Elsevier

American Heart Journal

Volume 156, Issue 5, November 2008, Pages 1010-1018
American Heart Journal

Clinical Investigation
Peripheral Vascular Disease
Long-term clinical outcome after intramuscular implantation of bone marrow mononuclear cells (Therapeutic Angiogenesis by Cell Transplantation [TACT] trial) in patients with chronic limb ischemia

https://doi.org/10.1016/j.ahj.2008.06.025Get rights and content

Background

Angiogenic cell therapy by intramuscular injection of autologous bone marrow mononuclear cells was first attempted in patients with peripheral artery disease (PAD) with critical limb ischemia, and the feasibility was shown by a randomized controlled Therapeutic Angiogenesis by Cell Transplantation (TACT) study.

Methods and Results

The present study was designed to assess the 3-year safety and clinical outcomes of this angiogenic cell therapy by investigating the mortality and leg amputation-free interval as primary end points. The median follow-up time for surviving patients was 25.3 months (range, 0.8-69.0 months), and 3-year overall survival rates were 80% (95% CI 68-91) in patients with atherosclerotic peripheral arterial disease (11 died in 74 patients) and 100% (no death) in 41 patients with thromboangiitis obliterans (TAO; Buerger's disease). Three-year amputation-free rate was 60% (95% CI 46-74) in PAD and 91% (95% CI 82-100) in patients with TAO. The multivariate analysis revealed that the severity of rest pain and repeated experience of bypass surgery were the prognostic factors negatively affecting amputation-free interval. The significant improvement in the leg pain scale, ulcer size, and pain-free walking distance was maintained during at least 2 years after the therapy, although the ankle brachial index and transcutaneous oxygen pressure value did not significantly change.

Conclusions

The angiogenic cell therapy using bone marrow mononuclear cells can induce a long-term improvement in limb ischemia, leading to extension of amputation-free interval. The safety and efficacy are not inferior to the conventional revascularization therapies.

Section snippets

Patients and procedures

The study protocol has been described in detail previously.2 In brief, patients with chronic limb ischemia (Fontaine stage III and IV, PAD n = 74 and TAO n = 41) were qualified for BM-MNCs implantation. These ischemic limbs were confirmed that they were not candidates for surgical or nonsurgical revascularization by the Eligibility Judgment Committee composed of vascular surgeons, cardiologists, and radiologists. The diagnosis of TAO was based on the criteria by Olin17 or Shionoya18 from the

Patient characteristics, primary end points, and safety issues

A total of 115 patients (PAD 74 limbs, TAO 41 limbs) from 11 different hospitals were included in this study. The clinical outcomes and adverse events were separately analyzed in PAD and TAO groups because the pathologic etiology of vascular occlusion (arteriosclerosis vs thromboembolic process) was distinct between these 2 diseases. In fact, Table I shows a great difference in the baseline clinical characteristics of patients. The average of age, risk factors, complications of ischemic heart

Discussions

Arterial occlusion may cause intermittent claudication and, in some cases, will lead to critical leg ischemia and/or limb loss. In such cases, interventional therapies such as bypass surgery or percutaneous transluminal angioplasty are performed, whereas these interventions show relatively high rates of reocclusion.19 Therefore, alternative, preferentially pharmacologic, strategies for symptomatic and functional improvement have been required. Cilostazol is the first substance shown to increase

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  • Cited by (0)

    S. Matoba, T. Tatsumi, T. Murohara, T. Imaizumi, Y. Katsuda, M. Ito, Y. Saito, S. Uemura, H. Suzuki, S. Fukumoto, Y. Yamamoto, and H Matsubara. contributed to the study design, enrollment, and clinical follow-up of patients, aspiration and intramuscular injection of bone marrow, and the writing of manuscript. Onodera R., Teramukai S., and Fukushima M. contributed to the study design and statistical analysis of data.

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    Co-investigators are listed in Appendix A.

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