Twenty-nine RCTs were included in the review. For the evaluation of antibiotic therapy, four RCTs (n=301) were included. Eight RCTs (n=446) and two non-randomised prospective controlled studies (n=140) evaluated dressings and topical agents and two RCTs (n=331) investigated the use of cultured human dermis. There was also one RCT (n=40) of casting, two RCTs (n=98) of hyperbaric oxygen therapy, two RCTs (n=201) of ketanserin, six RCTs (n=664) of growth factors, one RCT (n=40) of granulocyte-colony stimulating factor and one RCT (n=203) that investigated the use of education for patients with foot ulcers
Antibiotic therapy (4 RCTs):
Two trials addressed non-limb threatening infection, one addressed non-limb threatening, though treatment-resistant, infection, one addressed invasive infection.
The two outpatient trials of noninvasive infections found no difference between antibiotic regimens and no improvement relative to placebo. It is uncertain whether all antibiotics are ineffective in this group of patients or just the particular regimen used. The remaining two trials also found no significant difference between the treatment groups in clinical response. Despite the apparent treatment success reported by one trial (after 5 days, cure had been effected in 60% of the ampicillin/sulbactam group and 58% of the imipenem/cilastin group), 66% of their patients had a lower limb amputation during the following year, although the operation was limb sparing in most cases.
Dressings and topical agents for foot ulcers (8 RCTs and 2 controlled trials):
Trials were broadly grouped into those comparing newer dressings or gels (alginate, foam, hydrogel and hydrocolloid dressings) with gauze dressings (6 RCTs and two controlled trials) and those comparing the newer dressings with one another (2 RCTs).
For the comparison of newer dressings with gauze, although some findings appeared promising, neither a positive or negative finding could be regarded as conclusive when based on one small trial. The stated importance of the newer dressings and the inappropriateness of gauze do not appear substantiated by the limited evidence from RCTs. The two head-to-head trials comparing newer dressing technologies suggested broad equivalence but no firm conclusions could be drawn from these small unreplicated studies.
Cultured human dermis (2 industry-sponsored RCTs):
Although concerns about the trial estimates remain, a meta-analysis of trial results in terms of risk difference was conducted. Weekly Dermagraft is estimated to result in a non-significant 21% increase in ulcers healing at 12 weeks (95% CI: -13 to 56%) compared to control group.
Casting (1 RCT):
The absolute risk reduction for complete skin closure with no drainage was 58.9% (95% CI: 30.3 to78.3%) in favour of total contact casting. Mean time to ulcer healing and infections requiring hospitalisation also significantly favoured total contact casting (TCC).
Hyperbaric oxygen (2 RCTs):
One trial reported that ulcers in both groups improved significantly, but there was no significant difference between the groups at 2 weeks follow-up. One trial reported that major amputation was significantly lower in the treated group (8.6%) than the control group (33.0%) p=0.016). There were no significant differences in minor amputations. The two trials were reported to have had a number of differences that may explain their conflicting results which included severity of ulcers being investigated and the type of oxygen therapy used (topical versus to inhaled, and the use of substantially raised or sustained pressure as opposed to not).
Ketanserin (2 RCTs):
These trials report different end points, making comparison between studies problematic. The respective bioavailabilities of topical or oral ketanserin are not clear. One trial that was considered to be relatively large implied a clinically important benefit from topically applied ketanserin when used in addition to comprehensive care in relatively severe ulcers.
Growth factors (6 RCTs):
Four types of growth factor (GF) were evaluated by included trials (CT-102 which is derived from a thrombin-induced human platelet process (2 RCTs); rhPDGF which is a recombinant platelet derived GF (2 RCTs); rbFGF which is a recombinant basic fibroblast GF using Escherichia coli type beta (1 RCT); and RGDpm which is an arginine-glycine-aspartic acid peptide matrix (1RCT)).
The available trials of GFs suggest potentially important benefits from three applied GF in addition to conventional care: CT-102 (dilution 0.01), RGDpm and rhPDGF. On the basis of one small pilot study, there is no evidence for the use of rbFGF. When reported, GFs appear well tolerated, with no drug-related side-effects.
Granulocyte-colony stimulating factor (1 RCT):
There was a statistically significant reduction in median time to hospital discharge, resolution of cellulitis, withdrawal of intravenous antibiotics and negative swab culture for patients receiving G-CSF. At day 7, cellulitis had resolved in 55% of patients on G-CSF and 20% on placebo (P=0.05), and healing had occurred in 21% of patients on G-CSF and 0% on placebo (P=0.09).
Education of patients with foot ulcers (1 RCT):
The study showed a reduction in the combined end point of limbs free of infection, ulcer or amputation, favouring education (education 90%, control 72%). Although there were no significant difference in infection or mortality during follow-up, there was an excess of ulceration (education 5%, control 15%) and amputation (education 4%, control 12%) in the control group. Statistical calculations assumed 'independence' of limbs which may have resulted in over-precision.