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AIM: To assess the diagnostic accuracy of computed tomography coronary angiography (CTCA) using a combination of high-definition CT (HD-CTCA) and high level of reader experience, with invasive coronary angiography (ICA) as the reference standard, in high-risk patients for the investigation of coronary artery disease (CAD). MATERIALS AND METHODS: Three hundred high-risk patients underwent HD-CTCA and ICA. Independent experts evaluated the images for the presence of significant CAD, defined primarily as the presence of moderate (≥ 50%) stenosis and secondarily as the presence of severe (≥ 70%) stenosis in at least one coronary segment, in a blinded fashion. HD-CTCA was compared to ICA as the reference standard. RESULTS: No patients were excluded. Two hundred and six patients (69%) had moderate and 178 (59%) had severe stenosis in at least one vessel at ICA. The sensitivity, specificity, positive predictive value, and negative predictive value were 97.1%, 97.9%, 99% and 93.9% for moderate stenosis, and 98.9%, 93.4%, 95.7% and 98.3%, for severe stenosis, on a per-patient basis. CONCLUSION: The combination of HD-CTCA and experienced readers applied to a high-risk population, results in high diagnostic accuracy comparable to ICA. Modern generation CT systems in experienced hands might be considered for an expanded role.

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OBJECTIVES: To identify combinations of tests and treatments to predict and prevent spontaneous preterm birth. DATA SOURCES: Searches were run on the following databases up to September 2005 inclusive: MEDLINE, EMBASE, DARE, the Cochrane Library (CENTRAL and Cochrane Pregnancy and Childbirth Group trials register) and MEDION. We also contacted experts including the Cochrane Pregnancy and Childbirth Group and checked reference lists of review articles and papers that were eligible for inclusion. REVIEW METHODS: Two series of systematic reviews were performed: (1) accuracy of tests for the prediction of spontaneous preterm birth in asymptomatic women in early pregnancy and in women symptomatic with threatened preterm labour in later pregnancy; (2) effectiveness of interventions with potential to reduce cases of spontaneous preterm birth in asymptomatic women in early pregnancy and to reduce spontaneous preterm birth or improve neonatal outcome in women with a viable pregnancy symptomatic of threatened preterm labour. For the health economic evaluation, a model-based analysis incorporated the combined effect of tests and treatments and their cost-effectiveness. RESULTS: Of the 22 tests reviewed for accuracy, the quality of studies and accuracy of tests was generally poor. Only a few tests had LR+ > 5. In asymptomatic women these were ultrasonographic cervical length measurement and cervicovaginal prolactin and fetal fibronectin screening for predicting spontaneous preterm birth before 34 weeks. In this group, tests with LR- < 0.2 were detection of uterine contraction by home uterine monitoring and amniotic fluid C-reactive protein (CRP) measurement. In symptomatic women with threatened preterm labour, tests with LR+ > 5 were absence of fetal breathing movements, cervical length and funnelling, amniotic fluid interleukin-6 (IL-6), serum CRP for predicting birth within 2-7 days of testing, and matrix metalloprotease-9, amniotic fluid IL-6, cervicovaginal fetal fibronectin and cervicovaginal human chorionic gonadotrophin (hCG) for predicting birth before 34 or 37 weeks. In this group, tests with LR- < 0.2 included measurement of cervicovaginal IL-8, cervicovaginal hCG, cervical length measurement, absence of fetal breathing movement, amniotic fluid IL-6 and serum CRP, for predicting birth within 2-7 days of testing, and cervicovaginal fetal fibronectin and amniotic fluid IL-6 for predicting birth before 34 or 37 weeks. The overall quality of the trials included in the 40 interventional topics reviewed for effectiveness was also poor. Antibiotic treatment was generally not beneficial but when used to treat bacterial vaginosis in women with intermediate flora it significantly reduced the incidence of spontaneous preterm birth. Smoking cessation programmes, progesterone, periodontal therapy and fish oil appeared promising as preventative interventions in asymptomatic women. Non-steroidal anti-inflammatory agents were the most effective tocolytic agent for reducing spontaneous preterm birth and prolonging pregnancy in symptomatic women. Antenatal corticosteroids had a beneficial effect on the incidence of respiratory distress syndrome and the risk of intraventricular haemorrhage (28-34 weeks), but the effects of repeat courses were unclear. For asymptomatic women, costs ranged from 1.08 pounds for vitamin C to 1219 pounds for cervical cerclage, whereas costs for symptomatic women were more significant and varied little, ranging from 1645 pounds for nitric oxide donors to 2555 pounds for terbutaline; this was because the cost of hospitalisation was included. The best estimate of additional average cost associated with a case of spontaneous preterm birth was approximately 15,688 pounds for up to 34 weeks and 12,104 pounds for up to 37 weeks. Among symptomatic women there was insufficient evidence to draw firm conclusions for preventing birth at 34 weeks. Hydration given to women testing positive for amniotic fluid IL-6 was the most cost-effective test-treatment combination. Indomethacin given to all women without any initial testing was the most cost-effective option for preventing birth before 37 weeks among symptomatic women. For a symptomatic woman, the most cost-effective test-treatment combination for postponing delivery by at least 48 h was the cervical length (15 mm) measurement test with treatment with indomethacin for all those testing positive. This combination was also the most cost-effective option for postponing delivery by at least 7 days. Antibiotic treatment for asymptomatic bacteriuria of all women without any initial testing was the most cost-effective option for preventing birth before 37 weeks among asymptomatic women but this does not take into account the potential side effects of antibiotics or issues such as increased resistance. CONCLUSIONS: For primary prevention, an effective, affordable and safe intervention applied to all mothers without preceding testing is likely to be the most cost-effective approach in asymptomatic women in early pregnancy. For secondary prevention among women at risk of preterm labour in later pregnancy, a management strategy based on the results of testing is likely to be more cost-effective. Implementation of a treat-all strategy with simple interventions, such as fish oils, would be premature for asymptomatic women. Universal provision of high-quality ultrasound machines in labour wards is more strongly indicated for predicting spontaneous preterm birth among symptomatic women than direct management, although staffing issues and the feasibility and acceptability to mothers and health providers of such strategies need to be explored. Further research should include investigations of low-cost and effective tests and treatments to reduce and delay spontaneous preterm birth and reduce the risk of perinatal mortality arising from preterm birth.

