Dressings and topical agents for arterial leg ulcers.

BACKGROUND: It is estimated that up to 1% of people in high-income countries suffer from a leg ulcer at some time in their life. The majority of leg ulcers are associated with circulation problems; poor blood return in the veins causes venous ulcers (around 70% of ulcers) and poor blood supply to the legs causes arterial ulcers (around 22% of ulcers). Treatment of arterial leg ulcers is directed towards correcting poor arterial blood supply, for example by correcting arterial blockages (either surgically or pharmaceutically). If the blood supply has been restored, these arterial ulcers can heal following principles of good wound-care. Dressings and topical agents make up a part of good wound-care for arterial ulcers, but there are many products available, and it is unclear what impact these have on ulcer healing. This is the third update of a review first published in 2003. OBJECTIVES: To determine whether topical agents and wound dressings affect healing in arterial ulcers. To compare healing rates and patient-centred outcomes between wound dressings and topical agents. SEARCH METHODS: The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, Cochrane Central Register of Controlled Trials, MEDLINE, Embase, Cumulative Index to Nursing and Allied Health Literature and Allied and Complementary Medicine databases, the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials register to 28 January 2019. SELECTION CRITERIA: Randomised controlled trials (RCTs), or controlled clinical trials (CCTs) evaluating dressings and topical agents in the treatment of arterial leg ulcers were eligible for inclusion. We included participants with arterial leg ulcers irrespective of method of diagnosis. Trials that included participants with mixed arterio-venous disease and diabetes were eligible for inclusion if they presented results separately for the different groups. All wound dressings and topical agents were eligible for inclusion in this review. We excluded trials which did not report on at least one of the primary outcomes (time to healing, proportion completely healed, or change in ulcer area). DATA COLLECTION AND ANALYSIS: Two review authors independently extracted information on the participants' characteristics, the interventions, and outcomes using a standardised data extraction form. Review authors resolved any disagreements through discussion. We presented the data narratively due to differences in the included trials. We used GRADE to assess the certainty of the evidence. MAIN RESULTS: Two trials met the inclusion criteria. One compared 2% ketanserin ointment in polyethylene glycol (PEG) with PEG alone, used twice a day by 40 participants with arterial leg ulcers, for eight weeks or until healing, whichever was sooner. One compared topical application of blood-derived concentrated growth factor (CGF) with standard dressing (polyurethane film or foam); both applied weekly for six weeks by 61 participants with non-healing ulcers (venous, diabetic arterial, neuropathic, traumatic, or vasculitic). Both trials were small, reported results inadequately, and were of low methodological quality. Short follow-up times (six and eight weeks) meant it would be difficult to capture sufficient healing events to allow us to make comparisons between treatments. One trial demonstrated accelerated wound healing in the ketanserin group compared with the control group. In the trial that compared CGF with standard dressings, the number of participants with diabetic arterial ulcers were only reported in the CGF group (9/31), and the number of participants with diabetic arterial ulcers and their data were not reported separately for the standard dressing group. In the CGF group, 66.6% (6/9) of diabetic arterial ulcers showed more than a 50% decrease in ulcer size compared to 6.7% (2/30) of non-healing ulcers treated with standard dressing. We assessed this as very-low certainty evidence due to the small number of studies and arterial ulcer participants, inadequate reporting of methodology and data, and short follow-up period. Only one trial reported side effects (complications), stating that no participant experienced these during follow-up (six weeks, low-certainty evidence). It should also be noted that ketanserin is not licensed in all countries for use in humans. Neither study reported time to ulcer healing, patient satisfaction or quality of life. AUTHORS' CONCLUSIONS: There is insufficient evidence to determine whether the choice of topical agent or dressing affects the healing of arterial leg ulcers.

Outpatient versus inpatient treatment for acute pulmonary embolism.

