Vitamin K antagonists versus low-molecular-weight heparin for the long term treatment of symptomatic venous thromboembolism.

BACKGROUND: People with venous thromboembolism (VTE) generally are treated for five days with intravenous unfractionated heparin or subcutaneous low-molecular-weight heparin (LMWH), followed by three months of vitamin K antagonists (VKAs). Treatment with VKAs requires regular laboratory measurements and carries risk of bleeding; some patients have contraindications to such treatment. Treatment with LMWH has been proposed to minimise the risk of bleeding complications. This is the second update of a review first published in 2001. OBJECTIVES: The purpose of this review was to evaluate the efficacy and safety of long term treatment (three months) with LMWH versus long term treatment (three months) with VKAs for symptomatic VTE. SEARCH METHODS: For this update, the Cochrane Vascular Information Specialist searched the Specialised Register (last searched November 2016) and the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 10), The Cochrane Vascular Information Specialistalso searched clinical trials registries for ongoing studies. SELECTION CRITERIA: Randomised controlled trials comparing LMWH versus VKA for long treatment (three months) of symptomatic VTE. Two review authors independently evaluated trials for inclusion and methodological quality. DATA COLLECTION AND ANALYSIS: Review authors independently extracted data and assessed risk of bias. We resolved disagreements by discussion and performed meta-analysis using fixed-effect models with Peto odds ratios (Peto ORs) and 95% confidence intervals (CIs). Outcomes of interest were recurrent VTE, major bleeding, and mortality. We used GRADE to assess the overall quality of evidence supporting these outcomes. MAIN RESULTS: Sixteen trials, with a combined total of 3299 participants fulfilled our inclusion criteria. According to GRADE, the quality of evidence was moderate for recurrent VTE, low for major bleeding, and moderate for mortality. We downgraded the quality of the evidence for imprecision (recurrent VTE, mortality) and for risk of bias and inconsistency (major bleeding).We found no clear differences in recurrent VTE between LMWH and VKA (Peto OR 0.83, 95% confidence interval (CI) 0.60 to 1.15; P = 0.27; 3299 participants; 16 studies; moderate-quality evidence). We found less bleeding with LMWH than with VKA (Peto OR 0.51, 95% CI 0.32 to 0.80; P = 0.004; 3299 participants; 16 studies; low-quality evidence). However, when comparing only high-quality studies for bleeding, we observed no clear differences between LMWH and VKA (Peto OR 0.62, 95% CI 0.36 to 1.07; P = 0.08; 1872 participants; seven studies). We found no clear differences between LMWH and VKA in terms of mortality (Peto OR 1.08, 95% CI 0.75 to 1.56; P = 0.68; 3299 participants; 16 studies; moderate-quality evidence). AUTHORS' CONCLUSIONS: Moderate-quality evidence shows no clear differences between LMWH and VKA in preventing symptomatic VTE and death after an episode of symptomatic DVT. Low-quality evidence suggests fewer cases of major bleeding with LMWH than with VKA. However, comparison of only high-quality studies for bleeding shows no clear differences between LMWH and VKA. LMWH may represent an alternative for some patients, for example, those residing in geographically inaccessible areas, those who are unable or reluctant to visit the thrombosis service regularly, and those with contraindications to VKA.

Vascular closure devices for femoral arterial puncture site haemostasis.

