Background
Peripheral arterial disease (PAD) occurs when the blood flow to the limbs is restricted because of narrowed arteries. This circulatory problem is increasing in the population because of increased levels of diabetes and because the population is ageing. Due to restricted blood flow, PAD can cause pain in the legs while walking, usually after some distance (known as 'intermittent claudication'). As the disease becomes more severe, a person can experience serious pain while at rest, as well as ulcers in the feet and legs (known as 'critical limb ischaemia'). PAD can be treated with medication or through interventions such as surgical or endovascular procedures (less invasive than surgery, endovascular intervention is carried out through a small incision to access the vessels). However, many people will not respond to medication, and surgical or endovascular procedures may not be appropriate because of medical risks. In these cases, for extreme PAD, the only option for treating the condition is amputation. Therapies are needed that can help repair the vessels in the limbs of people with PAD to restore adequate blood flow.
Gene therapy is a novel approach whereby genetic material, encoded for proteins that may help to improve blood flow by restoring blood vessels, is injected into a person's legs. Trials have shown that this treatment is safe, but whether it is effective in reducing the risk of amputation or improving quality of life remains unknown.
Review question
Is there a difference in outcomes of effectiveness (such as amputation, death, ulcer healing, and quality of life) between patients with symptomatic PAD who are given gene therapy and those who are not given gene therapy?
Study characteristics
We included 17 studies that had a total of 1988 participants (evidence current until November 2017). These studies used various types of gene therapy as well as different dosages, some providing single treatments and some repeated treatments. Most of the studies included people with critical limb ischaemia; three studies included people with intermittent claudication.
Key results
When combining the data, we found no clear differences between people who received gene therapy and those who did not in terms of amputation-free survival (patients who did not have an amputation and did not die), major amputation (above the ankle), or death. We did see improvement in complete ulcer healing in the gene therapy treatment group compared to the control group. Studies show no clear differences in pain symptom scores, but we evaluated only two studies for this outcome. Not enough data are available to show if there was a difference between groups for the measure of blood flow known as the 'ankle brachial index'. We were not able to combine data on quality of life or pain-free walking distances (distances one can walk without experiencing leg pain).
Quality of the evidence
Risk of bias of the included studies varied greatly, and this was a concern because studies did not clearly report on their methods nor on follow-up of participants. Most studies used a placebo control, which increases the risk that outcomes may have been different if people knew they were given treatment or control. Corporations that produce the tested treatments sponsored all included trials.
The quality of evidence varied from moderate to very low. For amputation-free survival, major amputation, and death, we considered the quality of evidence to be moderate because of differences between studies. For ulcer healing, risk of bias was a matter of concern, and study results were imprecise because few events were reported. The quality of evidence for quality of life was very low because of differences between studies and insufficient information to combine study findings. The quality of evidence for the ankle brachial index was low because only one study with few participants reported this outcome. For pain symptom scores, the quality of evidence was very low because of technical problems within one of the two studies, as well as differences between the two studies and few participants.
Moderate-quality evidence shows no clear differences in amputation-free survival, major amputation, and all-cause mortality between those treated with gene therapy and those not receiving gene therapy. Some evidence suggests that gene therapy may lead to improved complete ulcer healing, but this outcome needs to be explored with improved reporting of the measure, such as decreased ulcer area in cm², and better description of ulcer types and healing. Further standardised data that are amenable to meta-analysis are needed to evaluate other outcomes such as quality of life, ankle brachial index, symptom scores, and claudication distance.
Peripheral arterial disease (PAD), caused by narrowing of the arteries in the limbs, is increasing in incidence and prevalence as our population is ageing and as diabetes is becoming more prevalent. PAD can cause pain in the limbs while walking, known as intermittent claudication, or can be more severe and cause pain while at rest, ulceration, and ultimately gangrene and limb loss. This more severe stage of PAD is known as 'critical limb ischaemia'. Treatments for PAD include medications that help to reduce the increased risk of cardiovascular events and help improve blood flow, as well as endovascular or surgical repair or bypass of the blocked arteries. However, many people are unresponsive to medications and are not suited to surgical or endovascular treatment, leaving amputation as the last option. Gene therapy is a novel approach in which genetic material encoding for proteins that may help increase revascularisation is injected into the affected limbs of patients. This type of treatment has been shown to be safe, but its efficacy, especially regarding ulcer healing, effects on quality of life, and other symptomatic outcomes remain unknown.
To assess the effects of gene therapy for symptomatic peripheral arterial disease.
The Cochrane Vascular Information Specialist searched Cochrane CENTRAL, the Cochrane Vascular Specialised Register, MEDLINE Ovid, Embase Ovid, CINAHL, and AMED, along with trials registries (all searched 27 November 2017). We also checked reference lists of included studies and systematic reviews for further studies.
We included randomised and quasi-randomised studies that evaluated gene therapy versus no gene therapy in people with PAD. We excluded studies that evaluated direct growth hormone treatment or cell-based treatments.
Two review authors independently selected studies, performed quality assessment, and extracted data from the included studies. We collected pertinent information on each study, as well as data for the outcomes of amputation-free survival, ulcer healing, quality of life, amputation, all-cause mortality, ankle brachial index, symptom scores, and claudication distance.
We included in this review a total of 17 studies with 1988 participants (evidence current until November 2017). Three studies limited their inclusion to people with intermittent claudication, 12 limited inclusion to people with varying levels of critical limb ischaemia, and two included people with either condition. Study investigators evaluated many different types of gene therapies, using different protocols. Most studies evaluated growth factor-encoding gene therapy, with six studies using vascular endothelial growth factor (VEGF)-encoding genes, four using hepatocyte growth factor (HGF)-encoding genes, and three using fibroblast growth factor (FGF)-encoded genes. Two studies evaluated hypoxia-inducible factor 1-alpha (HIF-1α) gene therapy, one study used a developmental endothelial locus-1 gene therapy, and the final study evaluated a stromal cell-derived factor-1 (SDF-1) gene therapy. Most studies reported outcomes after 12 months of follow-up, but follow-up ranged from three months to two years.
Overall risk of bias varied between studies, with many studies not providing sufficient detail for adequate determination of low risk of bias for many domains. Two studies did not utilise a placebo control, leading to risk of performance bias. Several studies reported in previous protocols or in their Methods sections that they would report on certain outcomes for which no data were then reported, increasing risk of reporting bias. All included studies reported sponsorships from corporate entities that led to unclear risk of other bias. The overall quality of evidence ranged from moderate to very low, generally as the result of heterogeneity and imprecision, with few or no studies reporting on outcomes.
Evidence suggests no clear differences for the outcomes of amputation-free survival, major amputation, and all-cause mortality between those treated with gene therapy and those not receiving this treatment (all moderate-quality evidence). Low-quality evidence suggests improvement in complete ulcer healing with gene therapy (odds ratio (OR) 2.16, 95% confidence interval (CI) 1.02 to 4.59; P = 0.04). We could not combine data on quality of life and can draw no conclusions at this time regarding this outcome (very low-quality evidence). We included one study in the meta-analysis for ankle brachial index, which showed no clear differences between treatments, but we can draw no overall association (low-quality evidence). We combined in a meta-analysis pain symptom scores as assessed by visual analogue scales from two studies and found no clear differences between treatment groups (very low-quality evidence). We carried out extensive subgroup analyses by PAD classification, dosage schedule, vector type, and gene used but identified no substantial differences.