Matt Stevenson

Diagnosis of DVT: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

BACKGROUND Objective testing for DVT is crucial because clinical assessment alone is unreliable and the consequences of misdiagnosis are serious. This guideline focuses on the identification of optimal strategies for the diagnosis of DVT in ambulatory adults. METHODS The methods of this guideline follow those described in Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. RESULTS We suggest that clinical assessment of pretest probability of DVT, rather than performing the same tests in all patients, should guide the diagnostic process for a first lower extremity DVT (Grade 2B). In patients with a low pretest probability of first lower extremity DVT, we recommend initial testing with D-dimer or ultrasound (US) of the proximal veins over no diagnostic testing (Grade 1B), venography (Grade 1B), or whole-leg US (Grade 2B). In patients with moderate pretest probability, we recommend initial testing with a highly sensitive D-dimer, proximal compression US, or whole-leg US rather than no testing (Grade 1B) or venography (Grade 1B). In patients with a high pretest probability, we recommend proximal compression or whole-leg US over no testing (Grade 1B) or venography (Grade 1B). CONCLUSIONS Favored strategies for diagnosis of first DVT combine use of pretest probability assessment, D-dimer, and US. There is lower-quality evidence available to guide diagnosis of recurrent DVT, upper extremity DVT, and DVT during pregnancy.

Granulocyte colony-stimulating factors for febrile neutropenia prophylaxis following chemotherapy: systematic review and meta-analysis

BackgroundFebrile neutropenia (FN) occurs following myelosuppressive chemotherapy and is associated with morbidity, mortality, costs, and chemotherapy reductions and delays. Granulocyte colony-stimulating factors (G-CSFs) stimulate neutrophil production and may reduce FN incidence when given prophylactically following chemotherapy.MethodsA systematic review and meta-analysis assessed the effectiveness of G-CSFs (pegfilgrastim, filgrastim or lenograstim) in reducing FN incidence in adults undergoing chemotherapy for solid tumours or lymphoma. G-CSFs were compared with no primary G-CSF prophylaxis and with one another. Nine databases were searched in December 2009. Meta-analysis used a random effects model due to heterogeneity.ResultsTwenty studies compared primary G-CSF prophylaxis with no primary G-CSF prophylaxis: five studies of pegfilgrastim; ten of filgrastim; and five of lenograstim. All three G-CSFs significantly reduced FN incidence, with relative risks of 0.30 (95% CI: 0.14 to 0.65) for pegfilgrastim, 0.57 (95% CI: 0.48 to 0.69) for filgrastim, and 0.62 (95% CI: 0.44 to 0.88) for lenograstim. Overall, the relative risk of FN for any primary G-CSF prophylaxis versus no primary G-CSF prophylaxis was 0.51 (95% CI: 0.41 to 0.62). In terms of comparisons between different G-CSFs, five studies compared pegfilgrastim with filgrastim. FN incidence was significantly lower for pegfilgrastim than filgrastim, with a relative risk of 0.66 (95% CI: 0.44 to 0.98).ConclusionsPrimary prophylaxis with G-CSFs significantly reduces FN incidence in adults undergoing chemotherapy for solid tumours or lymphoma. Pegfilgrastim reduces FN incidence to a significantly greater extent than filgrastim.

Randomized controlled trial and cost-effectiveness analysis of silver-donating antimicrobial dressings for venous leg ulcers (VULCAN trial)

Antimicrobial silver dressings are used beneath graduated compression in the treatment of venous ulceration. There is little information on whether their use is effective. This was a prospective randomized trial and cost‐effectiveness analysis of silver‐donating versus non‐silver low‐adherence dressings in the treatment of venous leg ulcers.