BACKGROUND: Vascular closure devices (VCDs) are widely used to achieve haemostasis after procedures requiring percutaneous common femoral artery (CFA) puncture. There is no consensus regarding the benefits of VCDs, including potential reduction in procedure time, length of hospital stay or time to patient ambulation. No robust evidence exists that VCDs reduce the incidence of puncture site complications compared with haemostasis achieved through extrinsic (manual or mechanical) compression. OBJECTIVES: To determine the efficacy and safety of VCDs versus traditional methods of extrinsic compression in achieving haemostasis after retrograde and antegrade percutaneous arterial puncture of the CFA. SEARCH METHODS: The Cochrane Vascular Trials Search Co-ordinator searched the Specialised Register (April 2015) and the Cochrane Central Register of Controlled Trials (CENTRAL) (2015, Issue 3). Clinical trials databases were searched for details of ongoing or unpublished studies. References of articles retrieved by electronic searches were searched for additional citations. SELECTION CRITERIA: We included randomised and quasi-randomised controlled trials in which people undergoing a diagnostic or interventional procedure via percutaneous CFA puncture were randomised to one type of VCD versus extrinsic compression or another type of VCD. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data and assessed the methodological quality of trials. We resolved disagreements by discussion with the third author. We performed meta-analyses when heterogeneity (I(2)) was < 90%. The primary efficacy outcomes were time to haemostasis and time to mobilisation (mean difference (MD) and 95% confidence interval (CI)). The primary safety outcome was a major adverse event (mortality and vascular injury requiring repair) (odds ratio (OR) and 95% CI). Secondary outcomes included adverse events. MAIN RESULTS: We included 52 studies (19,192 participants) in the review. We found studies comparing VCDs with extrinsic compression (sheath size ≤ 9 Fr), different VCDs with each other after endovascular (EVAR) and percutaneous EVAR procedures and VCDs with surgical closure after open exposure of the artery (sheath size ≥ 10 Fr). For primary outcomes, we assigned the quality of evidence according to GRADE (Grades of Recommendation, Assessment, Development and Evaluation) criteria as low because of serious imprecision and for secondary outcomes as moderate for precision, consistency and directness.For time to haemostasis, studies comparing collagen-based VCDs and extrinsic compression were too heterogenous to be combined. However, both metal clip-based (MD -14.81 minutes, 95% CI -16.98 to -12.63 minutes; five studies; 1665 participants) and suture-based VCDs (MD -14.58 minutes, 95% CI -16.85 to -12.32 minutes; seven studies; 1664 participants) were associated with reduced time to haemostasis when compared with extrinsic compression.For time to mobilisation, studies comparing collagen-, metal clip- and suture-based devices with extrinsic compression were too heterogeneous to be combined. No deaths were reported in the studies comparing collagen-based, metal clip-based or suture-based VCDs with extrinsic compression. For vascular injury requiring repair, meta-analyses demonstrated that neither collagen (OR 2.81, 95% CI 0.47 to 16.79; six studies; 5731 participants) nor metal clip-based VCDs (OR 0.49, 95% CI 0.03 to 7.95; three studies; 783 participants) were more effective than extrinsic compression. No cases of vascular injury required repair in the study testing suture-based VCD with extrinsic compression.Investigators reported no differences in the incidence of infection between collagen-based (OR 2.14, 95% CI 0.88 to 5.22; nine studies; 7616 participants) or suture-based VCDs (OR 1.66, 95% CI 0.22 to 12.71; three studies; 750 participants) and extrinsic compression. No cases of infection were observed in studies testing suture-based VCD versus extrinsic compression. The incidence of groin haematoma was lower with collagen-based VCDs than with extrinsic compression (OR 0.46, 95% CI 0.40 to 0.54; 25 studies; 10,247 participants), but no difference was evident when metal clip-based (OR 0.79, 95% CI 0.46 to 1.34; four studies; 1523 participants) or suture-based VCDs (OR 0.65, 95% CI 0.41 to 1.02; six studies; 1350 participants) were compared with extrinsic compression. The incidence of pseudoaneurysm was lower with collagen-based devices than with extrinsic compression (OR 0.74, 95% CI 0.55 to 0.99; 21 studies; 9342 participants), but no difference was noted when metal clip-based (OR 0.76, 95% CI 0.20 to 2.89; six studies; 1966 participants) or suture-based VCDs (OR 0.79, 95% CI 0.25 to 2.53; six studies; 1527 participants) were compared with extrinsic compression. For other adverse events, researchers reported no differences between collagen-based, clip-based or suture-based VCDs and extrinsic compression.Limited data were obtained when VCDs were compared with each other. Results of one study showed that metal clip-based VCDs were associated with shorter time to haemostasis (MD -2.24 minutes, 95% CI -2.54 to -1.94 minutes; 469 participants) and shorter time to mobilisation (MD -0.30 hours, 95% CI -0.59 to -0.01 hours; 469 participants) than suture-based devices. Few studies measured (major) adverse events, and those that did found no cases or no differences between VCDs.Percutaneous EVAR procedures revealed no differences in time to haemostasis (MD -3.20 minutes, 95% CI -10.23 to 3.83 minutes; one study; 101 participants), time to mobilisation (MD 1.00 hours, 95% CI -2.20 to 4.20 hours; one study; 101 participants) or major adverse events between PerClose and ProGlide. When compared with sutures after open exposure, VCD was associated with shorter time to haemostasis (MD -11.58 minutes, 95% CI -18.85 to -4.31 minutes; one study; 151 participants) but no difference in time to mobilisation (MD -2.50 hours, 95% CI -7.21 to 2.21 hours; one study; 151 participants) or incidence of major adverse events. AUTHORS' CONCLUSIONS: For time to haemostasis, studies comparing collagen-based VCDs and extrinsic compression were too heterogeneous to be combined. However, both metal clip-based and suture-based VCDs were associated with reduced time to haemostasis when compared with extrinsic compression. For time to mobilisation, studies comparing VCDs with extrinsic compression were too heterogeneous to be combined. No difference was demonstrated in the incidence of vascular injury or mortality when VCDs were compared with extrinsic compression. No difference was demonstrated in the efficacy or safety of VCDs with different mechanisms of action. Further work is necessary to evaluate the efficacy of devices currently in use and to compare these with one other and extrinsic compression with respect to clearly defined outcome measures.

Ankle brachial index for the diagnosis of lower limb peripheral arterial disease.

