Critical limb ischaemia occurs when blood flow to the legs is reduced because of the worsening of peripheral arterial disease. Initially, patients experience cramping leg pain that limits walking (termed intermittent claudication), but over time some patients experience more severe symptoms including pain at rest, leg ulceration and gangrene. The available treatment options are very limited when the disease reaches this stage, especially when surgical or catheter revascularisation is not an option. A substantial proportion of these patients require amputation of the affected limb. A new therapy (mononuclear cell therapy using the patient’s own cells) offers the possibility of an alternative treatment for patients, by supplying cells that could stimulate the formation of stable capillary vessels to improve the blood flow in the affected limb. These cells can be obtained from the bone marrow or from peripheral blood following subcutaneous injections (of granulocyte colony-stimulating factor) for five days. They are then treated in a laboratory and injected into the large muscle at the back of the lower leg.
The review authors identified only two small randomised controlled trials with a combined total of 57 participants testing the safety and effectiveness of this treatment. The findings were inconsistent. In one trial, pain at rest, pain-free walking distance, ankle brachial blood pressure index, and the number of amputations all clearly improved in the group receiving mononuclear cell implantation. In the other trial only the number of amputations showed a significant improvement in the treatment group compared with the control group. No deaths were reported during the study period.
Quality of the evidence
The two included studies differed from each other in how they obtained the cells for injection and assessed the clinical effects at different time points, up to three months in one trial, and six months in the other. They were classified as having a moderate risk of bias with unclear issues regarding their methods and the overall quality of the evidence was considered moderate.
The data from the published trials suggest that there is insufficient evidence to support this treatment. These results were based on only two trials which had a very small number of participants. Therefore evidence from larger randomised controlled trials is needed in order to provide adequate statistical power to assess the role of intramuscular mononuclear cell implantation in patients with CLI.
Peripheral arterial disease is a major health problem, and in about 1% to 2% of patients the disease progresses to critical limb ischaemia (CLI). In a substantial number of patients with CLI, no effective treatment option other than amputation is available and around a quarter of these patients will require a major amputation during the following year. This is an update of the review first published in 2011.
To determine the effectiveness and safety of local intramuscular transplantation of autologous adult bone marrow mononuclear cells (BMMNCs) as a treatment for critical limb ischaemia (CLI).
For this update the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched February 2014) and the Cochrane Central Register of Controlled Trials (CENTRAL; 2014, Issue 1).
We included all randomised controlled trials of CLI in which participants were randomly allocated to intramuscular administration of autologous adult BMMNCs or control (either no intervention or conventional conservative therapy). We excluded studies on patients with intermittent claudication.
Two authors independently selected trials, assessed trials for eligibility and methodological quality, and extracted data. Disagreements were resolved by consensus or by the third author.
Only two small studies, with a combined total of 57 participants, met our inclusion criteria and were finally included. They were classified as having a moderate risk of bias with unclear issues regarding their methods, and according to the GRADE approach, the overall quality of the evidence would be considered as moderate. In one study the effects of intramuscular injections of BMMNCs in the ischaemic lower limbs of patients with CLI were compared with control (standard conservative treatment). No deaths were reported and no significant difference was observed between the two groups for either pain (P = 0.37) or the ankle brachial index (ABI) parameter. However, the treatment group showed a significantly smaller proportion of participants undergoing amputation compared with the control group (P = 0.026).
In the other study, following subcutaneous injections of granulocyte colony-stimulating factor (G-CSF) for five days, peripheral blood derived mononuclear cells were collected and then transplanted by intramuscular injections into ischaemic lower limbs. The effects were compared with daily intravenous prostaglandin E1 injections (control group). No deaths were reported. Pain reduction was greater in the treatment group than in the control group (P < 0.001) as was increase in ABI (mean increase 0.13 versus 0.02, P < 0.01). The treatment group experienced a statistically significant increase in pain-free walking distance (PFWD) compared with the control group (mean increase 306.4 m versus 78.6 m, P = 0.007). A smaller proportion of participants underwent amputation in the treatment group compared with the control group (0% versus 36%, P = 0.007).