Every PACE counts—Learning about Blood cells and Blood flow in PAD

In my care of patients with peripheral artery disease (PAD), the fundamental goal is to: “Walk more, Suffer less.” More than 200 million people worldwide have PAD.¹ Patients with PAD experience limb ischemia leading to claudication, disability, and risk of amputation. Available therapies to enhance limb function remain inadequate. Even with optimal medical therapy including cilostazol and supervised exercise intervention, many PAD patients experience declining walking ability.² Revascularization with surgical or endovascular approaches may restore function but carries procedural risks and may have limited durability. Thus, considerable need exists for novel approaches to treat limb symptoms in PAD.

Obstructive atherosclerotic lesions precipitate limb ischemia in PAD. However, available evidence indicates that the generation of claudication symptoms is more complex.³ Hemodynamic compromise measured by the ankle-brachial index correlates poorly with symptom severity and is not changed along with improvements in walking ability induced by exercise intervention. Animal models of PAD suggest that insufficient microvascular flow contributes to limb ischemia. The concept of a therapy to promote vascular growth remains an appealing therapeutic strategy to help patients with PAD walk more. Several approaches to increase blood flow including growth factors and cell-based therapies have been tested in prior studies predominantly in patients with advanced PAD, critical limb ischemia, and have been largely disappointing.⁴

The Patients with Intermittent Claudication Injected with ALDH Bright Cells (PACE) trial reported in this issue of Circulation by Moyé and colleagues is an important contribution to the field of PAD pathophysiology and treatment.^{5, 6} Patients with infra-inguinal PAD and claudication were randomized in a double-blind fashion to receive intramuscular injection of aldehyde dehydrogenase bright cells (ALDHbr) isolated from autologous bone-marrow aspirates or cell-free placebo medium. The co-primary endpoints included both the standard claudication outcome of peak walking time on a treadmill and three magnetic resonance imaging (MRI) based endpoints: collateral count, peak hyperemic popliteal flow, and capillary perfusion. In the 78 patients with evaluable data (38 ALDHbr-treated, 40 placebo-treated), there were no differences in the change in peak walking time between the cell injection and placebo groups at 6 months (mean difference 0.9±0.8 minutes 95% CI −0.6 to 2.5 minutes, p=0.24). Further, there were no differences in the MRI-based measures of skeletal muscle blood flow. The lack of efficacy was similar across multiple pre-specified clinical subgroups. Cell injection did not have a significant beneficial effect on self-reported quality of life measures.

The trial raises several important questions. The major issue is whether the lack of efficacy indicates that bone-marrow derived cells have limited potential as a treatment for claudication. Prior experimental studies supported the utility of ALDHbr cells to enhance revascularization in animal models that do not appear to translate in a simple fashion to patients with chronic claudication.⁷ It remains possible that alternate delivery, higher doses or treatment of patients with different clinical characteristics would show benefit. The authors speculate that the observed nonsignificant 0.9 minute change in peak walk time with ALDHbr treatment might justify a larger study. The findings must be interpreted with the firm understanding that in the present study the change was not different than in the placebo group and may reflect chance. Even if confirmed in a larger study, an increase of less than a minute in peak walking time would be modest for a treatment that involves bone-marrow aspiration and muscular injections.

Another key issue is the relevance of limb perfusion measures in claudication. The MRI-based assessment of collateral count, peak hyperemic flow, and capillary perfusion provide a refined picture of skeletal muscle blood flow as compared to hemodynamic measures such as ankle-brachial index.⁸ But all three MRI-based measures were not associated with peak walking time at baseline or after treatment, suggesting a divergence of tissue blood flow and functional status in PAD. It is possible that a treatment that delivered a more profound effect on tissue perfusion would be needed to evaluate the relevance of these imaging metrics. An alternate explanation is that factors independent of blood flow determine limb symptoms and response to therapy. Several prior studies support the contribution of skeletal muscle metabolism, muscle structure, and inflammation to functional status that may serve as robust physiologic measures in future claudication studies.⁹ The authors report an exploratory analysis of selected anatomic subgroups. In the patients with an occluded superficial femoral artery or with no baseline collaterals, there were potential changes in MR-based measures. These results should be interpreted with caution given the small sample sizes in the subgroups and the lack of change in the functional measures to accompany the perfusion measures.

The crisis of peripheral artery disease demands new therapies.¹⁰ The PACE trial provides additional insight into the complexities of treating claudication. A simple model of stimulating blood flow may be inadequate to encompass the pathophysiology of walking impairment in PAD. Future studies are needed to refine our understanding of the claudication mechanisms and to evaluate whether alternate cell-based approaches to augment perfusion will achieve clinical benefit. The lack of clear improvement in the PACE trial should not discourage further trials to help our PAD patients walk more and suffer less.