BACKGROUND: Peripheral arterial disease (PAD) of the lower limb is common, with prevalence of both symptomatic and asymptomatic disease estimated at 13% in the over 50 age group. Symptomatic PAD affects about 5% of individuals in Western populations between the ages of 55 and 74 years. The most common initial symptom of PAD is muscle pain on exercise that is relieved by rest and is attributed to reduced lower limb blood flow due to atherosclerotic disease (intermittent claudication). The ankle brachial index (ABI) is widely used by a variety of healthcare professionals, including specialist nurses, physicians, surgeons and podiatrists working in primary and secondary care settings, to assess signs and symptoms of PAD. As the ABI test is non-invasive and inexpensive and is in widespread clinical use, a systematic review of its diagnostic accuracy in people presenting with leg pain suggestive of PAD is highly relevant to routine clinical practice. OBJECTIVES: To estimate the diagnostic accuracy of the ankle brachial index (ABI) - also known as the ankle brachial pressure index (ABPI) - for the diagnosis of peripheral arterial disease in people who experience leg pain on walking that is alleviated by rest. SEARCH METHODS: We carried out searches of the following databases in August 2013: MEDLINE (Ovid SP),Embase (Ovid SP), the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (EBSCO), Latin American and Caribbean Health Sciences (LILACS) (Bireme), Database of Abstracts of Reviews of Effects and the Health Technology Assessment Database in The Cochrane Library, the Institute for Scientific Information (ISI) Conference Proceedings Citation Index - Science, the British Library Zetoc Conference search and Medion. SELECTION CRITERIA: We included cross-sectional studies of ABI in which duplex ultrasonography or angiography was used as the reference standard. We also included cross-sectional or diagnostic test accuracy (DTA) cohort studies consisting of both prospective and retrospective studies.Participants were adults presenting with leg pain on walking that was relieved by rest, who were tested in primary care settings or secondary care settings (hospital outpatients only) and who did not have signs or symptoms of critical limb ischaemia (rest pain, ischaemic ulcers or gangrene).The index test was ABI, also called the ankle brachial pressure index (ABPI) or the Ankle Arm Index (AAI), which was performed with a hand-held doppler or oscillometry device to detect ankle vessels. We included data collected via sphygmomanometers (both manual and aneroid) and digital equipment. DATA COLLECTION AND ANALYSIS: Two review authors independently replicated data extraction by using a standard form, which included an assessment of study quality, and resolved disagreements by discussion. Two review authors extracted participant-level data when available to populate 2×2 contingency tables (true positives, true negatives, false positives and false negatives).After a pilot phase involving two review authors working independently, we used the methodological quality assessment tool the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2), which incorporated our review question - along with a flow diagram to aid reviewers' understanding of the conduct of the study when necessary and an assessment of risk of bias and applicability judgements. MAIN RESULTS: We screened 17,055 records identified through searches of databases. We obtained 746 full-text articles and assessed them for relevance. We scrutinised 49 studies to establish their eligibility for inclusion in the review and excluded 48, primarily because participants were not patients presenting solely with exertional leg pain, investigators used no reference standard or investigators used neither angiography nor duplex ultrasonography as the reference standard. We excluded most studies for more than one reason.Only one study met the eligibility criteria and provided limb-level accuracy data from just 85 participants (158 legs). This prospective study compared the manual doppler method of obtaining an ABI (performed by untrained personnel) with the automated oscillometric method. Limb-level data, as reported by the study, indicated that the accuracy of the ABI in detecting significant arterial disease on angiography is superior when stenosis is present in the femoropopliteal vessels, with sensitivity of 97% (95% confidence interval (CI) 93% to 99%) and specificity of 89% (95% CI 67% to 95%) for oscillometric ABI, and sensitivity of 95% (95% CI 89% to 97%) and specificity of 56% (95% CI 33% to 70%) for doppler ABI. The ABI threshold was not reported. Investigators attributed the lower specificity for doppler to the fact that a tibial or dorsalis pedis pulse could not be detected by doppler in 12 of 27 legs with normal vessels or non-significant lesions. The superiority of the oscillometric (automated) method for obtaining an ABI reading over the manual method with a doppler probe used by inexperienced operators may be a clinically important finding. AUTHORS' CONCLUSIONS: Evidence about the accuracy of the ankle brachial index for the diagnosis of PAD in people with leg pain on exercise that is alleviated by rest is sparse. The single study included in our review provided only limb-level data from a few participants. Well-designed cross-sectional studies are required to evaluate the accuracy of ABI in patients presenting with early symptoms of peripheral arterial disease in all healthcare settings. Another systematic review of existing studies assessing the use of ABI in alternative patient groups, including asymptomatic, high-risk patients, is required.

D-dimer test for excluding the diagnosis of pulmonary embolism.

