Cost-effectiveness analysis of a randomized clinical trial of early versus deferred endovenous ablation of superficial venous reflux in patients with venous ulceration.

BACKGROUND: Treatment of superficial venous reflux in addition to compression therapy accelerates venous leg ulcer healing and reduces ulcer recurrence. The aim of this study was to evaluate the costs and cost-effectiveness of early versus delayed endovenous treatment of patients with venous leg ulcers. METHODS: This was a within-trial cost-utility analysis with a 1-year time horizon using data from the EVRA (Early Venous Reflux Ablation) trial. The study compared early versus deferred endovenous ablation for superficial venous truncal reflux in patients with a venous leg ulcer. The outcome measure was the cost per quality-adjusted life-year (QALY) over 1 year. Sensitivity analyses were conducted with alternative methods of handling missing data, alternative preference weights for health-related quality of life, and per protocol. RESULTS: After early intervention, the mean(s.e.m.) cost was higher (difference in cost per patient £163(318) (€184(358))) and early intervention was associated with more QALYs at 1 year (mean(s.e.m.) difference 0·041(0·017)). The incremental cost-effectiveness ratio (ICER) was £3976 (€4482) per QALY. There was an 89 per cent probability that early venous intervention is cost-effective at a threshold of £20 000 (€22 546)/QALY. Sensitivity analyses produced similar results, confirming that early treatment of superficial reflux is highly likely to be cost-effective. CONCLUSION: Early treatment of superficial reflux is highly likely to be cost-effective in patients with venous leg ulcers over 1 year. Registration number: ISRCTN02335796 (http://www.isrctn.com).

Graduated Compression Stockings as an Adjunct to Low Dose Low Molecular Weight Heparin in Venous Thromboembolism Prevention in Surgery: A Multicentre Randomised Controlled Trial.

BACKGROUND: The evidence base upon which current global venous thromboembolism (VTE) prevention recommendations have been made is not optimal. The cost of purchasing and applying graduated compression stockings (GCS) in surgical patients is considerable and has been estimated at £63.1 million per year in England alone. OBJECTIVE: The aim was to determine whether low dose low molecular weight heparin (LMWH) alone is non-inferior to a combination of GCS and low dose LMWH for the prevention of VTE. METHODS: The randomised controlled Graduated compression as an Adjunct to Pharmacoprophylaxis in Surgery (GAPS) Trial (ISRCTN 13911492) will randomise adult elective surgical patients identified as being at moderate and high risk of VTE to receive either the current "standard" combined thromboprophylactic LMWH with GCS mechanical thromboprophylaxis, or thromboprophylactic LMWH pharmacoprophylaxis alone. To show non-inferiority (3.5% non-inferiority margin) for the primary endpoint of all VTE within 90 days, 2236 patients are required. Recruitment will be from seven UK centres. Secondary outcomes include quality of life, compliance with stockings and LMWH, overall mortality, and GCS or LMWH related complications (including bleeding). Recruitment commenced in April 2016 with the seven UK centres coming "on-line" in a staggered fashion. Recruitment will be over a total of 18 months. The GAPS trial is funded by the National Institute for Health Research Health Technology Assessment in the UK (14/140/61).

Observations from the IMPROVE trial concerning the clinical care of patients with ruptured abdominal aortic aneurysm.

BACKGROUND: Single-centre series of the management of patients with ruptured abdominal aortic aneurysm (AAA) are usually too small to identify clinical factors that could improve patient outcomes. METHODS: IMPROVE is a pragmatic, multicentre randomized clinical trial in which eligible patients with a clinical diagnosis of ruptured aneurysm were allocated to a strategy of endovascular aneurysm repair (EVAR) or to open repair. The influences of time and manner of hospital presentation, fluid volume status, type of anaesthesia, type of endovascular repair and time to aneurysm repair on 30-day mortality were investigated according to a prespecified plan, for the subgroup of patients with a proven diagnosis of ruptured or symptomatic AAA. Adjustment was made for potential confounding factors. RESULTS: Some 558 of 613 randomized patients had a symptomatic or ruptured aneurysm: diagnostic accuracy was 91·0 per cent. Patients randomized outside routine working hours had higher operative mortality (adjusted odds ratio (OR) 1·47, 95 per cent confidence interval 1·00 to 2·17). Mortality rates after primary and secondary presentation were similar. Lowest systolic blood pressure was strongly and independently associated with 30-day mortality (51 per cent among those with pressure below 70 mmHg). Patients who received EVAR under local anaesthesia alone had greatly reduced 30-day mortality compared with those who had general anaesthesia (adjusted OR 0·27, 0·10 to 0·70). CONCLUSION: These findings suggest that the outcome of ruptured AAA might be improved by wider use of local anaesthesia for EVAR and that a minimum blood pressure of 70 mmHg is too low a threshold for permissive hypotension.