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Clarifying the existing evidence base is crucial to improve the effectiveness of transfusion practice. The UK Systematic Review Initiative has been pursuing this objective primarily through writing systematic reviews on important topics in transfusion medicine. Here, we describe our progress for the past 5 years. We are the only research group that identifies transfusion medicine randomized controlled trials (RCTs) for the Cochrane Central Register of Controlled Trials, and to date, we have contributed 3002 RCT citations. The article considers future challenges including the need for wider involvement from the transfusion medicine community in the process of maintaining and updating systematic reviews and the identification and prioritization of topics for further clinical research including clinical trials. Collaboration between international and local research groups is important if these challenges are to be met.

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OBJECTIVES: To investigate the accuracy of predictive tests for pre-eclampsia and the effectiveness of preventative interventions for pre-eclampsia. Also to assess the cost-effectiveness of strategies (test-intervention combinations) to predict and prevent pre-eclampsia. DATA SOURCES: Major electronic databases were searched to January 2005 at least. REVIEW METHODS: Systematic reviews were carried out for test accuracy and effectiveness. Quality assessment was carried out using standard tools. For test accuracy, meta-analyses used a bivariate approach. Effectiveness reviews were conducted under the auspices of the Cochrane Pregnancy and Childbirth Group and used standard Cochrane review methods. The economic evaluation was from an NHS perspective and used a decision tree model. RESULTS: For the 27 tests reviewed, the quality of included studies was generally poor. Some tests appeared to have high specificity, but at the expense of compromised sensitivity. Tests that reached specificities above 90% were body mass index greater than 34, alpha-foetoprotein and uterine artery Doppler (bilateral notching). The only Doppler test with a sensitivity of over 60% was resistance index and combinations of indices. A few tests not commonly found in routine practice, such as kallikreinuria and SDS-PAGE proteinuria, seemed to offer the promise of high sensitivity, without compromising specificity, but these would require further investigation. For the 16 effectiveness reviews, the quality of included studies was variable. The largest review was of antiplatelet agents, primarily low-dose aspirin, and included 51 trials (36,500 women). This was the only review where the intervention was shown to prevent both pre-eclampsia and its consequences for the baby. Calcium supplementation also reduced the risk of pre-eclampsia, but with some uncertainty about the impact on outcomes for the baby. The only other intervention associated with a reduction in RR of pre-eclampsia was rest at home, with or without a nutritional supplement, for women with normal blood pressure. However, this review included just two small trials and its results should be interpreted with caution. The cost of most of the tests was modest, ranging from 5 pounds for blood tests such as serum uric acid to approximately 20 pounds for Doppler tests. Similarly, the cost of most interventions was also modest. In contrast, the best estimate of additional average cost associated with an average case of pre-eclampsia was high at approximately 9000 pounds. The results of the modelling revealed that prior testing with the test accuracy sensitivities and specificities identified appeared to offer little as a way of improving cost-effectiveness. Based on the evidence reviewed, none of the tests appeared sufficiently accurate to be clinically useful and the results of the model favoured no-test/treat-all strategies. Rest at home without any initial testing appeared to be the most cost-effective 'test-treatment' combination. Calcium supplementation to all women, without any initial testing, appeared to be the second most cost-effective. The economic model provided little support that any form of Doppler test has sufficiently high sensitivity and specificity to be cost-effective for the early identification of pre-eclampsia. It also suggested that the pattern of cost-effectiveness was no different in high-risk mothers than the low-risk mothers considered in the base case. CONCLUSIONS: The tests evaluated are not sufficiently accurate, in our opinion, to suggest their routine use in clinical practice. Calcium and antiplatelet agents, primarily low-dose aspirin, were the interventions shown to prevent pre-eclampsia. The most cost-effective approach to reducing pre-eclampsia is likely to be the provision of an effective, affordable and safe intervention applied to all mothers without prior testing to assess levels of risk. It is probably premature to suggest the implementation of a treat-all intervention strategy at present, however the feasibility and acceptability of this to women could be explored. Rigorous evaluation is needed of tests with modest cost whose initial assessments suggest that they may have high levels of both sensitivity and specificity. Similarly, there is a need for high-quality, adequately powered randomised controlled trials to investigate whether interventions such as advice to rest are indeed effective in reducing pre-eclampsia. In future, an economic model should be developed that considers not just pre-eclampsia, but other related outcomes, particularly those relevant to the infant such as perinatal death, preterm birth and small for gestational age. Such a modelling project should make provision for primary data collection on the safety of interventions and their associated costs.

