Cell Therapy Shows Promise for Limb Ischemia Due to PAD, Buerger’s Disease

Bone marrow stem cell therapy appears safe and somewhat effective for patients with critical limb ischemia (CLI). The findings, which were especially encouraging for those with Buerger’s disease, appear in 2 papers published online January 4, 2011, ahead of print in Circulation: Cardiovascular Interventions.

Improved Healing, Less Pain

For the PROVASA trial, Andreas M. Zeiher, MD, of the University of Frankfurt (Frankfurt, Germany), and colleagues looked at 40 patients with CLI due to PAD (n = 32) or Buerger’s disease (n = 8). The multicenter, phase II, double-blind study randomized patients to receive either intraarterial administration of bone marrow mononuclear cells (BM-MNCs) or placebo; after 3 months, all subjects then underwent BM-MNC treatment. Thus, some received placebo and bone marrow stem cells, while others received 2 rounds of stem cell treatment.

Although the trial missed its primary endpoint of increased ankle-brachial index at 3 and 6 months, cell therapy conferred a statistically significant advantage in terms of improved ulcer healing and reduced rest pain (table 1). Limb salvage and amputation-free survival rates, meanwhile, were similar between BM-MNC and placebo patients.

Table 1. PROVASA Outcomes

^a As assessed on visual analog scale ranging from 0 to 10.

On multivariate analysis, complete ulcer healing and clinical improvement both were independently predicted by repeat BM-MNC treatment and the number and functionality of the administered cells.

“Given the long-standing chronic disease process leading to critical limb ischemia in [PAD], it is not surprising that ulcer healing appears to be significantly promoted by repeated BM-MNC administration,” the investigators comment. “The excellent procedural safety profile of bone marrow harvest and intraarterial BM-MNC administration documented in the present study provides the necessary framework for a repeated treatment strategy that can be easily implemented into clinical guidance of patients with critical limb ischemia.”

Foundation for Moving Forward

For the moment, “[t]his therapy should still be regarded as an experimental therapy, which needs to be established for widespread clinical use in larger randomized trials in patients with CLI and stable ulcers and rest pain,” Dr. Zeiher told TCTMD in an e-mail communication.

Having said that, the “results of the study are indeed promising, given that there is currently no effective pharmacological therapy in patients with CLI,” he commented, adding that this is the first trial to test intra-arterial, rather than intramuscular, cell injection for this indication. “The salient and novel findings of the study are threefold: First, bone marrow-derived mononuclear cell administration accelerates wound healing and pain reduction in CLI compared to placebo; second, complete wound healing requires repetitive treatment and takes on average more than 10 months; and third, patients with Buerger’s disease (thrombangiitis obliterans) respond extremely well to this treatment strategy.”

Dr. Zeiher said that because CLI patients tend to be older and have multiple comorbidities, autologous cells derived from bone marrow have limited therapeutic utility. “Therefore, current experimental work focuses mainly on improving cell functionality by ex-vivo incubation of the cells with small molecules prior to readministration in order to enhance their neovascularization capacity,” he explained. In addition, planning is underway for a new study of cell therapy specifically in patients with Buerger’s disease that will build on the experience of the PROVASA trial.

Asked about the potential of cell therapy for CLI compared with other conditions such as heart failure, Dr. Zeiher said, “In my personal view, CLI is the most promising indication for bone marrow-derived cell therapy with respect to achieving approval by regulatory authorities, since induction of new blood vessel formation and improved microcirculatory function are well established mechanisms of action of these cells. In addition, there is a tremendous need to develop novel therapies for patients with CLI.

“The problem of heart failure is much more complex, and improved blood supply might not be sufficient to recover contractile function of the heart in the majority of patients with chronic heart failure and depressed LV function,” he noted.

Fewer Amputations

In the second study, researchers led by Yukihito Higashi, MD, PhD, of Hiroshima University (Hiroshima, Japan), assessed long-term clinical outcomes after intramuscular BM-MNC implantation in 51 patients with CLI, of whom 25 had PAD and 26 had Buerger’s disease. Another 46 subjects with CLI (30 PAD and 16 Buerger’s disease patients) served as controls. Median follow-up was 4.8 years.

At 4-year follow-up, cell therapy increased survival from major amputation for both PAD and Buerger’s disease patients compared with their respective controls. The benefit was strongest for those with Buerger’s disease. However, the treatment did not alter overall survival in either group (table 2).

Table 2. Outcomes at 4 Years

Multivariable Cox proportional hazard analysis showed that amputation-free survival was positively influenced by BM-MNC implantation (HR 20.93; 95% CI 9.64-45.45) and negatively affected by diabetes (HR 0.52; 0.28-0.97) and hemodialysis (HR 0.41; 0.20-0.81).

Buerger’s disease patients who received cell therapy had a significant increase in ankle-brachial index and transcutaneous oxygen pressure at 1 month that remained high throughout 3-year follow-up. PAD patients also had improvements in these variables at 1 month but the values gradually decreased over the same time frame, eventually returning to baseline levels.

No severe acute adverse effects occurred in patients who underwent BM-MNC treatment; 4 had slight fever elevation within 3 days, 3 had worsened pain within 2 days at lesions in which cells were implanted, and 1 had vertigo within 1 day of therapy.

“In conclusion, BM-MNC implantation reduces major amputation rates and is safe and effective in patients with CLI, especially in patients with Buerger’s disease,” Dr. Higashi and colleagues write, adding that the results also “suggest that CLI patients with diabetes mellitus who are undergoing hemodialysis may not be eligible for cell therapy.”

 

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Sources:
1. Walter DH, Krankenberg H, Balzer JO, et al. Intraarterial administration of bone marrow mononuclear cells in patients with critical limb ischemia: A randomized-start, placebo-controlled pilot trial (PROVASA). Circ Cardiovasc Interv. 2011;Epub ahead of print.

2. Idei N, Soga J, Hata T, et al. Autologous bone-marrow mononuclear cell implantation reduces long-term major amputation risk in patients with critical limb ischemia: A comparison of atherosclerotic peripheral arterial disease and Buerger disease. Circ Cardiovasc Interv. 2011;Epub ahead of print.

 

 

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