Gaussian Process Modeling in Conjunction with Individual Patient Simulation Modeling: A Case Study Describing the Calculation of Cost-Effectiveness Ratios for the Treatment of Established Osteoporosis

Individual patient-level models can simulate more complex disease processes than cohort-based approaches. However, large numbers of patients need to be simulated to reduce 1storder uncertainty, increasing the computational time required and often resulting in the inability to perform extensive sensitivity analyses. A solution, employing Gaussian process techniques, is presented using a case study, evaluating the cost-effectiveness of a sample of treatments for established osteoporosis. The Gaussian process model accurately formulated a statistical relationship between the inputs to the individual patient model and its outputs. This model reducedthe time required for future runs from 150 min to virtually-instantaneous, allowing probabilistic sensitivity analyses-to be undertaken. This reduction in computational time was achieved with minimal loss in accuracy. The authors believe that this case study demonstrates the value of this technique in handling 1st- and 2nd-order uncertainty in the context of health economic modeling, particularly when more widely used techniques are computationally expensive or are unable to accurately model patient histories.

Febuxostat for the management of hyperuricaemia in patients with gout: a NICE single technology appraisal.

As part of the National Institute for Health and Clinical Excellence (NICE) single technology appraisal (STA) process, the manufacturer of febuxostat (Adenuric®; Ipsen, UK) was invited to submit evidence for the clinical and cost effectiveness of febuxostat for the management of hyperuricaemia in patients with gout. The School of Health and Related Research Technology Appraisal Group (ScHARR-TAG) at the University of Sheffield were commissioned to act as the independent Evidence Review Group (ERG).This article provides details of the company’s initial submission, the ERG’s clarification questions and the ERG report submitted to NICE. The decision made by NICE is provided alongside a brief comment on additional results produced by a substantially different model, which were presented by the manufacturer after the production of the appraisal consultation document.The ERG produced a critical review of the evidence for the clinical evidence and cost effectiveness of the technology based upon the manufacturer’s submission to NICE.The clinical evidence was derived from two head-to-head, phase III, multiarm, randomized, double blind, controlled trials comparing the efficacy and safety of febuxostat with fixed-dose allopurinol (300/100mg/day) in patients with hyperuricaemia and gout. The ERG considered that the trials were of reasonable methodological quality and measured a clinically relevant range of outcomes. Although a simple pooled analysis of the individual patientlevel data from the two trials was undertaken, the statistical approach for combining the data was considered inappropriate by the ERG as it failed to preserve randomization and introduced bias and confounding. There was substantial uncertainty in the relationships reported by the manufacturer regarding serum uric acid levels and the incidence of gout flares and underlying patient utility. The mathematical model developed was flawed and was not corrected despite ERG comments. It focused only on patients receiving febuxostat (80mg/day titrated to 120mg/day if necessary) with fixed-dose allopurinol (300/100mg/day). Sequential treatment was not modeled, nor was titrating allopurinol to 900mg/day, which is regarded as best practice. Numerous other errors were identified, which included the uncertain price of febuxostat being sampled within the probabilistic sensitivity analyses. Supplementary exploratory modelling addressing the position of febuxostat where patients were intolerant or contraindicated to allopurinol was provided to the NICE Appraisal Committee following the release of the appraisal consultation document.The NICE Appraisal Committee concluded that febuxostat be recommended as an option for the management of chronic hyperuricaemia in gout only for people who are intolerant to allopurinol or for whom allopurinol is contraindicated.

Hemiarthroplasty and Total Hip Arthroplasty for Treating Primary Intracapsular Fracture of the Hip: A Systematic Review and Cost-Effectiveness Analysis