BACKGROUND: Pulmonary embolism (PE) can occur when a thrombus (blood clot) travels through the veins and lodges in the arteries of the lungs, producing an obstruction. People who are thought to be at risk include those with cancer, people who have had a recent surgical procedure or have experienced long periods of immobilisation and women who are pregnant. The clinical presentation can vary, but unexplained respiratory symptoms such as difficulty breathing, chest pain and an increased respiratory rate are common.D-dimers are fragments of protein released into the circulation when a blood clot breaks down as a result of normal body processes or with use of prescribed fibrinolytic medication. The D-dimer test is a laboratory assay currently used to rule out the presence of high D-dimer plasma levels and, by association, venous thromboembolism (VTE). D-dimer tests are rapid, simple and inexpensive and can prevent the high costs associated with expensive diagnostic tests. OBJECTIVES: To investigate the ability of the D-dimer test to rule out a diagnosis of acute PE in patients treated in hospital outpatient and accident and emergency (A&E) settings who have had a pre-test probability (PTP) of PE determined according to a clinical prediction rule (CPR), by estimating the accuracy of the test according to estimates of sensitivity and specificity. The review focuses on those patients who are not already established on anticoagulation at the time of study recruitment. SEARCH METHODS: We searched 13 databases from conception until December 2013. We cross-checked the reference lists of relevant studies. SELECTION CRITERIA: Two review authors independently applied exclusion criteria to full papers and resolved disagreements by discussion.We included cross-sectional studies of D-dimer in which ventilation/perfusion (V/Q) scintigraphy, computerised tomography pulmonary angiography (CTPA), selective pulmonary angiography and magnetic resonance pulmonary angiography (MRPA) were used as the reference standard.• PARTICIPANTS: Adults who were managed in hospital outpatient and A&E settings and were suspected of acute PE were eligible for inclusion in the review if they had received a pre-test probability score based on a CPR.• INDEX TESTS: quantitative, semi quantitative and qualitative D-dimer tests.• Target condition: acute symptomatic PE.• Reference standards: We included studies that used pulmonary angiography, V/Q scintigraphy, CTPA and MRPA as reference standard tests. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed quality using Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2). We resolved disagreements by discussion. Review authors extracted patient-level data when available to populate 2 × 2 contingency tables (true-positives (TPs), true-negatives (TNs), false-positives (FPs) and false-negatives (FNs)). MAIN RESULTS: We included four studies in the review (n = 1585 patients). None of the studies were at high risk of bias in any of the QUADAS-2 domains, but some uncertainty surrounded the validity of studies in some domains for which the risk of bias was uncertain. D-dimer assays demonstrated high sensitivity in all four studies, but with high levels of false-positive results, especially among those over the age of 65 years. Estimates of sensitivity ranged from 80% to 100%, and estimates of specificity from 23% to 63%. AUTHORS' CONCLUSIONS: A negative D-dimer test is valuable in ruling out PE in patients who present to the A&E setting with a low PTP. Evidence from one study suggests that this test may have less utility in older populations, but no empirical evidence was available to support an increase in the diagnostic threshold of interpretation of D-dimer results for those over the age of 65 years.

Screening for peripheral arterial disease.

BACKGROUND: In the general population, up to 10% of people younger than 70 years and 15% to 20% of people older than 70 years have peripheral arterial disease (PAD). Symptomatic and asymptomatic PAD has an estimated prevalence of 13% in the over 50 years age group. However, asymptomatic PAD can account for up to 75% of PAD patients and only 10% of PAD patients have typical intermittent claudication. People with PAD are at an increased risk of death, heart and cerebrovascular disease and are recommended to receive treatment to manage their cardiac risk. They suffer from significant functional limitations in their daily activities and the most severely affected are at risk of limb loss. Many people with PAD do not have any symptoms. Only some people have discomfort or pain in the lower legs when walking, so PAD often goes undetected. Given the high incidence of asymptomatic and undiagnosed PAD, it is important to determine the effectiveness of a screening intervention in preventing cardiovascular adverse outcomes, both fatal and non-fatal. OBJECTIVES: To determine the effectiveness of screening for PAD in asymptomatic and undiagnosed individuals in terms of reduction of all-cause mortality, cardiovascular events (for example myocardial infarction and stroke), morbidity from PAD (intermittent claudication, amputation, reduced walking distance) and improvement in quality of life. SEARCH METHODS: The Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched November 2013) and CENTRAL (2013, Issue 10). SELECTION CRITERIA: All published and unpublished randomised controlled trials (RCTs) of screening for PAD were sought without language restriction. DATA COLLECTION AND ANALYSIS: Studies identified for potential inclusion in the review were independently assessed by both review authors. We planned to conduct data collection and analysis in accordance with the Cochrane Handbook for Systematic Review of Interventions. MAIN RESULTS: No RCTs were identified that met the inclusion criteria. AUTHORS' CONCLUSIONS: Unfortunately, no randomised controlled trial data are available regarding screening for PAD. Therefore, we are unable to determine the effects of screening for PAD in order to guide decision making by healthcare providers and planners. High quality randomised controlled trials evaluating the effectiveness of screening for PAD in asymptomatic and undiagnosed individuals in terms of reduction of all-cause mortality, cardiovascular events (for example myocardial infarction and stroke), morbidity from PAD (intermittent claudication, amputation, reduced walking distance) and improvement in quality of life are needed.

Intravascular brachytherapy for peripheral vascular disease.