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BACKGROUND: Thalassaemia major is a genetic disease characterised by a reduced ability to produce haemoglobin. Management of the resulting anaemia is through transfusions of red blood cells. Repeated transfusions result in excessive accumulation of iron in the body (iron overload), removal of which is achieved through iron chelation therapy. A commonly used iron chelator, deferiprone, has been found to be pharmacologically efficacious. However, important questions exist about the efficacy and safety of deferiprone compared to another iron chelator, desferrioxamine. OBJECTIVES: To summarise data from trials on the clinical efficacy and safety of deferiprone and to compare the clinical efficacy and safety of deferiprone for thalassaemia with desferrioxamine. SEARCH STRATEGY: We searched the Group's Haemoglobinopathies Trials Register, MEDLINE, EMBASE, Biological Abstracts, ZETOC, Current Controlled Trials and bibliographies of relevant publications. We contacted the manufacturers of deferiprone and desferrioxamine. Most recent searches: June 2006. SELECTION CRITERIA: Randomised controlled trials comparing deferiprone with another iron chelator; or comparing two schedules of deferiprone, in people with transfusion-dependent thalassaemia. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. Missing data were requested from the original investigators. MAIN RESULTS: Ten trials involving 398 people (range 10 to 144 people) were included. Nine trials compared deferiprone with desferrioxamine or a combination of deferiprone and desferrioxamine and one compared different schedules of deferiprone. There was little consistency between outcomes and little information to fully assess the methodological quality of most of the included trials. No trial reported long-term outcomes (mortality and end organ damage). There was no consistent effect on reduction of iron overload between all treatment comparisons, with the exception of urinary iron excretion in comparisons of deferiprone with desferrioxamine. An increase in iron excretion levels favoured deferiprone in one trial and desferrioxamine in three trials, even though measurement of urinary iron excretion underestimates total iron excretion by desferrioxamine.Adverse events were recorded in trials comparing deferiprone with desferrioxamine. There was evidence of adverse events in all treatment groups. Adverse events in one trial were significantly more likely with deferiprone than desferrioxamine, relative risk 2.24 (95% confidence interval 1.19 to 4.23). AUTHORS' CONCLUSIONS: We found no reason to change current treatment recommendations, namely deferiprone is indicated for treating iron overload in people with thalassaemia major when desferrioxamine is contraindicated or inadequate. However, there is an urgent need for adequately-powered, high quality trials comparing the overall clinical efficacy and long-term outcome of deferiprone with desferrioxamine.

