Interventional management of hyperhidrosis in secondary care: a systematic review.

BACKGROUND: Hyperhidrosis is uncontrollable excessive sweating, which occurs at rest, regardless of temperature. The symptoms of hyperhidrosis can significantly affect quality of life. OBJECTIVES: To undertake a systematic review of the clinical effectiveness and safety of treatments available in secondary care for the management of primary hyperhidrosis. METHODS: Fifteen databases (including trial registers) were searched to July 2016 to identify studies of secondary-care treatments for primary hyperhidrosis. For each intervention randomized controlled trials (RCTs) were included where available; where RCT evidence was lacking, nonrandomized trials or large prospective case series were included. Outcomes of interest included disease severity, sweat rate, quality of life, patient satisfaction and adverse events. Trial quality was assessed using a modified version of the Cochrane Risk of Bias tool. Results were pooled in pairwise meta-analyses where appropriate, otherwise a narrative synthesis was presented. RESULTS: Fifty studies were included in the review: 32 RCTs, 17 nonrandomized trials and one case series. The studies varied in terms of population, intervention and methods of outcome assessment. Most studies were small, at high risk of bias and poorly reported. The interventions assessed were iontophoresis, botulinum toxin (BTX) injections, anticholinergic medications, curettage and newer energy-based technologies that damage the sweat gland. CONCLUSIONS: The evidence for the effectiveness and safety of treatments for primary hyperhidrosis is limited overall, and few firm conclusions can be drawn. However, there is moderate-quality evidence to support the use of BTX for axillary hyperhidrosis. A trial comparing BTX with iontophoresis for palmar hyperhidrosis is warranted.

Simple tests for the diagnosis of childhood obesity: a systematic review and meta-analysis.

There is a need to accurately quantify levels of adiposity in order to identify overweight and obesity in children. This systematic review aimed to identify all diagnostic accuracy studies evaluating simple tests for obesity and adiposity, including body mass index (BMI), skin-fold thickness and waist circumference, compared against high-quality reference tests. Twenty-four cohort studies including 25,807 children were included. BMI had good performance when diagnosing obesity: a sensitivity of 81.9% (95% confidence interval [CI]: 73.0 to 93.8) for a specificity of 96.0% (95% CI: 93.8 to 98.1). It was less effective at diagnosing overweight (sensitivity: 76.3%, 95% CI: 70.2 to 82.4; specificity: 92.1% 95% CI: 90.0 to 94.3). When diagnosing obesity, waist circumference had similar performance (sensitivity: 83.8%; specificity: 96.5%). Skin-fold thickness had slightly poorer performance (sensitivity: 72.5%; specificity: 93.7%). Few studies considered any other tests. There was no conclusive evidence that any test was generally superior to the others. BMI is a good simple diagnostic test for identifying childhood adiposity. It identifies most genuinely obese and adipose children while misclassifying only a small number as obese. There was no conclusive evidence that any test should be preferred to BMI, and the extra complexity of skin-fold thickness tests does not appear to improve diagnostic accuracy.

Childhood obesity as a predictor of morbidity in adulthood: a systematic review and meta-analysis.

Obese children are at higher risk of being obese as adults, and adult obesity is associated with an increased risk of morbidity. This systematic review and meta-analysis investigates the ability of childhood body mass index (BMI) to predict obesity-related morbidities in adulthood. Thirty-seven studies were included. High childhood BMI was associated with an increased incidence of adult diabetes (OR 1.70; 95% CI 1.30-2.22), coronary heart disease (CHD) (OR 1.20; 95% CI 1.10-1.31) and a range of cancers, but not stroke or breast cancer. The accuracy of childhood BMI when predicting any adult morbidity was low. Only 31% of future diabetes and 22% of future hypertension and CHD occurred in children aged 12 or over classified as being overweight or obese. Only 20% of all adult cancers occurred in children classified as being overweight or obese. Childhood obesity is associated with moderately increased risks of adult obesity-related morbidity, but the increase in risk is not large enough for childhood BMI to be a good predictor of the incidence of adult morbidities. This is because the majority of adult obesity-related morbidity occurs in adults who were of healthy weight in childhood. Therefore, targeting obesity reduction solely at obese or overweight children may not substantially reduce the overall burden of obesity-related disease in adulthood.