BACKGROUND: Interventional treatment of arteries that are narrowed and obstructed by atherosclerosis involves either bypassing the blockage using a graft; widening the artery from the inside with a balloon, a procedure known as percutaneous transluminal angioplasty (PTA); or providing a strut to hold the vessel open, known as a stent. All of these treatments are, however, limited by the high numbers that fail within a year. Intravascular brachytherapy is the application of radiation directly to the site of vessel narrowing. It is known to inhibit the processes that lead to restenosis (narrowing) of vessels and grafts after treatment. This is an update of a review first published in 2002. OBJECTIVES: To assess the efficacy of, and complications associated with, intravascular brachytherapy (IVBT) for maintaining patency after angioplasty or stent insertion in native vessels or bypass grafts of the iliac or infrainguinal arteries. SEARCH METHODS: For this update the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched their Specialised Register (last searched August 2013) and CENTRAL (2013, Issue 7). SELECTION CRITERIA: Randomised controlled trials of the use of brachytherapy as an adjunct to the endovascular treatment of people with peripheral arterial disease (PAD) or stenosed bypass grafts of the iliac or infrainguinal arteries versus the procedure without brachytherapy. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and two other review authors independently extracted the data. Adverse event information was collected from the trials. MAIN RESULTS: Eight trials with a combined total of 1090 participants were included in this review. All included studies used the femoropopliteal artery. We did not identify any studies that used the iliac arteries. All studies compared PTA with or without stenting plus IVBT versus PTA with or without stenting alone. No trials were found comparing IVBT to technologies such as drug eluting stents or balloons, or cryoplasty. Follow-up ranged from six months to five years. The quality of the included trials was moderate with our concerns relating to the difficulty of blinding due to the nature of the procedures and the small sample sizes for some studies. Primary outcomes (patency or restenosis and need for re-intervention) were reported in the majority of the trials, but reporting at various time points and the use of multiple definitions of the outcomes by the included studies meant that not all data were available for pooling. The secondary outcomes were not reported in many of the included studies.For brachytherapy, cumulative patency was higher at 24 months (odds ratio (OR) 2.36, 95% confidence interval (CI) 1.36 to 4.10, n = 222, P = 0.002). A statistically significant difference was found for restenosis at six months (OR 0.27, 95% CI 0.11 to 0.66, n = 562, P = 0.004), 12 months (OR 0.44, 95% CI 0.28 to 0.68, n = 375, P = 0.0002) and 24 months (OR 0.41, 95% CI 0.21 to 0.78, n = 164, P = 0.007) in favour of IVBT. No difference was found after five years as measured in one study. The need for re-interventions was reported in six studies. Target lesion revascularisation was significantly reduced in trial participants treated with IVBT compared with angioplasty alone (OR 0.51, 95% CI 0.27 to 0.97, P = 0.04) at six months after the interventions. No statistically significant difference was found between the procedures on the need for re-intervention at 12 and 24 months after the procedures.A statistically significant lower number of occlusions was found in the control group at more than three months (OR 11.46, 95% CI 1.44 to 90.96, n = 363, P = 0.02) but no differences were found at less than one month nor at 12 months after the procedures making the clinical significance uncertain. Ankle brachial index was statistically significantly better for IVBT at the 12 month follow-up (mean difference 0.08, 95% CI 0.02 to 0.14, n = 100, P = 0.02) but no statistically significant differences were found at 24 hours and at six months.Quality of life, complications, limb loss, cardiovascular deaths, death from all causes, pain free walking distance and maximum walking distance on a treadmill were similar for the two arms of the trials with no statistically significant difference found between the treatment groups. AUTHORS' CONCLUSIONS: The evidence for using peripheral artery brachytherapy as an adjunct to percutaneous transluminal angioplasty to maintain patency and for the prevention of restenosis in people with peripheral vascular disease is limited, mainly due to the inconsistency of assessment and reporting of clinically relevant outcomes. More data are needed on clinically relevant outcomes such as health related quality of life (HRQOL) or limb salvage and longer-term outcomes, together with comparisons with other techniques such as drug eluting balloons and stents. Adequately powered randomised controlled trials, health economics and cost-effectiveness data are required before the procedure could be recommended for widespread use.

Prostanoids for intermittent claudication.

BACKGROUND: Peripheral arterial disease (PAD) is a common cause of morbidity in the general population. While numerous studies have established the efficacy of prostanoids in PAD stages III and IV, the question of the role of prostanoids as an alternative or additive treatment in patients suffering from intermittent claudication (PAD II) has not yet been clearly answered. This is an update of a Cochrane Review first published in 2004. OBJECTIVES: To determine the effects of prostanoids in patients with intermittent claudication (IC) Fontaine stage II. SEARCH METHODS: For this update, the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator (TSC) searched the Specialised Register (last searched January 2013) and CENTRAL (2012, Issue 12). Clinical trials databases were searched for details of ongoing or unpublished studies. In addition, reference lists of relevant articles were checked. SELECTION CRITERIA: Randomised clinical trials of prostanoids versus placebo or alternative ('control') treatment in people with intermittent claudication were considered for inclusion. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. Primary outcomes included pain-free walking distance (PFWD) and maximum walking distance (MWD), presented as mean change in walking distance during the course of the trial (% improvement) and as final walking distance (that is walking distance, in metres, after treatment) for the prostanoid and control groups. MAIN RESULTS: Eighteen trials with a total of 2773 patients were included (16 in the original review and a further two in this update). As the majority of trials did not report standard deviations for the primary PFWD and MWD outcomes, it was often not possible to test for the statistical significance of any improvements in walking distance between groups. The quality of individual trials was variable and usually unclear due to insufficient reporting information. Comparison between trials was hampered by the use of different treadmill testing protocols, including different walking speeds and gradients. Such limitations in the data and the trial heterogeneity meant it was not possible to meaningfully pool results by meta-analysis.Four trials compared prostaglandin E1 (PGE1) with placebo; individual trials showed significant increases in walking distances with administration of PGE1 and in several trials the walking capacity remained increased after termination of treatment. Compared with pentoxifylline, PGE1 was associated with a higher final PFWD and MWD but these results were based on final walking distances rather than changes in walking distance from baseline. When PGE1 was compared with other treatments including laevadosin, naftidrofuryl and L-arginine, improvements in walking distances over time were observed for both PGE1 and the alternative treatment, but it was not possible from the data available to analyse statistically whether or not one treatment was more effective than the other.Six studies compared various preparations of prostacyclins (PGI2) with placebo. In one study using three different dosages of iloprost, PFWD and MWD appeared to increase in a dose-dependent manner; iloprost was associated with headache, pain, nausea and diarrhoea, leading to a higher rate of treatment withdrawal. Of three studies using beraprost sodium, one showed an improvement in PFWD and MWD compared with placebo while two showed no significant benefit. Beraprost sodium was associated with an increased incidence of drug-related adverse events. Of two studies on taprostene, the results of one in particular must be interpreted with caution due to an imbalance in walking capacity at baseline.Comprehensive, high quality data on outcomes such as quality of life, ankle brachial index, venous occlusion plethysmography and haemorrheological parameters were lacking. AUTHORS' CONCLUSIONS: Whilst results from some individual studies suggested a beneficial effect of PGE1, the quality of these studies and of the overall evidence available is insufficient to determine whether or not patients with intermittent claudication derive clinically meaningful benefit from the administration of prostanoids. Further well-conducted randomised, double blinded trials with a sufficient number of participants to provide statistical power are required to answer this question.