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There continues to be a general but unfounded enthusiasm for fresh frozen plasma (FFP) usage across a range of clinical specialties in hospital practice. Clinical use of plasma has grown steadily over the last two decades in many countries. In England and Wales, there has not been a significant reduction in the use of FFP over the last few years, unlike red cells. There is also evidence of variation in usage among countries--use in England and Wales may be proportionately less per patient than current levels of usage in other European countries and the United States. Plasma for transfusion is most often used where there is abnormal coagulation screening tests, either therapeutically in the face of bleeding, or prophylactically in non-bleeding subjects prior to invasive procedures or surgery. Little evidence exists to inform best therapeutic plasma transfusion practice. Most studies have described plasma use in a prophylactic setting, in which laboratory abnormalities of coagulation tests are considered a predictive risk factor for bleeding prior to invasive procedures. The strongest randomised controlled trial (RCT) evidence indicates that prophylactic plasma for transfusion is not effective across a range of different clinical settings and this is supported by data from non-randomised studies in patients with mild to moderate abnormalities in coagulation tests. There are also uncertainties whether plasma consistently improves the laboratory results for patients with mild to moderate abnormalities in coagulation tests. There is a need to undertake new trials evaluating the efficacy and adverse effects of plasma, both in bleeding and non-bleeding patients, to understand whether the "presumed" benefits outweigh the "real risks". In addition, new haemostatic tests should be validated which better define risk of bleeding.

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Randomised, controlled trials of good quality are a recognised means to robustly assess the efficacy of interventions in clinical practice. A systematic identification and appraisal of all randomised trials involving fresh frozen plasma (FFP) indicates that most clinical indications for FFP, as currently recommended by practice guidelines, are not supported by evidence from randomised trials. This chapter will largely consider the implications of some of the findings from this systematic review. Many published trials on the use of FFP have enrolled small numbers of patients, and provided inadequate information on the ability of the trial to detect meaningful differences in outcomes between the two patient groups. Other concerns about the design of the trials include the dose of FFP used, and the potential for bias; no studies had taken adequate account of the extent to which adverse effects might negate the clinical benefits of treatment with FFP. In addition, there is little evidence for the effectiveness of the prophylactic use of FFP. There is a pressing need to consider how best to develop new trials to determine the effectiveness of FFP. How this can be achieved can be illustrated by reference to studies of albumin in critical care. A recent, large and well-designed randomised trial (Saline versus Albumin Fluid Evaluation study; SAFE) in critical care found no evidence of an increase in mortality with the use of albumin compared to saline, which had been hypothesised in an earlier systematic review. How the study findings will actually now influence the clinical use of albumin remains to be seen. Although the SAFE trial showed no increase in mortality with albumin compared with saline, it is difficult to justify its use in critical care given its considerably greater cost.

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Summary Randomized controlled trials of good quality are a recognized means to robustly assess the efficacy of interventions in clinical practice. A systematic identification and appraisal of all randomized trials involving fresh frozen plasma (FFP) has been undertaken in parallel to the drafting of the updated British Committee for Standards in Haematology guidelines on the use of FFP. A total of 57 trials met the criteria for inclusion in the review. Most clinical uses of FFP, currently recommended by practice guidelines, are not supported by evidence from randomized trials. In particular, there is little evidence for the effectiveness of the prophylactic use of FFP. Many published trials on the use of FFP have enrolled small numbers of patients, and provided inadequate information on the ability of the trial to detect meaningful differences in outcomes between the two patient groups. Other concerns about the design of the trials include the dose of FFP used, and the potential for bias. No studies have taken adequate account of the extent to which adverse effects might negate the clinical benefits of treatment with FFP. There is a need to consider how best to develop new trials to determine the efficacy of FFP in different clinical scenarios to provide the evidence base to support national guidelines for transfusion practice. Trials of modified FFP (e.g. pathogen inactivated) are of questionable value when there is little evidence that the standard product is an effective treatment.

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AIM: To ascertain and describe the number and epidemiology of randomised controlled trials (RCTs) focused on orthopaedic fractures. METHODS: A sensitive literature search was carried out for the period 1966-May 1999. Labels were applied to each identified RCT to indicate the fracture type, and the main type of intervention. RESULTS: 648 RCTs related to surgery of which 123 focused on adjuvant therapies and 88 related mainly to anaesthesia, analgesia, and radiography. The number of trials have increased exponentially with time so that the present decade has seen more RCTs published than all the other years added together. CONCLUSION: There is clearly an encouraging trend in the number of RCTs published. However there is a need to ensure that trials are on fracture types where there is most need for guidance. This growing evidence base should fuel systematic reviews and clinical guidelines within orthopaedics.