Treatment decisions for descending thoracic aneurysm: preferences for thoracic endovascular aneurysm repair or surveillance in a discrete choice experiment.

OBJECTIVE: To investigate and rank factors that influence endovascular treatment decisions by specialists for patients with descending thoracic aortic aneurysm (dTAA). METHODS: Specialists completed a diagrammatic survey describing uncertainty about the benefit of thoracic endovascular aneurysm repair (TEVAR) for dTAA with respect to age, sex, and aneurysm diameter. Subsequently, a detailed discrete choice experiment was designed. Specialists were recruited and asked to indicate treatment their preference (TEVAR or surveillance) in 25 hypothetical cases of dTAA, with variable patient attributes: age, sex, American Society of Anesthesiologists (ASA) grade, aneurysm diameter, adequate landing zone distal to left subclavian artery (LSA), and length of aortic coverage. Data were analysed using multiple logistic regression. RESULTS: The diagrammatic survey, based on 50 respondents, showed that uncertainty about the benefits of TEVAR was greatest for patients aged 80-85 years (up to 47% of respondents were "unsure") and that uncertainty increased with increasing aneurysm diameter (for an 80-year-old man, 7% were unsure at 5.5 cm and 33% were unsure at 7.0 cm). Seventy-one specialists (mainly from Europe and North America, 86% vascular surgeons and 98% working in units offering TEVAR) completed the discrete choice experiment. Preference for TEVAR increased greatly with enlarging diameter: adjusted odds ratios (OR) >5.5-6.0 cm = 15.8 (95% confidence interval [CI] 9.83-25.40); >6.0-6.5 cm = 393.0 (95% CI 202.00-766.00); >6.5-7.0 cm = 1829.0 (95% CI 400.00-4,181.00). TEVAR was less likely to be preferred in patients older than 75 years (>75-80 years OR 0.32, 95% CI 0.21-0.49; >80-85 years = 0.18, 95% CI 0.11-0.28); in women (OR 0.52, 95% CI 0.37-0.74); in patients classified as ASA grade 4 (OR 0.44, 95% CI 0.36-0.57); and in patients with aorta coverage >25 cm (OR 0.48, 95% CI 0.32-0.74). The proximal landing zone did not influence preference. CONCLUSION: Specialists' preferences for endovascular repair of degenerative dTAA vary widely, and demonstrate clinical uncertainty, especially in octogenarians, and a reluctance to offer TEVAR to women. Aneurysm diameter dominates treatment preferences, but patient fitness and length of aortic coverage (>25 cm) also were influential, although the landing zone distal to LSA was not.

Cost-effectiveness of treatments for superficial venous reflux in patients with chronic venous ulceration.

BACKGROUND: Venous leg ulcers impair quality of life significantly, with substantial costs to health services. The aim of this study was to estimate the cost-effectiveness of interventional procedures alongside compression therapy versus compression therapy alone for the treatment of chronic venous leg ulceration. METHODS: A Markov decision analytical model was developed. The main outcome measures were quality-adjusted life-years (QALYs) and lifetime costs per patient, from the perspective of the UK National Health Service at 2015 prices. Resource use included the initial procedures, compression therapy, primary care and outpatient consultations. The interventional procedures included superficial venous surgery, endothermal ablation and ultrasound-guided foam sclerotherapy (UGFS). The study population was patients with a chronic venous ulcer who were eligible for either compression therapy or an interventional procedure. Data were obtained from systematic review and meta-analysis of RCTs. RESULTS: Surgery gained 0·112 (95 per cent c.i. -0·011 to 0·213) QALYs compared with compression therapy alone, with a difference in lifetime costs of €-1330 (-3570 to 1262). Given the expected savings in community care, the procedure would pay for itself within 4 years. There was insufficient evidence regarding endothermal ablation and UGFS to draw conclusions. DISCUSSION: This modelling study found surgery to be more effective and less costly than compression therapy alone. Further RCT evidence is required for both endothermal ablation and UGFS.

