Treating people with reduced blood supply to the legs with substances stimulating new vessel formation (growth factors)

Background and review question

Different diseases, such as atherosclerosis, can cause reduced blood supply to the legs. Depending on the disease severity this may be associated with symptoms such as leg pain when walking or resting, ulceration (open sores) and gangrene of the leg. Reduced blood supply to the legs affects 3% to 10% of all people and 15% to 20% of people over 70 years of age. It is a major cause of decreased mobility and quality of life and of increased risks for amputation or death.

The treatment strategy generally comprises behavioural changes (e.g. smoking cessation, exercise and diet), drugs (e.g. antiplatelets, statins) and catheter-based or surgical interventions. However, for some patients the only option is leg amputation.

Some substances naturally produced in the body, called growth factors, can stimulate new vessel formation. Nowadays, these substances are laboratory produced with the attempt to treat people with reduced blood supply to the legs. Therefore, we evaluated the evidence from clinical studies on the effects of growth factors in those people.

Key results and implications

We identified 20 studies and analysed the results of 14 published studies involving approximately 1400 patients and assessing three types of growth factors (evidence current to June 2016).

Our review shows that the effects of growth factors on the most important clinical parameters comprising limb amputations above the ankle, death and adverse events are uncertain (low-quality evidence up to two years, although moderate-quality evidence for one year). However, the rate of all limb amputations may decrease (low-quality evidence). In addition, growth factors may improve parameters of blood flow (low-quality evidence), ulceration (very low-quality evidence) and rest pain (very low-quality evidence) at up to one year, but have little or no effect on walking ability (low-quality evidence). We downgraded the quality of evidence mostly due to low statistical power and poor study quality. We did not identify any relevant differences in effects between growth factors.

This review does not support growth factor therapy in people with reduced blood supply to the legs to prevent limb amputations above the ankle or death or to improve walking ability. However, using growth factors may improve parameters of blood flow and prevent limb amputations below the ankle with an uncertain effect on adverse events; an improvement of ulceration and rest pain is very uncertain. New high-quality studies are needed to generate evidence with more certainty.

Authors' conclusions: 

The results of this review do not support the use of therapy with the growth factors FGF, HGF or VEGF in people with PAD of the lower extremities to prevent death or major limb amputation or to improve walking ability. However, the use of these growth factors may improve haemodynamic measures and decrease the rate of any limb amputations (probably due to preventing minor amputations) with an uncertain effect on adverse events; an improvement of ulceration and rest pain is very uncertain. New trials at low risk of bias are needed to generate evidence with more certainty.

Read the full abstract...
Background: 

Peripheral artery disease (PAD) is associated with a high clinical and socioeconomic burden. Treatments to alleviate the symptoms of PAD and decrease the risks of amputation and death are a high societal priority. A number of growth factors have shown a potential to stimulate angiogenesis. Growth factors delivered directly (as recombinant proteins), or indirectly (e.g. by viral vectors or DNA plasmids encoding these factors), have emerged as a promising strategy to treat patients with PAD.

Objectives: 

To assess the effects of growth factors that promote angiogenesis for treating people with PAD of the lower extremities.

Search strategy: 

The Cochrane Vascular Information Specialist searched the Specialised Register (June 2016) and CENTRAL (2016, Issue 5). We searched trial registries for details of ongoing or unpublished studies. We also checked the reference lists of relevant publications and, if necessary, tried to contact the trialists for details of the studies.

Selection criteria: 

We included randomised controlled trials comparing growth factors (delivered directly or indirectly) with no intervention, placebo or any other intervention not based on the growth factor's action in patients with PAD of the lower extremities. The primary outcomes were limb amputation, death and adverse events. The secondary outcomes comprised walking ability, haemodynamic measures, ulceration and rest pain.

Data collection and analysis: 

Two review authors independently selected trials and assessed the risk of bias. We used outcomes of the studies at low risk of bias for the main analysis and of all studies in the sensitivity analyses. We calculated odds ratios (OR) for dichotomous outcomes and mean differences for continuous outcomes with 95% confidence intervals (CI). We evaluated statistical heterogeneity using the I2 statistic and Cochrane's Q test. We conducted meta-analysis for the overall effect and for each growth factor as a subgroup analysis using OR in a fixed-effect model. We evaluated the robustness of the results in a sensitivity analysis using risk ratio (RR) and/or a random-effects model. We also assessed the quality of the evidence for each outcome.

Main results: 

We included 20 trials in the review and used 14 studies (on approximately 1400 participants) with published results in the analyses. Six published studies compared fibroblast growth factors (FGF), four studies hepatocyte growth factors (HGF) and another four studies vascular endothelial growth factors (VEGF), versus placebo or no therapy. Six of these studies exclusively or mainly investigated participants with intermittent claudication and eight studies exclusively participants with critical limb ischaemia. Follow-up generally ranged from three months to one year. Two small studies provided some data at 2 years and one of them also at 10 years.

The direction and size of effects for growth factors on major limb amputations (OR 0.99, 95% CI 0.71 to 1.38; 10 studies, N = 1075) and death (OR 0.99, 95% CI 0.69 to 1.41; 12 studies, N = 1371) at up to two years are uncertain. The quality of the evidence is low due to risk of bias and imprecision (at one year, moderate-quality evidence due to imprecision). However, growth factors may decrease the rate of any limb amputations (OR 0.56, 95% CI 0.31 to 0.99; 6 studies, N = 415). The quality of the evidence is low due to risk of bias and selective reporting.

The direction and size of effects for growth factors on serious adverse events (OR 1.09, 95% CI 0.79 to 1.50; 13 studies, N = 1411) and on any adverse events (OR 1.10, 95% CI 0.73 to 1.64; 4 studies, N = 709) at up to two years are also uncertain. The quality of the evidence is low due to risk of bias and imprecision (for serious adverse events at one year, moderate-quality evidence due to imprecision).

Growth factors may improve haemodynamic measures (low-quality evidence), ulceration (very low-quality evidence) and rest pain (very low-quality evidence) up to one year, but they have little or no effect on walking ability (low-quality evidence). We did not identify any relevant differences in effects between growth factors (FGF, HGF and VEGF).

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