Why is this question important?
Critical limb ischaemia, or critical limb-threatening 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 (known as intermittent claudication), but over time some patients will 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 (a procedure to restore blood flow in blocked arteries or veins) is not an option. Many of these patients will go on to have the affected limb amputated. The use of 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. They are purified in a laboratory and injected into the large muscle at the back of the lower leg.
What did we find?
We searched for randomised controlled trials (a type of study where participants are randomly assigned to one of two or more treatment groups) that compared treating people using selected bone marrow cells with control (either no intervention, conventional conservative therapy, or placebo (dummy treatment)). We found four studies with a combined total of 176 participants testing the safety and effectiveness of this treatment. The studies compared the cell therapy to different controls. Our analysis showed there is no clear effect of cell therapy on death from any cause. The studies measured pain in different ways, and not all information was reported, so we were unable to pool the data. Individually, three studies did not find any difference in the reduction of pain between the therapy and control groups. One study reported that pain was reduced more in the cell therapy group than in the control group. Pooling data from all four studies showed that cell therapy might reduce amputations, but we are not certain about this because the possible benefit was lost when we redid the analysis excluding data from studies we had concerns about. Three studies reported no improvements in the ankle-brachial index (a way to measure the blood flow in the leg), whilst one study reported a greater improvement in the ankle-brachial index in the cell therapy group compared to the control group. No improvements were seen in pain-free walking distance between groups. No clear difference was seen in side effects between groups.
How confident are we in the evidence?
Our confidence in the evidence was very low because of concerns about how the studies were carried out. The four included studies differed from each other in how they measured effects at different time points; they used different controls; there were small numbers of events and participants overall; and there were differences in individual study results.
We identified a small number of studies that met our inclusion criteria, and these differed in the controls they used and how they measured important outcomes. Limited data from these trials provide very low- to low-certainty evidence, and we are unable to draw conclusions to support the use of local intramuscular transplantation of BMMNC for improving clinical outcomes in people with CLI. Evidence from larger RCTs is needed in order to provide adequate statistical power to assess the role of this procedure.
Peripheral arterial disease is a major health problem, and in about 1% to 2% of patients, the disease progresses to critical limb ischaemia (CLI), also known as critical limb-threatening ischaemia. In a substantial number of individuals with CLI, no effective treatment options other than amputation are available, with around a quarter of these patients requiring a major amputation during the following year. This is the second update of a review first published in 2011.
To evaluate the benefits and harms of local intramuscular transplantation of autologous adult bone marrow mononuclear cells (BMMNCs) as a treatment for CLI.
We used standard, extensive Cochrane search methods. The latest search date was 8 November 2021.
We included all randomised controlled trials (RCTs) of CLI in which participants were randomly allocated to intramuscular administration of autologous adult BMMNCs or control (either no intervention, conventional conservative therapy, or placebo).
We used standard Cochrane methods. Our primary outcomes of interest were all-cause mortality, pain, and amputation. Our secondary outcomes were angiographic analysis, ankle-brachial index (ABI), pain-free walking distance, side effects and complications. We assessed the certainty of the evidence using the GRADE approach.
We included four RCTs involving a total of 176 participants with a clinical diagnosis of CLI. Participants were randomised to receive either intramuscular cell implantation of BMMNCs or control. The control arms varied between studies, and included conventional therapy, diluted autologous peripheral blood, and saline. There was no clear evidence of an effect on mortality related to the administration of BMMNCs compared to control (risk ratio (RR) 1.00, 95% confidence interval (CI) 0.15 to 6.63; 3 studies, 123 participants; very low-certainty evidence). All trials assessed changes in pain severity, but the trials used different forms of pain assessment tools, so we were unable to pool data. Three studies individually reported that no differences in pain reduction were observed between the BMMNC and control groups. One study reported that reduction in rest pain was greater in the BMMNC group compared to the control group (very low-certainty evidence). All four trials reported the rate of amputation at the end of the study period. We are uncertain if amputations were reduced in the BMMNC group compared to the control group, as a possible small effect (RR 0.52, 95% CI 0.27 to 0.99; 4 studies, 176 participants; very low-certainty evidence) was lost after undertaking sensitivity analysis (RR 0.52, 95% CI 0.19 to 1.39; 2 studies, 89 participants). None of the included studies reported any angiographic analysis. Ankle-brachial index was reported differently by each study, so we were not able to pool the data. Three studies reported no changes between groups, and one study reported greater improvement in ABI (as haemodynamic improvement) in the BMMNC group compared to the control group (very low-certainty evidence). One study reported pain-free walking distance, finding no clear difference between BMMNC and control groups (low-certainty evidence). We pooled the data for side effects reported during the follow-up, and this did not show any clear difference between BMMNC and control groups (RR 2.13, 95% CI 0.50 to 8.97; 4 studies, 176 participants; very low-certainty evidence). We downgraded the certainty of the evidence due to the concerns about risk of bias, imprecision, and inconsistency.