Synthesis and dopaminergic properties of some exo- and endo-2-aminobenzonorbornenes designed as rigid analogue of dopamine.

Stereospecific syntheses of exo-2-amino-5,6-dihydroxybenzonorbornene (11f), exo-2-amino-6,7-dihydroxybenzonorbornene (11h), exo-2-amino-7,8-dihydroxybenzonorbornene (11g), and endo-2-amino-6,7-dihydroxybenzonorbornene (14d), rigid analogues of dopamine, are described. Compounds 11 h and 14d, their N-methyl (11i and 11j) and N,N-dimethyl (14i and 14j) derivatives, and compounds 11f and 11g were inactive as dopamine agonists when evaluated for dopaminergic activity by their ability to induce stereotyped behavior in mice after subcutaneous injection and by their ability to cause hyperactivity in rats after bilateral injection into the nucleus accumbens. However, compounds 11f, 11g, 11h, and the N-methyl derivatives 11i and 14d were all effective in displacing [3H]-2-amino-6,7-dihydroxytetralin ([3H]ADTN) and [3h[-N-n-propylnorapomorphine ([3H]NPA) from rat striatal membranes.

Glutaraldehyde treated bovine fibrocartilage arthroplasty for the scaphoid: a case history and discussion.

Avascular necrosis of the proximal pole of the carpal scaphoid following fracture often leads to degeneration and carpal collapse. Replacement arthroplasty as a treatment for this condition using a variety of materials has not been universally successful. A case is described in which a new arthroplasty material-glutaraldehyde treated bovine fibrocartilage-was used as a spacer to restore carpal height.

Functional restoration of an articular surface using a heterotopic xenograft: biology of host-implant interactions in the canine patella.

Glutaraldehyde-treated bovine meniscal fibrocartilage has been used as a heterotopic bioprosthesis to repair large osteochondral defects in the canine patella. An efficient, functional articulating surface was reformed and the graft did not elicit a significant immunological response. Although tissue bonding between the host and graft was often excellent, the implant did not become revascularized or replaced by host tissue but acted as an inert space occupier. This material may offer some potential for conservative treatment of articular defects in the patella in appropriate circumstances.

In vivo corrosion of 316L stainless-steel hip implants: morphology and elemental compositions of corrosion products.

Eleven surgically retrieved stainless steel implants showing varying degrees of surface corrosion were examined to characterize the morphology and composition of corrosion products. The implants were fabricated to the specification AISI316L (Muller) and BS 3531 pt 1 1971-78 (Charnley). They had been in place for 9-21 y (Mean :13 y) and failures were due to aseptic loosening. The morphology and chemical compositions of corrosion products were recorded using scanning electron microscopy (SEM) and energy dispersive X-ray analysis (EDX). Nine implants had areas of corrosion covering 1-5 cm of the stem, partially or all round. Corrosion existed in layers. The layers consisted either of chromium in association with sulfur, or iron in association with phosphorus. Variable amounts of calcium and chlorine were also present in all layers. Nickel, which makes up 13% of the alloy, was persistently absent. The presence and extent of corrosion was independent of the alloy composition and could not be related to the duration of implantation.

The use of meniscal fibrocartilage as a surface arthroplasty to effect the repair of osteochondral defects: an experimental study.

Meniscal fibrocartilage autografts, homografts, glutaraldehyde treated homografts and glutaraldehyde treated xenografts were inserted into articular defects in the rabbit patello-femoral groove. They appeared capable of restoring a functional articular surface. Considerable variation in the type of bond formed between the host and graft occurred but no evidence of rejection was observed. This tissue would appear to offer potential for restoring localized articular osteochondral defects.