Homocysteine lowering interventions for peripheral arterial disease and bypass grafts.

BACKGROUND: Elevated plasma levels of the amino acid homocysteine (hyperhomocysteinaemia) are associated with narrowing or blocking of the arteries (atherosclerosis). Treatment to lower homocysteine levels has been shown to be both effective and cheap in healthy volunteers. However, the impact of reducing homocysteine levels on the progression of atherosclerosis and patency of the vessels after treatment for atherosclerosis is still unknown and forms the basis for this review. This is the second update of a review first published in 2002. OBJECTIVES: To assess the effects of plasma homocysteine lowering therapy on the clinical progression of disease in people with peripheral arterial disease (PAD) and hyperhomocysteinaemia including, as a subset, those who have undergone surgical or radiological intervention. SEARCH METHODS: For this update, the Cochrane Peripheral Vascular Disease Group Trials Search Co-ordinator (TSC) searched the Specialised Register (last searched January 2013) and CENTRAL (2012, Issue 12). Trial databases were searched by the TSC (January 2013) for details of ongoing and unpublished studies. We also searched the reference lists of relevant articles. SELECTION CRITERIA: Randomised trials in which participants with PAD and hyperhomocysteinaemia were allocated to either homocysteine lowering therapy or no treatment, including participants before and after surgical or radiological interventions. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted the data. Information on adverse events was collected from the trials. MAIN RESULTS: Two randomised trials with a total of 161 participants were included in this review. The studies did not report on mortality and rate of limb loss. One randomised trial with a total of 133 participants showed that there was a significant improvement in ankle brachial index (ABI) in participants who received folic acid compared with placebo (mean difference (MD) 0.07, 95% confidence interval (CI) 0.04 to 0.11, P < 0.001) and in participants who received 5-methyltetrahydrofolate (5-MTHF) versus placebo (MD 0.05, 95% CI 0.01 to 0.10, P = 0.009). A second trial with a total of 18 participants showed that there was no difference (P non-significant) in ABI in participants who received a multivitamin B supplement (mean ± SEM: 0.7 ± 01) compared with placebo (mean ± SEM: 0.8 ± 0.1). No major events were reported. AUTHORS' CONCLUSIONS: Currently, no recommendation can be made regarding the value of treatment of hyperhomocysteinaemia in peripheral arterial disease. Further, well constructed trials are urgently required.

Cryoplasty for peripheral arterial disease.

BACKGROUND: Percutaneous balloon angioplasty is an endovascular technique for restoring blood flow through an artery that has become narrowed or blocked by atherosclerosis. Narrowing of the artery following angioplasty (restenosis) is the major cause of long-term failure. Cryoplasty offers a different approach to improving long-term angioplasty results. It combines the dilation force of balloon angioplasty with cooling of the vessel wall. This systematic review evaluated cryoplasty in peripheral arterial disease and provides focus for further research in the field. This is an update of a review first published in 2007. OBJECTIVES: To assess the efficacy of, and complications associated with, cryoplasty for maintaining patency in the iliac, femoropopliteal and crural arteries in the short and medium term. SEARCH METHODS: For this update the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched October 2012) and CENTRAL (2012, Issue 10). Trial databases were searched for ongoing or unpublished studies. We also searched the reference lists of relevant articles. SELECTION CRITERIA: All randomised controlled trials in which participants with peripheral arterial disease (PAD) of the lower limbs, or lower limb bypass graft stenoses, were randomised to cryoplasty with or without another procedure versus a procedure without cryoplasty were considered. This included trials where all participants received angioplasty and the randomisation was for cryoplasty versus no cryoplasty and trials where cryoplasty was used as an adjunct to conventional treatment (for example stenting) against a control. DATA COLLECTION AND ANALYSIS: Two review authors independently reviewed, assessed and selected trials, extracted data and assessed risk of bias. MAIN RESULTS: Seven trials (six primary cryoplasty and one adjunctive cryoplasty trial) with a combined total of 478 patients were included in this review. The trials reported patency and restenosis either by participant, lesion or vessel location. Follow-up ranged from 30 days to three years.Target lesion patency measured at various time points in two primary cryoplasty trials showed no statistically significant difference between the treatment groups. The adjunctive cryoplasty study showed that cryoplasty was associated with improved patency only at six months (OR 5.37, 95% CI 1.09 to 26.49, n = 90).Restenosis measured per patient (two primary cryoplasty trials) showed no statistically significant difference between the treatments. Restenosis measured by lesion (two primary cryoplasty trials) showed a statistically significant difference only within 24 hours of the procedure (OR 0.08, 95% CI 0.04 to 0.18, n = 192) favouring cryoplasty.Need for re-intervention was not significantly different in primary cryoplasty trial participants (per participant: OR 0.27, 95% CI 0.05 to 1.52, n = 241, I(2) = 89%; per lesion: OR 0.59, 95% CI 0.06 to 5.69, n = 307, I(2) = 94%). The adjunctive cryoplasty trial did not report on need for intervention.Immediate success of procedure (within 24 hours) was not significantly different in primary cryoplasty trial participants (per participant: OR 1.63, 95% CI 0.14 to 19.55, n = 340, I(2) = 95%; per lesion: OR 1.81, 95% CI 0.19 to 17.36, n = 397, I(2) = 90%). The adjunctive cryoplasty trial reported 100% success.Limb loss, deaths from all causes and the risk of complications immediately after treatment showed no statistically significant differences between the treatments. AUTHORS' CONCLUSIONS: The benefit of cryoplasty over conventional angioplasty cannot be established as the number of randomised controlled trials is small and their quality is not sufficiently high. The technical success and primary patency rates seen in these trials are inconsistent and do not necessarily suggest a future role for cryoplasty in the treatment of PAD, but they cannot be reliably interpreted. Currently there are insufficient data to support the routine use of cryoplasty over conventional balloon angioplasty in the treatment of PAD.