BACKGROUND Hip fracture is a common problem in people aged > 60 years. The treatment options for individuals with high pre-fracture mobility, function and independence are hemiarthroplasty (HA) and total hip arthroplasty (THA). OBJECTIVE The aim of this report is to assess the clinical effectiveness and cost-effectiveness evidence of THA compared with HA in patients with displaced intracapsular fracture who are cognitively intact with high pre-fracture mobility or function. DATA SOURCES A systematic search was made of 11 databases of published and unpublished literature from their inception to december 2010: MEDLINE, EMBASE, Cumulative Index to Nursing and Allied Health Literature, The Cochrane Library, Biological Science Citation Index, Social Science Citation Index, Conference Proceedings Citation Index - Science, UK Clinical Trials Research Network and the National Research Register archive, Current Controlled Trials and ClinicalTrials.gov. REVIEW METHODS A systematic review of randomised controlled trials (RCTs) to assess the effectiveness of THA compared with HA in terms of dislocations, revisions, pain and function, and quality of life. Meta-analysis, independent subgroup analyses and exploratory cost-effectiveness modelling were performed. RESULTS The literature search identified 532 unique citations, of which eight RCTs with almost 1000 participants satisfied the criteria for the effectiveness review. Meta-analysis found a statistically significant increased risk of dislocation for patients treated with THA compared with HA (p = 0.01), but a reduced risk of revision (p = 0.0003). There were no differences in terms of mortality. In all trials, individuals treated with THA reported better function and mobility and less pain than those treated with HA. Four trials reporting utility data found similar trends. Sensitivity analyses indicated that there were no statistically significant differences in outcomes based on follow-up, study quality, surgical approach taken, type of head or the use of cement. Four papers reported a cost-utility analysis or the cost-effectiveness of THA compared with HA. Exploratory modelling was undertaken that showed that THA is likely to be cost-effective compared with HA even when the limitations of the data and methodology are considered. LIMITATIONS The costs and disutilities associated with revisions and dislocations were not included in the economic evaluation. CONCLUSIONS THA appears to be more cost-effective than HA. It is likely that THA will be associated with increased costs in the initial 2-year period, but lower longer-term costs, owing to potentially lower revision rates. However, these longer-term costs have not been modelled. The capacity and experience of surgeons to perform THA have not been explored and these would need to be addressed at local level were THA to become recommended for active, elderly patients in whom THA is not contraindicated. Further studies examining the impact of surgeon experience on performing the two procedures may offer more robust evidence on outcomes. FUNDING The National Institute for Health Research Health Technology Assessment programme.

Integration of meta-analysis and economic decision modeling for evaluating diagnostic tests.

Meta-analysis of diagnostic test accuracy data is more difficult than of effectiveness data because of 1) statistical challenges of dealing with multiple measures of accuracy (e.g., sensitivity and specificity) simultaneously and 2) incorporating threshold effects. A number of meta-analysis models are in use, ranging from naïve synthesis of independent sensitivity and specificity to optimization of a hierarchical summary receiver operating characteristic (SROC) curve. Little work has been done on how such analyses should inform decision models. This article aims to present a unified framework for the synthesis of primary data and economic evaluation of alternative diagnostic testing strategies using Bayesian Markov Chain Monte Carlo simulation methods. The authors extend this previous work by using systematic review to derive model parameters, fully allowing for uncertainty in their estimation, and formally incorporating variability between study results into the decision analysis. Using a simple decision model comparing alternative testing strategies for suspected deep vein thrombosis as an example, the authors consider how to use outputs of different alternative meta-analysis models in decision models. They also explore the limitations of diagnostic test studies, particularly when there is no obvious threshold value. To correct some of the limitations of diagnostic test studies, they propose that tests with implicit and explicit thresholds should be studied using distinctly different frameworks. Specifically, when a threshold exists, quantitative threshold information should be included in meta-analysis models to aid interpretation of SROCs. Setting policy to relate to a specific point may be much more difficult for studies with implicit thresholds.

Clinical effectiveness and cost-effectiveness of minimally invasive techniques to manage varicose veins: a systematic review and economic evaluation