Evaluation of preserved bovine tendon xenografts: a histological, biomechanical and clinical study.

Glutaraldehyde treated bovine tendon xenografts have been introduced into clinical trials as human knee ligament replacements recently, following animal experiments. This paper reports a further clinical study in which complications arose from implant debris. A laboratory study showed that the implants were not absorbed or integrated into the tissues of the host animals, as had been claimed by the originators. Mechanical tests of tendon reconstructions showed that the implants were not functional. It was concluded that this material is not suitable for clinical use within the knee joint as a cruciate ligament prosthesis.

Evaluation of Gateshead carbon fibre rod as an implant material for repair of osteochondral defects: a morphological and mechanical study in the rabbit knee.

Use of the Gateshead carbon fibre rod system remains controversial. Although it has been shown to enhance the repair of lesions in load bearing areas of convex articular surfaces, there is a lack of evidence to support the claim that it provides an inert scaffold for ingrowth of organised fibrous tissue. and thereby increasing the rate and quality of articular surface regeneration. This study examined osteochondral repair following implantation of a Gateshead rod in the femoral condyles of 25 rabbits for up to 32 weeks. using radiology, histology, scanning electron microscopy and mechanical testing. The repaired fibrocartilaginous surface layer was found to be persistently softer than the normal control and some repaired surfaces were worn, exposing the rod at 32 weeks. Whilst fibrous tissue grew into the outer braided sheath of the rod, the core remained impervious. The rod appeared to act as a space occupier, initially providing better subsurface support than found in natural healing. In the long term, however, it prevented subchondral bone restoration and re-establishment of the normal osteochondral junction, resulting in a quality of repair which did not differ from that found in naturally healing defects.

Flucloxacillin in bone.

Ten patients undergoing total hip replacement for osteoarthritis were each given intramuscular flucloxacillin about two hours preoperatively; bone and serum were sampled simultaneously at operation. Trabecular and compact bone were separated, partly dried, reduced to powders, and then extracted with buffer. The concentration of flucloxacillin in bone washings and serum was determined by well-diffusion assay. The mean concentration of flucloxacillin in serum was 8.9 mg/l, in trabecular bone washings, 1.3 mg/l, and in compact bone washings 0.9 mg/l. The amount of blood contaminating the bone washings was measured, and was calculated to account for at most 26% of the flucloxacillin present. The significance of these findings is discussed in relation to the prophylactic use of flucloxacillin in hip replacement surgery.

Late functional deterioration following paralytic poliomyelitis.

Many patients with previous poliomyelitis develop 'post-polio syndrome' (PPS) in which late functional deterioration follows a period of relative stability. The frequency with which PPS can be attributed to clearly defined causes remains uncertain. We reviewed 283 newly-referred patients with previous poliomyelitis seen consecutively over a 4-year period; 239 patients developed symptoms of functional deterioration at a mean of 35 (5-65) years after the paralytic illness. Functional deterioration was associated with orthopaedic disorders in 170 cases, neurological disorders in 35, respiratory disorders in 19 and other disorders in 15. Progressive post-polio muscular atrophy was not observed. Functional deterioration following paralytic polio-myelitis is common, and associated with orthopaedic, neurological, respiratory and general medical factors which are potentially treatable.

The cost-effectiveness of magnetic resonance imaging for investigation of the knee joint.