Vitamin K antagonists or low-molecular-weight heparin for the long term treatment of symptomatic venous thromboembolism.

BACKGROUND: People with venous thromboembolism (VTE) are generally treated for five days with intravenous unfractionated heparin or subcutaneous low-molecular-weight heparin (LMWH) followed by three months of vitamin K antagonist treatment. Treatment with vitamin K antagonists requires regular laboratory measurements and some patients have contraindications to treatment. This is an update of a review first published in 2000 and updated in 2002. OBJECTIVES: To evaluate the efficacy and safety of long term treatment of VTE with LMWH compared to vitamin K antagonists. SEARCH METHODS: For this update the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched their Specialised Register (last searched February 2012) and CENTRAL (2012, Issue 1). SELECTION CRITERIA: Two authors evaluated trials independently for methodological quality. DATA COLLECTION AND ANALYSIS: The review authors extracted data independently. Primary analysis included all trial participants randomised to the allocated treatment groups. Separate analyses were performed according to the quality of the trials and for subgroups such as trials initially using similar treatments in both trial arms and those that did not, trials concerning deep vein thrombosis (DVT) and pulmonary embolism (PE) and the different periods of follow-up. MAIN RESULTS: All 15 trials, with a combined total of 3197 patients, fulfilling our criteria were combined in a meta-analysis. We found a non-statistically significant reduction in the risk of recurrent VTE between the two treatments (odds ratio (OR) 0.82, 95% CI 0.59 to 1.13). Analysis of pooled data for category I trials (those with a high methodological quality) showed a non-significant reduction in the odds of recurrent VTE favouring LMWH treatment (OR 0.80, 95% CI 0.54 to 1.18).For all trials combined, the difference in bleeding significantly favoured treatment with LMWH (OR 0.50, 95% CI 0.31 to 0.79). Considering only category I trials, a non-significant trend favouring LMWH remained (OR 0.62, 95% CI 0.36 to 1.07). No difference was observed in mortality (OR 1.06, 95% CI 0.74 to 1.54). AUTHORS' CONCLUSIONS: LMWHs are possibly as effective as vitamin K antagonists in preventing symptomatic VTE after an episode of symptomatic deep venous thrombosis, but are much more expensive. Treatment with LMWH is significantly safer than treatment with vitamin K antagonists. LMWH may result in fewer episodes of bleeding and is possibly a safe alternative in some patients, especially those in geographically inaccessible areas, are reluctant to visit the thrombosis service regularly, or with contraindications to vitamin K antagonists. However, treatment with vitamin K antagonists remains the treatment of choice for the majority of patients.

Exploring the cultural effects of gender on perceptions of cutaneous leishmaniasis: a systematic literature review.

BACKGROUND: More than one million people each year become infected by parasites that cause the disease cutaneous leishmaniasis (CL). This disease manifests as one or more skin lesions or ulcers that are slow to heal with variable response rates to drug treatments. Thus far, little attention has been paid to how the cultural effects of gender shape perceptions and experiences of CL. This review aims to bring together and analyse existing studies which use qualitative data to explore these differences. These studies offered insights into our specific research questions. METHODS: We conducted a systematic review of the literature pertaining to either CL or muco-cutaneous leishmaniasis (MCL) through EBSCO, EMBASE, Medline, Scopus and Web of Science databases. To meet inclusion criteria, articles had to be either qualitative or mixed-method with a qualitative component. They also had to include a reflection on how the gender of participants impacted the findings and addressed the lived experiences of CL. We did not exclude articles based on the language they were published in or in which country the study took place. RESULTS: From a total of 1589 potential articles, we found that thirteen met the inclusion criteria. These articles were published in English, Spanish or Portuguese and reported on studies carried out in various countries in Africa, Asia and South America. After using the principles of a meta-ethnography to analyse these studies, we generated several key themes. We found that health-seeking behaviours, treatment choices, stigma and the impact of scarring are shaped by gender in a variety of contexts. CONCLUSIONS: Gender impacts on an individual's experience of CL. In particular, women are more constricted in their health-seeking behaviours and experience more stigma both from the active lesions and from scarring than men. In many contexts, however, men are more at risk of becoming infected by the parasite that causes CL and may turn to more harmful or aggressive self-treatments. We recommend that future research on CL should consider the impact of gender as this can create very different experiences for individuals.