BACKGROUND Varicose veins are enlarged, visibly lumpy knotted veins, usually in the legs. Uncomplicated varicose veins can cause major discomfort and some complications. They are part of chronic venous disease (CVD), which is reported to have a substantial negative impact on health-related quality of life (HRQoL). Traditional treatments for varicose veins involve surgical stripping and ligation and liquid sclerotherapy (LS), but can be invasive and painful. New minimally invasive treatments offer an alternative. These treatments typically involve use of laser, radiofrequency or foam sclerosant. They are increasingly widely used and offer potential benefits such as reduced complications, faster recovery, fewer physical limitations and improved quality of life. OBJECTIVE The aim of this report is to evaluate the clinical effectiveness, safety and cost-effectiveness of the minimally invasive techniques of foam sclerotherapy (FS), endovenous laser ablation (EVLA) and radiofrequency ablation (RFA) in comparison with other techniques, including traditional surgical techniques, LS and conservative management, in the management of varicose veins. DATA SOURCES A systematic search was made of 11 bibliographic databases of published and unpublished literature from their inception to July 2011: MEDLINE; EMBASE; Cumulative Index to Nursing and Allied Health Literature; The Cochrane Library; Biological Abstracts; Science Citation Index (SCI); Social Sciences Citation Index; Conference Proceedings Citation Index-Science; UK Clinical Research Network; Current Controlled Trials; and ClinicalTrials.gov. REVIEW METHODS A systematic review of randomised controlled trials (RCTs) to assess the clinical effectiveness of minimally invasive techniques compared with other treatments, principally surgical stripping, in terms of recurrence of varicose veins, retreatment and clinical symptoms, as measured by the Venous Clinical Severity Score (VCSS), pain and quality of life. Network meta-analysis and exploratory cost-effectiveness modelling were performed. RESULTS The literature search identified 1453 unique citations, of which 34 RCTs (54 papers) satisfied the criteria for the clinical effectiveness review. The minimally invasive techniques reported clinical outcomes similar to surgery. Rates of recurrence were slightly lower for EVLA, RFA and FS, especially for longer follow-up periods; VCSS score was lower for EVLA and FS than for stripping, but slightly higher for RFA; short-term pain was less for FS and RFA but higher for EVLA; higher quality-of-life scores were reported for all evaluated interventions than for stripping. Differences between treatments were therefore negligible in terms of clinical outcomes, so the treatment with the lowest cost appears to be most cost-effective. Our central estimate is that total FS costs were lowest and FS is marginally more effective than stripping. However, this result was sensitive to the model time horizon. Threshold analysis indicated that EVLA and RFA might be considered cost-effective if their costs are equivalent to stripping. These findings are subject to uncertainty on account of the risk of bias present in the evidence base and the variation in costs. LIMITATIONS The relative clinical effectiveness and cost-effectiveness of the techniques are principally based on rates of post-operative technical recurrence rather than symptomatic recurrence, as this was the reported outcome in all trials. The true proportion of treated individuals who are likely to present with symptoms of recurrence requiring retreatment is therefore not certain. A figure reflecting the likely proportion of treated individuals who would experience symptomatic recurrence requiring retreatment (with its associated costs), therefore, had to be calculated by the authors based on a small number of studies. The findings of this report also need to be verified by data from future trials with longer follow-up and using more standardised outcome measures. CONCLUSIONS This assessment of the currently available evidence suggests there is little to choose between the minimally invasive techniques in terms of efficacy or cost, and each offers a viable, clinically effective alternative to stripping. FS might offer the most cost-effective alternative to stripping, within certain time parameters. High-quality RCT evidence is needed. Future trials should aim to measure and report outcomes in a standardised manner, which would permit more efficient pooling of their results. STUDY REGISTRATION PROSPERO number CRD42011001355. FUNDING The National Institute for Health Research Health Technology Assessment programme.

Non-Invasive Diagnostic Assessment Tools for the Detection of Liver Fibrosis in Patients with Suspected Alcohol-Related Liver Disease: A Systematic Review and Economic Evaluation