OBJECTIVES: This study considered the role of magnetic resonance imaging (MRI) in the diagnosis of knee injuries in a district general hospital (DGH) setting. The principal objective was to identify whether the use of MRI had a major impact on the clinical management of patients presenting with chronic knee problems, in whom surgery was being considered, whether it reduced overall costs and whether it improved patient outcome. In addition, the research: (1) explored the 'diagnostic accuracy' of initial clinical investigation of the knee by an orthopaedic trainee, consultant knee specialist and consultant radiologist; (2) considered the variability and diagnostic accuracy of interpretations of knee MRI investigations between radiologists; (3) measured the strength of preference for the potential diagnostic/therapeutic impact of knee MRI (i.e. the avoidance of surgery). METHODS - RANDOMISED CONTROLLED TRIAL: The research was based on a single-centre randomised controlled trial conducted at Kent and Canterbury Hospital. Patients attending with knee problems in whom surgery was being considered were recruited from routine orthopaedic clinics. Most patients had been referred by their general practitioner. Patients were randomised to either investigation using an MRI scan (MRI trial arm) or investigation using arthroscopy (no-MRI trial arm). The study investigated the benefits of knee MRI at two levels: diagnostic/therapeutic impact (i.e. avoidance of surgery) and patient outcome (using the Short Form with 36 items and EQ-5D quality-of-life measurement instruments). Quality of life was assessed at baseline and at 6 and 12 months. Costs were assessed from the perspectives of the NHS and patients. All analyses were by intention to treat. METHODS - SUBSTUDIES (INVESTIGATION OF DIAGNOSTIC ACCURACY): For the investigation of diagnostic accuracy of initial clinical investigation, the sample comprised 114 patients recruited in a separate study conducted at St Thomas' Hospital. The sample was drawn from patients presenting at the Accident and Emergency Department with an acute knee injury. All study patients received an MRI scan, but initial diagnosis was made without access to the scan or the radiologist's report. After 12 months, all clinical notes and MRI scans of study patients were reviewed and a final 'reference standard' diagnosis for each patient was reached. Comparison was made between the diagnosis recorded by each clinician (i.e. orthopaedic trainee, knee specialist and consultant radiologist) and the reference diagnosis. METHODS - SUBSTUDIES (INVESTIGATION OF THE GENERALISABILITY OF RESULTS): For this substudy, the MRI images from 80 patients (recruited at St Thomas' Hospital) were interpreted independently by seven consultant radiologists at DGHs and the St Thomas' Hospital MRI radiologist. For each area of the knee, the level of agreement (measured using weighted kappa) between the responses of the eight radiologists and the reference standard diagnosis was assessed. METHODS - SUBSTUDIES (INVESTIGATION OF PREFERENCES): The investigation of potential patient preferences for the diagnostic/therapeutic impact of MRI was explored using a discrete choice conjoint measurement research design. Choices involved selecting between two alternative scenarios described using four attributes, and data were collected from 585 undergraduate sports science students and analysed using a random-effects probit model. RESULTS - RANDOMISED CONTROLLED TRIAL: The trial recruited 118 patients (59 randomly allocated to each arm). The two groups were similar in important respects at baseline. The central finding was of no statistically significant differences between groups in all measures of health outcome, although a trend in favour of the no-MRI group was observed. However, the use of MRI was found to be associated with a positive diagnostic/therapeutic impact: a significantly smaller proportion of patients in the MRI group underwent surgery (MRI = 0.41, no-MRI = 0.71; p = 0.001). There was a similar mean overall NHS cost for both groups. RESULTS - SUBSTUDIES (INVESTIGATION OF DIAGNOSTIC ACCURACY): The exploration of diagnostic accuracy found that, when compared to orthopaedic trainees (44% correct diagnoses) or to radiologists reporting an MRI scan (68% correct diagnoses), the accuracy rate was higher for knee specialists (72% correct diagnoses). RESULTS - SUBSTUDIES (INVESTIGATION OF THE GENERALISABILITY OF RESULTS): This generalisability study indicated that, in general terms, radiologists in DGHs provide accurate interpretations of knee MRI images that are similar to a radiologist at a specialist centre. The one area of the knee for which this did not hold was the lateral collateral ligament. RESULTS - SUBSTUDIES (INVESTIGATION OF PREFERENCES): The central finding for this substudy was that, on average and within the range specified, choices in this group of potential patients were not significantly influenced by variation in the chance of avoiding surgery. CONCLUSIONS - IMPLICATIONS FOR HEALTHCARE: The evidence presented in this report supports the conclusions that the use of MRI in patients presenting at DGHs with chronic knee problems in whom arthroscopy was being considered did not increase NHS costs overall, was not associated with significantly worse outcomes and avoided surgery in a significant proportion of patients. CONCLUSIONS - RECOMMENDATIONS FOR FURTHER RESEARCH (IN PRIORITY ORDER): (1) The trial data demonstrated that the use of MRI in patients with chronic knee problems reduced the need for surgery. However, the link between diagnostic processes and changes in health outcome is indirect and the finding of no-MRI-related effect on health outcome may, therefore, be a consequence of the limited power of the trial. Further research to confirm (or contradict) these findings would be valuable. (2) The investigation of diagnostic accuracy involved comparison with a reference diagnosis established by a panel of two clinical members of the research team. It would be interesting to explore the extent to which the results would differ using an external panel. (3) The result from the preference study, indicating that the potential diagnostic/therapeutic impact of knee MRI was not highly valued, is a surprising finding that would be important to explore in general public or patient populations. (4) The focus for the trial-based aspects of this research was the DGH and patients presenting with chronic knee problems who were being considered for surgery. Care should be taken in generalising from these results to other patient groups (e.g. acute knee injuries) or to other settings (e.g. specialist centres). Further clinical trials would be required in order to answer such questions.