Predicting adult obesity from childhood obesity: a systematic review and meta-analysis.

A systematic review and meta-analysis was performed to investigate the ability of simple measures of childhood obesity such as body mass index (BMI) to predict future obesity in adolescence and adulthood. Large cohort studies, which measured obesity both in childhood and in later adolescence or adulthood, using any recognized measure of obesity were sought. Study quality was assessed. Studies were pooled using diagnostic meta-analysis methods. Fifteen prospective cohort studies were included in the meta-analysis. BMI was the only measure of obesity reported in any study, with 200,777 participants followed up. Obese children and adolescents were around five times more likely to be obese in adulthood than those who were not obese. Around 55% of obese children go on to be obese in adolescence, around 80% of obese adolescents will still be obese in adulthood and around 70% will be obese over age 30. Therefore, action to reduce and prevent obesity in these adolescents is needed. However, 70% of obese adults were not obese in childhood or adolescence, so targeting obesity reduction solely at obese or overweight children needs to be considered carefully as this may not substantially reduce the overall burden of adult obesity.

Omalizumab for the treatment of severe persistent allergic asthma: a systematic review and economic evaluation.

BACKGROUND: Allergic asthma is a long-term disorder of the airways resulting from overexpression of immunoglobulin E (IgE) in response to environmental allergens. Patients with poorly controlled asthma are at high risk of exacerbations requiring additional treatment, including hospitalisations. Severe exacerbations are potentially life threatening. Guidelines identify five treatment steps for both adults and children. Omalizumab (Xolair(®)) is a recombinant DNA-derived humanised monoclonal antibody indicated as an add-on therapy in patients aged ≥ 6 years with severe persistent allergic asthma uncontrolled at treatment step 4 or 5. OBJECTIVE: To determine the clinical effectiveness, safety and cost-effectiveness of omalizumab, as an add-on therapy to standard care, within its licensed indication, compared with standard therapy alone for the treatment of severe persistent allergic asthma in adults and adolescents aged ≥ 12 years and children aged 6-11 years. DATA SOURCES: Eleven electronic databases (including MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials) and additional sources including regulatory agency reports were searched from inception to October 2011. Additional data sources include: the manufacturer's submission (MS); two previous National Institute for Health and Care Excellence (NICE) single technology appraisal (STA) submissions; and existing reviews on the safety of omalizumab and oral corticosteroids (OCSs). REVIEW METHODS: Systematic reviews of the clinical effectiveness and cost-effectiveness evidence for omalizumab were performed. The primary outcome was number of clinically significant (CS) exacerbations. Other outcomes included asthma symptoms, unscheduled health-care use, asthma-related mortality, OCS use and health-related quality of life (HRQoL). Because of methodological and clinical heterogeneity between trials, a narrative synthesis was applied. Pragmatic reviews with best evidence syntheses were used to assess adverse events of omalizumab and OCSs. The cost-effectiveness of omalizumab was assessed from the perspective of the UK NHS in the two separate populations: adults and adolescents, and children, using a cohort Markov model. Costs and outcomes were discounted at 3.5% per annum. Results are presented for additional subgroup populations: (1) hospitalised for asthma in the previous year, (2) adults and adolescents on maintenance OCSs and (3) three or more exacerbations in the previous year. RESULTS: Eleven randomised controlled trials (RCTs) and 13 observational studies were identified, including four RCTs/subgroups in the adult licensed population and one subgroup in children. A minority of patients were on maintenance OCSs. No evidence comparing omalizumab with OCSs was identified. Omalizumab significantly reduced the incidence of CS exacerbations in both adults and children [adults: INvestigatioN of Omalizumab in seVere Asthma Trial (INNOVATE): rate ratio 0.74; 95% CI 0.55 to 1.00; children IA-05 EUP (the a priori subgroup of patients who met the European Medicines Agency license criteria) 0.66; 95% CI 0.44 to 1.00]. Significant benefits were observed for a range of other outcomes in adults. Subgroup evidence showed benefits in adults on maintenance OCSs. Evidence for an OCS-sparing effect of omalizumab was limited but consistent. Omalizumab is available as 75 mg and 150 mg prefilled syringes at prices of £128.07 and £256.15 respectively. The incremental cost-effectiveness ratio (ICER) for adults and adolescents is £83,822 per quality-adjusted life-year (QALY) gained, whereas the ICER for children is £78,009 per QALY gained. The results are similar for the subgroup population of ≥ 3 exacerbations in the previous year, whereas the ICER for the other subgroup populations are lower; £46,431 for the hospitalisation subgroup in adults and adolescents, £44,142 for the hospitalisation subgroup in children and £50,181 for the maintenance OCS subgroup. CONCLUSION: Omalizumab reduces the incidence of CS exacerbations in adults and children, with benefits on other outcomes in adults. Limited, underpowered subgroup evidence exists that omalizumab reduces exacerbations and OCS requirements in adults on OCSs. Evidence in children is weaker and more uncertain. The ICERs are above conventional NHS thresholds of cost-effectiveness. The key drivers of cost-effectiveness are asthma-related mortality risk and, to a lesser extent, HRQoL improvement and OCS-related adverse effects. An adequately powered double-blind RCT in both adults and children on maintenance OCSs and an individual patient data meta-analysis of existing trials should be considered. A registry of all patients on omalizumab should be established. STUDY REGISTRATION: The study was registered as PROSPERO CRD42011001625. FUNDING: This report was commissioned by the National Institute for Health Research Health Technology Assessment programme on behalf of NICE as project number HTA 10/128/01.