BACKGROUND Excessive alcohol consumption may lead to the development of alcohol-related liver disease (ALD). Liver biopsy may be used in patients with suspected ALD to confirm the diagnosis, exclude other or additional liver pathologies, and provide accurate staging of the degree of liver injury in order to enable the prediction of prognosis and inform treatment decisions. However, as it is an invasive procedure that carries the risk of morbidity and mortality, current UK guidance recommends that biopsy is not required to confirm the diagnosis in patients with a high clinical suspicion of ALD in whom blood tests have excluded other causes of liver disease, unless it is necessary to confirm a diagnosis of acute alcoholic hepatitis in order to inform specific treatment decisions. OBJECTIVES To evaluate the diagnostic accuracy, cost-effectiveness, and effect on patient outcomes of four non-invasive tests for liver fibrosis [the Enhanced Liver Fibrosis (ELF™) test (Siemens Healthcare Diagnostic Inc., Tarrytown, NY, USA), FibroTest (BioPredictive, Paris, France), FibroMAX (BioPredictive, Paris, France) and transient elastography (FibroScan(®); produced by EchoSens, Paris, France and distributed in the UK by Artemis Medical Ltd, Kent, UK)] in patients suspected of having ALD. DATA SOURCES A systematic review was undertaken to identify studies reporting the diagnostic and prognostic accuracy of the ELF test, FibroTest, FibroMAX, and FibroScan for the identification of liver fibrosis and associated conditions in patients with suspected ALD. The following databases were searched in January 2010: MEDLINE (from 1950 to January 2010), MEDLINE In-Process & Other Non-Indexed Citations (from 1950 to January 2010), EMBASE (from 1980 to January 2010), Cochrane Database of Systematic Reviews (from 1996 to January 2010), Cochrane Central Register of Controlled Trials (from 1898 to January 2010), Cochrane Methodology Register (from 1904 to January 2010), Database of Abstracts of Reviews of Effects (from 1995 to January 2010), HTA Database (from 1995 to January 2010), NHS Economic Evaluation Database (from 1995 to January 2010), Cumulative Index to Nursing and Allied Health Literature (from 1982 to January 2010), Web of Knowledge and Science Citation Index (from 1969 to January 2010). REVIEW METHODS Study quality was assessed using the QUADAS (Quality Assessment of Diagnostic Accuracy Studies) checklist. Owing to the heterogeneity of the studies, no formal meta-analysis was undertaken. A de novo mathematical model was constructed to estimate the incremental costs and incremental quality-adjusted life-years (QALYs) associated with alternative strategies compared with a biopsy-all strategy. The tests are assessed first as a replacement for liver biopsy, and secondly as an additional test prior to liver biopsy. Thirty-six scenarios were assessed for each non-invasive test strategy, which varied the sensitivity of biopsy, the anxiety associated with biopsy, sensitivity and specificity values and whether or not the biopsy was percutaneous or transjugular. For each scenario, threshold levels were reported where biopsying all patients was more cost-effective than the strategy for two parameters (the decreased level of abstinence associated with the strategy compared with biopsying all and the level of incidental QALY gain associated with biopsy). RESULTS No studies were identified that specifically assessed the ELF test, although a study was identified that evaluated the diagnostic accuracy of the European Liver Fibrosis Test (essentially, the ELF test with the addition of age to the algorithm) compared with biopsy. Three studies of FibroTest, no relevant studies of FibroMax, and six studies of FibroScan assessing accuracy compared with biopsy in patients with known or suspected alcohol-related liver disease were identified. In all studies, the number of patients with suspected ALD was small, meaning that the estimated sensitivities and specificities were not robust. No conclusive estimate of the cost per QALY of each non-invasive test could be provided. Scenarios exist in which each of the strategies analysed is more cost-effective than biopsying all patients and, in contrast, scenarios exist in which each strategy is less cost-effective than biopsying all patients. LIMITATIONS Study selection and data analysis were undertaken by one reviewer. CONCLUSIONS No conclusive result can be provided on the most cost-effective strategy until further data are available. A large number of parameters require data; however, the following are selected as being of most importance: (1) the sensitivity and specificity of each non-invasive liver test (NILT) against biopsy at validated and pre-selected cut-off thresholds; (2) the influence of potential confounding variables such as current drinking behaviour and the degree of hepatic inflammation on the performance of NILTs; and (3) the likelihood, and magnitude, of decreases in abstinence rates associated with a diagnosis of significant ALD by diagnostic modality and the incidental gains in QALYs that may be associated with biopsy. FUNDING The National Institute for Health Research Technology Assessment programme.