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OBJECTIVE: to investigate the effects of supported discharge after an acute admission in older people with undifferentiated clinical problems. DESIGN: a systematic review of randomized controlled trials. METHODS: we searched MEDLINE, CINAHL, the Cochrane Library, PsycLit and the Social Science Citation Index up to the end of 1997. This was augmented by hand-searching, follow-up of bibliographies and.direct enquiry of authors of included studies. Application of inclusion decisions, quality assessment and data abstraction were carried out independently by at least two of the reviewers. We tabulated the results of the included studies and used meta-analysis where appropriate to refine conclusions. RESULTS: we finally included nine studies in the review, assessment of which revealed that bias was present, dictating the need for caution in interpreting results. Despite this, there was relative certainty that the proportion of those at home 6-12 months after admission is greater with supported discharge (odds ratio 1.4, 95% confidence interval 1.1- 2.0). This was associated with a consistent pattern of reduction in admission to long-stay care over the same period, without apparent increases in mortality. There was uncertainty about the effect of supported discharge on hospitalization. There were no rigorous research data on functional status, patient and carer satisfaction, and, in consequence, uncertainty about the overall effectiveness of supported discharge. CONCLUSIONS: we believe that the results of this review provide reassurance that supporting discharge from hospital to home is of value. However, important sources of uncertainty remain, suggesting the need for further research.

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OBJECTIVE: To identify and qualitatively synthesise the findings from all studies that have examined the performance and effect of near patient tests in the primary care setting. DESIGN: Systematic review of published and unpublished research 1986-99. MAIN OUTCOME MEASURES: Test performance characteristics, measures of effect on clinical practice or patient outcome. RESULTS: 101 relevant publications were identified. The general quality of these papers was low, and consequently only 32 papers were assessed in detail. Although these papers gave some indication of the value of near patient testing in areas such as anticoagulation monitoring and group A beta haemolytic streptococcus testing, the research raised many more questions than it answered. Almost no reports were found of unbiased assessment of the effect of near patient tests in primary care on patient outcomes, organisational outcomes, or cost. CONCLUSIONS: Available research provides little evidence to guide the expansion of use of near patient testing in primary care. Further research is needed in areas of clinical practice where near patient tests might be most beneficial.

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AIMS AND OBJECTIVES: The aim was to identify publications relating to near patient testing (NPT), the use of alternative delivery systems between laboratory and general practice, including electronic data interchange (EDI), and computerised diagnostic decision support (CDDS), in the primary care setting to answer the following questions. What is the availability of NPT for primary care? What evidence is available to support the clinical effectiveness of NPT? What evidence is available on the accuracy and reliability of NPT within primary care? What evidence is available on the cost-effectiveness of different NPTs? How may CDDS improve the effectiveness of NPT? What evidence is available that compares NPT and existing laboratory services? What evidence is available on the cost-effectiveness of EDI or alternative delivery systems? HOW THE RESEARCH WAS CONDUCTED: Eight databases were searched, and the bibliographies from relevant publications checked for completeness. Unpublished work and publications not included in the databases were obtained by personal contact with collaborators, and from a postal survey sent to heads of academic departments of general practice and clinical chemistry and to researchers active or interested in the field worldwide. Questionnaires were also sent to 150 commercial organisations. Publications that met agreed definitions and reported original data were included in the systematic review. Of the 1057 publications identified, 102 (92 related to NPT, eight to CDDS, and two to EDI) were passed to the reviewers for appraisal of validity. The limited amount of published research relating to any particular NPT prohibited meta-analysis. Scoring systems to assess the validity of evaluations were also difficult to apply. RESEARCH FINDINGS: A wide variety of NPT systems have been developed. In general, the quality of the methods reported in the literature was poor. The issue of patient convenience and acceptability has not been adequately addressed. No evaluations of alternative delivery systems met the review criteria. No studies have evaluated the telephone or fax machine as a means of reporting results. For EDI, the majority of papers were descriptive. EDI and alternative delivery systems are not a replacement for NPT when the provision of an immediate result might have an impact on the quality of care. EDI may have clinical and cost advantages over traditional means of communication, but this has not been evaluated. The advisory role of the laboratory can be supported by CDDS. The use of CDDS and NPT has not, however, been fully evaluated. Few economic analyses have been conducted, and most were simple cost analyses. There are insufficient data for conclusions to be drawn on the cost-effectiveness of NPT in primary care. RECOMMENDATIONS: FURTHER SYSTEMATIC REVIEWS: Subject-specific systematic reviews are required that include laboratory and secondary care studies, and consider the potential for altering current management and patient acceptability. Priority topics include: biochemistry profiles on desktop analysers; cholesterol testing; urinalysis for the diagnosis of urinary tract infection; anticoagulation control; NPTs for the identification of acute infection. (ABSTRACT TRUNCATED)

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The use of research evidence depends on more than its quality. If one considers other factors that influence the use of evidence, the quantity of accessible evidence and initiatives ensuring a wider understanding of it must be equally important. In consequence, improving the quality of research evidence alone will not necessarily lead to its greater use.

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