Protocol for establishing a child and adolescent twin register for mental health research and capacity building in Sri Lanka and other low and middle-income countries in South Asia.

INTRODUCTION: Worldwide, 10%-20% of children and adolescents experience mental health conditions. However, most such disorders remain undiagnosed until adolescence or adulthood. Little is known about the factors that influence mental health in children and adolescents, especially in low and middle-income countries (LMIC), where environmental threats, such as poverty and war, may affect optimal neurodevelopment. Cohort studies provide important information on risks and resilience across the life course by enabling tracking of the effects of early life environment on health during childhood and beyond. Large birth cohort studies, including twin cohorts that can be aetiologically informative, have been conducted within high-income countries but are not generalisable to LMIC. There are limited longitudinal birth cohort studies in LMIC. METHODS: We sought to enhance the volume of impactful research in Sri Lanka by establishing a Centre of Excellence for cohort studies. The aim is to establish a register of infant, child and adolescent twins, including mothers pregnant with twins, starting in the districts of Colombo (Western Province) and Vavuniya (Northern Province). We will gain consent from twins or parents for future research projects. This register will provide the platform to investigate the aetiology of mental illness and the impact of challenges to early brain development on future mental health. Using this register, we will be able to conduct research that will (1) expand existing research capacity on child and adolescent mental health and twin methods; (2) further consolidate existing partnerships and (3) establish new collaborations. The initiative is underpinned by three pillars: high-quality research, ethics, and patient and public involvement and engagement (PPIE). ETHICS AND DISSEMINATION: Ethical approval for this study was obtained from the Ethics Review Committee of Sri Lanka Medical Association and Keele University's Ethical Review Panel. In addition to journal publications, a range of PPIE activities have been conducted.

Ecological network analysis: an application to the evaluation of effects of pesticide use in an agricultural environment.

Ecological network analysis is used to evaluate the impact of pesticide use on ecological systems in the context of agricultural farmland environments. The aim is to provide support for the design of effective and minimally damaging pest control strategies. The ecological network analysis can identify species that are important to the integrity of the ecological network. The methodology can be used to monitor the impact of shifts in terms of types of pesticide used on the ecological system. The authors' intention is to use this methodology to provide supporting evidence for the UK Voluntary Initiative programme aimed at convincing farmers voluntarily to make improved choices in the use of a wide range of pesticides.

Type 2 diabetes: A side effect of the adaptation of neurons and fat cells to support increased cognitive performance.

Type 2 diabetes is a serious disease that is affecting an increasing part of the population in most countries. A new hypothesis is presented in this paper about the underlying causes and mechanisms that lead to the development of this disease. It is proposed that the disease is the price that the organism pays for having improved cognitive performance that is achieved through increased level of neurite growth dynamics of neurons. The suggested mechanism of the disease development involves neural centres that deal with the sensing of fat and sugar levels in the blood and cerebro-spinal fluid, the regulation of the mobilisation of these resources in the body, the regulation of the storage of sugar and fat in the body, and the regulation of feeding behaviour. The key idea of the proposed mechanism is that the hypothesised resource mobilisation neural centre overestimates the resource needs of neurons and generates and inflated resource requesting signals. The paper discusses how short- and long-term equilibrium regulation of fat and sugar resources may emerge and how this regulation may get imbalanced leading to the emergence of type 2 diabetes in the animal or human. The paper proposes a number of experimental tests that can confirm or deny the validity of the hypothesis formulated here. Possible implications for development of new drugs aimed to prevent or reduce the negative impacts of type 2 diabetes are also discussed.

Synaptic proteins and choline acetyltransferase loss in visual cortex in dementia with Lewy bodies.

Functional neuroimaging studies have consistently reported abnormalities in the visual cortex in patients with dementia with Lewy bodies (DLB), but their neuropathologic substrates are poorly understood. We analyzed synaptic proteins and choline acetyltransferase (ChAT) in the primary (BA17) and association (BAs18/19) visual cortex in DLB and similar aged control and Alzheimer disease (AD) subjects. We found lower levels of synaptophysin, syntaxin, SNAP-25, and γ-synuclein in DLB subjects versus both aged control (68%-78% and 27%-72% for BA17 and BAs18/19, respectively) and AD cases (54%-67% and 10%-56% for BA17 and BAs18/19, respectively). The loss in ChAT activity in DLB cases was also greater in BA17 (72% and 87% vs AD and control values, respectively) than in BAs18/19 (52% and 65% vs AD and control groups, respectively). The observed synaptic and ChAT changes in the visual cortices were not associated with tau or ß-amyloid pathology in the occipital or the frontal, temporal, and parietal neocortex. However, the neocortical densities of LBs, particular those in BA17 and BAs18/19, correlated with lower synaptic and ChAT levels in these brain areas. These findings draw attention to molecular changes within the primary visual cortex in DLB and correlate with the neuroimaging findings within the occipital lobe in patients with this disorder.