Measurement of tibial torsion--a new technique applicable to ultrasound and computed tomography.

A new method for measuring tibial torsion is described which can be applied to both ultrasound (US) and computed tomography (CT). The method has been validated in dry tibiae by comparison with direct measurements and with Jend's established CT method. In clinical practice a good statistical level of agreement has been demonstrated between the values obtained from US and CT scans. Both compared well with values obtained using Jend's CT technique. The use of US avoids exposure to radiation and is therefore suited to studying young subjects and controls and making repeat measurements.

Secondary structure in glycosaminoglycuronans: N.M.R. spectra in dimethyl sulphoxide of disaccharides related to hyaluronic acid and chondroitin sulphate.

1H-N.m.r.spectra for solutions in dimethyl sulphoxide-d6 of disaccharides related to hyaluronate and chondroitin sulphate are compared with those of their methylated derivatives. All resonances, including those of HO and HN groups, have been assigned. The temperature and concentration dependences suggest that HO-4 of the hexosamine residue in hyalobiouronate (but not that in chondrosinate) is hydrogen-bonded to O-5 of the uronic acid residue. The resonance of HO-2 of the uronate residue of chondrosinate also shows anomalies that may arise from intra-residue hydrogen-bonding. These findings confirm the existence of some features previously suggested to be present in glycosaminoglycuronan polymers. The resonance of HO-4 of the uronate residue in the disaccharides and in sodium (methyl alpha-D-glucopyranosid)uronate behaves as though there was a hydrogen bond between the carboxylate group and HO-4.

The meniscus--can it be repaired? An experimental investigation in rabbits.

In rabbits, repair of incisions in the central part of the meniscus has been demonstrated after surgical excision of the peripheral rim. Healing took place via a highly cellular but relatively avascular fibrous tissue stroma which proliferated from the synovial margin and invaded along the cut edge of the meniscus. Suturing facilitated this healing process by providing stability and possibly by supplying bridges for synovial cells to migrate onto the meniscus. Transformation of fibrous tissue into fibrocartilage has also been observed.

Sodium phosphate crystals in chondromalacic patellar cartilage.

We report the finding of sodium- and phosphorus-based crystallisation in abnormal human articular cartilage. We prepared five chondromalacic, five osteoarthritic and four macroscopically normal specimens of patellar cartilage by a cryofracturing technique and examined them in a scanning electron microscope. An energy-dispersive X-ray microanalysis system was used to identify the crystals, which were found in only three of the five chondromalacic specimens. Star-shaped crystals were seen either individually or in clusters in the matrix of the cartilage. They consisted of sodium and phosphorus, and we have found no previous reports of such findings. The calcified zone, the bone, and the articular surface were free from crystals.

The incidence of deep-vein thrombosis after upper tibial osteotomy. A venographic study.

We performed postoperative venography on 84 consecutive patients who had undergone upper tibial osteotomy for medial compartment osteoarthritis of the knee. Deep-vein thrombosis was demonstrated in 41%. Only 15% of the cases were diagnosed clinically, all in the calf veins. Cases of proximal thromboses (3) and mixed-vein thromboses (12) were only revealed by venography.