Acupuncture and other physical treatments for the relief of pain due to osteoarthritis of the knee: network meta-analysis.

OBJECTIVE: To compare the effectiveness of acupuncture with other relevant physical treatments for alleviating pain due to knee osteoarthritis. DESIGN: Systematic review with network meta-analysis, to allow comparison of treatments within a coherent framework. Comprehensive searches were undertaken up to January 2013 to identify randomised controlled trials in patients with osteoarthritis of the knee, which reported pain. RESULTS: Of 156 eligible studies, 114 trials (covering 22 treatments and 9,709 patients) provided data suitable for analysis. Most trials studied short-term effects and many were classed as being of poor quality with high risk of bias, commonly associated with lack of blinding (which was sometimes impossible to achieve). End of treatment results showed that eight interventions: interferential therapy, acupuncture, TENS, pulsed electrical stimulation, balneotherapy, aerobic exercise, sham acupuncture, and muscle-strengthening exercise produced a statistically significant reduction in pain when compared with standard care. In a sensitivity analysis of satisfactory and good quality studies, most studies were of acupuncture (11 trials) or muscle-strengthening exercise (9 trials); both interventions were statistically significantly better than standard care, with acupuncture being statistically significantly better than muscle-strengthening exercise (standardised mean difference: 0.49, 95% credible interval 0.00-0.98). CONCLUSIONS: As a summary of the current available research, the network meta-analysis results indicate that acupuncture can be considered as one of the more effective physical treatments for alleviating osteoarthritis knee pain in the short-term. However, much of the evidence in this area of research is of poor quality, meaning there is uncertainty about the efficacy of many physical treatments.

The clinical effectiveness and cost-effectiveness of technologies used to visualise the seizure focus in people with refractory epilepsy being considered for surgery: a systematic review and decision-analytical model.