BACKGROUND: Pulmonary embolism (PE) is a common life-threatening cardiovascular condition, with an incidence of 23 to 69 new cases per 100,000 people each year. For selected low-risk patients with acute PE, outpatient treatment might provide several advantages over traditional inpatient treatment, such as reduction of hospitalisations, substantial cost savings, and improvements in health-related quality of life. This is an update of the review first published in 2014. OBJECTIVES: To compare the efficacy and safety of outpatient versus inpatient treatment in low-risk patients with acute PE for the outcomes of all-cause and PE-related mortality; bleeding; adverse events such as haemodynamic instability; recurrence of PE; and patients' satisfaction. SEARCH METHODS: The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, CINAHL and AMED databases, and the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers, to 26 March 2018. We also undertook reference checking to identify additional studies. SELECTION CRITERIA: We included randomised controlled trials of outpatient versus inpatient treatment of adults (aged 18 years and over) diagnosed with low-risk acute PE. DATA COLLECTION AND ANALYSIS: Two review authors selected relevant trials, assessed methodological quality, and extracted and analysed data. We calculated effect estimates using risk ratio (RR) with 95% confidence intervals (CIs), or mean differences (MDs) with 95% CIs. We used standardised mean differences (SMDs) to combine trials that measured the same outcome but used different methods. We assessed the quality of the evidence using GRADE criteria. MAIN RESULTS: One new study was identified for this 2018 update, bringing the total number of included studies to two and the total number of participants to 451. Both trials discharged patients randomised to the outpatient group within 36 hours of initial triage and both followed participants for 90 days. One study compared the same treatment regimens in both outpatient and inpatient groups, and the other study used different treatment regimes. There was no clear difference in treatment effect for the outcomes of short-term mortality (30 days) (RR 0.33, 95% CI 0.01 to 7.98, P = 0.49; low-quality evidence), long-term mortality (90 days) (RR 0.98, 95% CI 0.06 to 15.58, P = 0.99, low-quality evidence), major bleeding at 14 days (RR 4.91, 95% CI 0.24 to 101.57, P = 0.30; low-quality evidence) and at 90 days (RR 6.88, 95% CI 0.36 to 132.14, P = 0.20; low-quality evidence), minor bleeding (RR 1.08, 95% CI 0.07 to 16.79; P = 0.96, low-quality evidence), recurrent PE within 90 days (RR 2.95, 95% CI 0.12 to 71.85, P = 0.51, low-quality evidence), and participant satisfaction (RR 0.97, 95% CI 0.90 to 1.04, P = 0.39; moderate-quality evidence). We downgraded the quality of the evidence because the CIs were wide and included treatment effects in both directions, the sample sizes and numbers of events were small, and because the effect of missing data and the absence of publication bias could not be verified. PE-related mortality, and adverse effects such as haemodynamic instability and compliance, were not assessed by the included studies. AUTHORS' CONCLUSIONS: Currently, only low-quality evidence is available from two published randomised controlled trials on outpatient versus inpatient treatment in low-risk patients with acute PE. The studies did not provide evidence of any clear difference between the interventions in overall mortality, bleeding and recurrence of PE.

Rutosides for treatment of post-thrombotic syndrome.

