo group (P = .021).
In addition, among patients who had occluded femoral arteries at baseline (having more collateral vessels than peers with patent femoral arteries), the number of collaterals increased by 1.5 in the cell therapy group, compared with 0.3 in the placebo group (P = .047).
“This suggests an arteriogenic effect of cell therapy in patients with an occluded femoral artery substrate,” said Dr. Perin, who disclosed that he received a research grant from the National Heart, Lung, and Blood Institute.
NEW ORLEANS – Therapy with cells known to repair ischemic damage does not improve intermittent claudication of the legs in unselected patients, according to data from the randomized, phase II PACE trial reported at the American Heart Association scientific sessions. But some patients had evidence of new vessel formation.
“Administration of ALDH [aldehyde dehydrogenase] bright cells was feasible and safe, [but] administration at this dose and in this PAD [peripheral artery disease] cohort did not change peak walking time or MRI-based anatomic and perfusion endpoints,” reported Emerson C. Perin, MD, director of Clinical Research for Cardiovascular Medicine and medical director of the Stem Cell Center, both at the Texas Heart Institute, Houston.
However, “the MRI techniques developed and applied for the first time in a multicenter PAD clinical trial are now available for application in future PAD clinical research to determine if a clinically relevant therapeutic benefit might be achieved from cells or any other promising intervention,” he noted.
“One of the things in peripheral vascular disease that’s always been true is that peak walking time is a good clinical endpoint,” said session panelist Doris A. Taylor, PhD, director of Regenerative Medicine Research at the Texas Heart Institute. “[You] proposed some MRI parameters, but those didn’t correlate with peak walking time. So is the takeaway from this trial these MRI parameters? And if they don’t necessarily correlate, why would you advocate for them?”
Dr. Perin replied: “PAD is kind of the stepchild of cardiovascular medicine, it’s very poorly understood. And I think with the PACE trial, we’ve actually taken a huge step in understanding how we can treat these patients and how to study these patients.”
“Even though intermittent claudication or PAD starts with the flow limitation, what you wind up getting later down the road is not something that just relates to flow,” he elaborated. “We were able to study flow completely in this study – we owned it. What we weren’t able to study, and at the time we couldn’t, but now we can, is the metabolic, endothelial, and mitochondrial function. That is, what’s happening at the level of the muscle that is the missing link, together with the flow, that will give us these answers. So I think PACE [Patients With Intermittent Claudication Injected With ALDH Bright Cells] was very important to give us a greater understanding of where we can go now in PAD research.”
Trial details
Between 1 and 3 million people in the United States live with claudication, Dr. Perin noted when introducing the study. “It’s a very significant problem and a problem for which we really don’t have good solutions. We have one medicine [cilostazol], revascularization surgery, and stents that have recurrence – things that are less than perfect. There are also exercise programs, which not everyone has access to.”
The ALDH bright cells tested in PACE are collected from a patient’s bone marrow and express high levels of that enzyme. They are enriched for hematopoietic, endothelial progenitor, and multipotent mesenchymal colony-forming cells, and have shown ischemic repair capacity in preclinical models, with an increase in capillary density.
The investigators enrolled 82 patients with atherosclerotic peripheral arterial disease and symptom-limiting intermittent claudication of the legs. All had a pre-exercise ankle-brachial index of less than 0.9 or a pre-exercise toe-brachial index of less than 0.7, as well as stenosis greater than 50% or occlusion of infra-inguinal arteries by advanced imaging.
The patients were treated with 10 1-mL injections of ALDH bright cells or placebo into muscles of the posterior lower thigh and calf.
Results showed that after 6 months, peak treadmill walking time had improved by 2.2 minutes in the cell therapy group and 1.2 minutes in the placebo group, but the difference was not significant, Dr. Perin reported. The groups also were statistically indistinguishable overall with respect to changes in ankle-brachial index, walking impairment, and symptoms, and in MRI-assessed collateral count, peak hyperemic flow in the popliteal artery, and capillary perfusion.
However, among the subgroup of patients having a pre-exercise ankle-brachial index of 0.6 or less at baseline, collateral count increased by 2.4 in the cell therapy group, compared with 0.5 in the placebo group (P = .021).
In addition, among patients who had occluded femoral arteries at baseline (having more collateral vessels than peers with patent femoral arteries), the number of collaterals increased by 1.5 in the cell therapy group, compared with 0.3 in the placebo group (P = .047).
“This suggests an arteriogenic effect of cell therapy in patients with an occluded femoral artery substrate,” said Dr. Perin, who disclosed that he received a research grant from the National Heart, Lung, and Blood Institute.
Key clinical point:
Major finding: At 6 months, peak walking time had increased by 2.2 minutes in the cell therapy group and 1.2 minutes in the placebo group, a nonsignificant difference (P = .238).
Data source: PACE, a randomized phase II trial of 82 patients with PAD and symptom-limiting intermittent claudication of the legs.
Disclosures: Dr. Perin received a research grant from the National Heart, Lung, and Blood Institute.