Percutaneous vertebroplasty and percutaneous balloon kyphoplasty for the treatment of osteoporotic vertebral fractures: a systematic review and cost-effectiveness analysis

BACKGROUND Percutaneous vertebroplasty (PVP) is a minimally invasive surgical procedure in which bone cement is injected into a fractured vertebra. Percutaneous balloon kyphoplasty (BKP) is a variation of this approach, in which an inflatable balloon tamp is placed in the collapsed vertebra prior to cement injection. OBJECTIVES To systematically evaluate and appraise the clinical effectiveness and cost-effectiveness of PVP and percutaneous BKP in reducing pain and disability in people with osteoporotic vertebral compression fractures (VCFs) in England and Wales. DATA SOURCES A systematic review was carried out. Ten databases including MEDLINE and CINAHL were searched from inception to November 2011, and supplemented by hand-searching relevant articles and contact with an expert. Studies met the inclusion criteria if they were randomised controlled trials (RCTs) including people with painful osteoporotic VCFs with a group receiving PVP or BKP. In addition, lead authors of identified RCTs were contacted for unpublished data. REVIEW METHODS Primary outcomes were health-related quality of life; back-specific functional status/mobility; pain/analgesic use; vertebral body height and angular deformity; incidence of new vertebral fractures and progression of treated fracture. A manufacturer provided academic-in-confidence observational data indicating that vertebral augmentation may be associated with a beneficial mortality effect, and that, potentially, BKP was more efficacious than PVP. These data were formally critiqued. A mathematical model was constructed to explore the cost-effectiveness of BKP, PVP and operative placebo with local anaesthesia (OPLA) compared with optimal pain management (OPM). Six scenario analyses were conducted that assessed combinations of assumptions on mortality (differential beneficial effects for BKP and PVP; equal beneficial effects for BKP and PVP; and no effect assumed) and derivation of utility data (either mapped from visual analogue scale pain score data produced by a network meta-analysis or using direct European Quality of Life-5 Dimensions data from the trials). Extensive sensitivity analyses were conducted on each of the six scenarios. This report contains reference to confidential information provided as part of the National Institute for Health and Care Excellence appraisal process. This information has been removed from the report and the results, discussions and conclusions of the report do not include the confidential information. These sections are clearly marked in the report. RESULTS A total of nine RCTs were identified and included in the review of clinical effectiveness. This body of literature was of variable quality, with the two double-blind, OPLA-controlled trials being at the least risk of bias. The most significant methodological issue among the remaining trials was lack of blinding for both study participants and outcome assessors. Broadly speaking, the literature suggests that both PVP and BKP provide substantially greater benefits than OPM in open-label trials. However, in double-blinded trials PVP was shown to have no more benefit than local anaesthetic; no trials of BKP compared with local anaesthesia have been conducted. A formal analysis of observational mortality data undertaken within this report concluded that it was not possible to say with certainty if there is a difference in mortality between patients undergoing BKP and PVP compared with OPM. Results from the cost-effectiveness analyses were varied, with all of BKP, PVP and OPLA appearing the most cost-effective treatment dependent on the assumptions made regarding mortality effects, utility, hospitalisation costs and OPLA costs. LIMITATIONS Data on key parameters were uncertain and/or potentially confounded, making definitive conclusions difficult to make. CONCLUSION For people with painful osteoporotic VCFs refractory to analgesic treatment, PVP and BKP perform significantly better in unblinded trials than OPM in terms of improving quality of life and reducing pain and disability. However, there is as yet no convincing evidence that either procedure performs better than OPLA. The uncertainty in the evidence base means that no definitive conclusion on the cost-effectiveness of PVP or BKP can be provided. Further research should focus on establishing whether or not BKP and PVP have a mortality advantage compared with OPLA and on whether or not these provide any utility gain compared with OPLA. STUDY REGISTRATION This study was registered as PROSPERO number CRD42011001822. FUNDING The National Institute for Health Research Health Technology Assessment programme.