BACKGROUND: Post-thrombotic syndrome (PTS) is a long-term complication of deep venous thrombosis (DVT) that is characterised by pain, swelling, and skin changes in the affected limb. One in three patients with DVT will develop post-thrombotic sequelae within five years. Rutosides are a group of compounds derived from horse chestnut (Aesculus hippocastanum), a traditional herbal remedy for treating oedema formation in chronic venous insufficiency (CVI). However, it is not known whether rutosides are effective and safe in the treatment of PTS. This is the second update of the review first published in 2013. OBJECTIVES: To determine the effectiveness (improvement or deterioration in symptoms) and safety of rutosides for treatment of post-thrombotic syndrome (PTS) in patients with DVT compared to placebo, no intervention, elastic compression stockings (ECS) or any other treatment. SEARCH METHODS: The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase and CINAHL databases and World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers to 21 August 2018. SELECTION CRITERIA: Two review authors independently assessed studies for inclusion. Studies were included to allow the comparison of rutosides versus placebo or no treatment, rutosides versus ECS, and rutosides versus any other treatment. Two review authors extracted information from the trials. Disagreements were resolved by discussion. DATA COLLECTION AND ANALYSIS: Data were extracted using designated data extraction forms. The Cochrane 'Risk of bias' tool was used for all included studies to assist in the assessment of quality. Primary outcome measures were the occurrence of leg ulceration over time (yes or no) and any improvement or deterioration of post-thrombotic syndrome (yes or no). Secondary outcomes included reduction of oedema, pain, recurrence of DVT or pulmonary embolism, compliance with therapy, and adverse effects. All of the outcome measures were analysed using Mantel-Haenzel fixed-effect model odds ratios. The unit of analysis was the number of patients. We used GRADE to assess the quality of the evidence for each outcome. MAIN RESULTS: Ten reports of nine studies were identified following searching and three studies with a total of 233 participants met the inclusion criteria. Overall quality of evidence using the GRADE approach was low, predominantly due to the lack of both participant and researcher blinding in the included studies. The quality of the evidence was further limited as only three small studies contributed to the review findings. A subjective scoring system was used to obtain the symptoms of PTS so it was important that the assessors were blinded to the intervention. One study compared rutosides with placebo, one study compared rutosides with ECS and rutosides plus ECS versus ECS alone, and one study compared rutosides with an alternative venoactive remedy. Occurrence of leg ulceration was not reported in any of the included studies. There was no clear evidence to support a difference in PTS improvement between the rutosides or placebo/no treatment groups (OR 1.29, 95% CI 0.69 to 2.41; 164 participants; 2 studies; low-quality evidence); or between the rutosides and ECS groups (OR 0.80, 95% CI 0.31 to 2.03; 80 participants; 1 study ; low-quality evidence). Results from one small study reported less PTS improvement in the rutosides group compared to an alternative venoactive remedy (OR 0.18, 95% CI 0.04 to 0.94; 29 participants; 1 study; low-quality evidence). There was no clear evidence to support a difference in PTS deterioration when comparing rutosides with placebo/no treatment (OR 0.61, 95% CI 0.19 to 1.90; 80 participants; 1 study); with ECS (OR 0.61, 95% CI 0.19 to 1.90; 80 participants; 1 study); or an alternative venoactive remedy (OR 0.19, 95% CI 0.01 to 4.24; 29 participants; 1 study). No clear evidence of a difference in adverse effects between the rutosides and placebo/no treatment groups was seen ('mild side effects' reported in 7/41 and 5/42 respectively). In the study comparing rutosides with ECS, 2/80 could not tolerate ECS and 6/80 stopped medication due to side effects. The study comparing rutosides with an alternative venoactive remedy did not comment on side effects AUTHORS' CONCLUSIONS: There was no evidence that rutosides were superior to the use of placebo or ECS. Overall, there is currently limited low-quality evidence that 'venoactive' or 'phlebotonic' remedies such as rutosides reduce symptoms of PTS. Mild side effects were noted in one study. The three studies included in this review provide no evidence to support the use of rutosides in the treatment of PTS.

Subretinal delivery of adeno-associated virus serotype 2 results in minimal immune responses that allow repeat vector administration in immunocompetent mice.

BACKGROUND: Adeno-associated virus serotype 2 (AAV2) vectors show considerable promise for ocular gene transfer. However, one potential barrier to efficacious long-term therapy is the development of immune responses against the vector or transgene product. METHODS: We evaluated cellular and humoral responses in mice following both single and repeated subretinal administration of AAV2, and examined their effects on RPE65 and green fluorescent protein transgene expression. RESULTS: Following subretinal administration of vector, splenocytes and T-cells from draining lymph nodes showed minimal activation following stimulation by co-culture with AAV2. Neutralizing antibodies (NAbs) were not detected in the ocular fluids of any mice receiving AAV2 or in the serum of mice receiving a lower dose. NAbs were present in the serum of a proportion of mice receiving a higher dose of the vector. Furthermore, no differences in immunoglobulin titre in serum or ocular fluids against RPE65 protein or AAV2 capsid between treated and control mice were detected. Histological examination showed no evidence of retinal toxicity or leukocyte infiltration compared to uninjected eyes. Repeat administration of low-dose AAV.hRPE65.hRPE65 to both eyes of RPE65(-/-) mice resulted in transgene expression and functional rescue, but re-administration of high-dose AAV2 resulted in boosted NAb titres and variable transgene expression in the second injected eye. CONCLUSIONS: These data, which were obtained in mice, suggest that, following subretinal injection, immune responses to AAV2 are dose-dependent. Low-dose AAV2 is well tolerated in the eye, with minimal immune responses, and transgene expression after repeat administration of vector is achievable. Higher doses lead to the expression of NAbs that reduce the efficacy of repeated vector administration.