BACKGROUND: For patients who continue to have seizures despite ongoing treatment, surgical resection of the epileptic focus may be considered, and can result in seizure-freedom. Currently, non-invasive tests provide information to inform the scope and positioning of invasive electroencephalography (EEG) electrodes. However, these technologies could replace intracranial EEG in at least some patients if their ability to accurately locate a seizure focus could be established. In order to inform clinical practice, studies need to investigate the clinical value of a test, and the impact of the results of that test on the decision-making process and subsequently on clinical outcomes. OBJECTIVES: The aims of this systematic review were to determine the diagnostic accuracy of non-invasive technologies, how these technologies impact on the decision-making process, associations with surgical outcome, and the gaps in the current evidence base. In addition, a decision-analytical model was designed to consider the potential use of existing data to determine the cost-effectiveness of options for presurgical work-up. DATA SOURCES: Eighteen electronic databases were searched without language restrictions [including MEDLINE, EMBASE, BIOSIS Previews, PASCAL, ClinicalTrials.gov, Cochrane Database of Systematic Reviews (CDSR), Cochrane Central Register of Controlled Trials (CENTRAL) and the Cochrane Register of Diagnostic Studies] from 2003 to July 2010. A prior, wider-ranging HTA review in this area conducted by the Centre for Reviews and Dissemination was used as the source for studies prior to 2003. Reference lists of included studies and relevant reviews were also searched, and a citation search of key papers undertaken. REVIEW METHODS: Systematic reviews of the diagnostic accuracy, clinical utility and cost-effectiveness of non-invasive technologies used to define the seizure focus in patients with refractory epilepsy being considered for surgery were undertaken according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Thirteen diagnostic accuracy studies, seven outcome prediction studies and one study reporting the impact of test results on the decision-making process ('decision study') were included. The decision study was used to aid the development of a decision-analytical model to illustrate how data from appropriately designed clinical studies can be utilised. RESULTS: Data from the diagnostic accuracy studies could not determine the contribution of the tests to the decision-making process. The number of index tests that could not be classified as correctly, non- or wrongly localising as indicated by a surgical outcome was high, up to 53%. The decision study reported fluorodeoxyglucose positron emission tomography influencing the decision for or against surgery in 78 of the 110 patients. The constructed decision-analytical model provided provisional cost-effectiveness results from the included diagnostic strategies. It demonstrated the feasibility of extending such analysis to all diagnostic strategies if suitable data were to become available. LIMITATIONS: There were a number of limitations of the available evidence, and overall, the quality of the available evidence was poor; only one study met the inclusion criteria that evaluated the use an index test on the decision-making process. Most of the available data was from the diagnostic accuracy studies; those currently available did not provide information on either the diagnostic accuracy or clinical utility of the tests being evaluated. Further limitations were the generally small study sizes, patient selection bias and the substantial clinical heterogeneity across the studies. CONCLUSIONS: The current evidence base is abundant but not adequately informative; there is no acceptable reference standard, reporting of clinical outcomes tends to be only following surgery, and decision level and clinical effectiveness studies are lacking. The additional value of diagnostic technologies for the localisation of epileptic foci is related to the impact on treatment decisions and the value of the treatments themselves; this needs to be considered fully in informing cost-effectiveness. Appropriately designed studies are needed to determine the added value of diagnostic regimens. Ultimately, how research informs the actual decision problem(s) faced by clinicians and the NHS needs to be considered; decision modelling is central to this issue. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

EOS 2D/3D X-ray imaging system: a systematic review and economic evaluation.

BACKGROUND: EOS is a biplane X-ray imaging system manufactured by EOS Imaging (formerly Biospace Med, Paris, France). It uses slot-scanning technology to produce a high-quality image with less irradiation than standard imaging techniques. OBJECTIVE: To determine the clinical effectiveness and cost-effectiveness of EOS two-dimensional (2D)/three-dimensional (3D) X-ray imaging system for the evaluation and monitoring of scoliosis and other relevant orthopaedic conditions. DATA SOURCES: For the systematic review of EOS, electronic databases (MEDLINE, Allied and Complementary Medicine Database, BIOSIS Previews, Cumulative Index to Nursing and Allied Health Literature, The Cochrane Library, EMBASE, Health Management Information Consortium, Inspec, ISI Science Citation Index and PASCAL), clinical trials registries and the manufacturer's website were searched from 1993 to November 2010. REVIEW METHODS: A systematic review of studies comparing EOS with standard X-ray [film, computed radiography (CR) or digital radiography] in any orthopaedic condition was performed. A narrative synthesis was undertaken. A decision-analytic model was developed to assess the cost-effectiveness of EOS in the relevant indications compared with standard X-ray and incorporated the clinical effectiveness of EOS and the adverse effects of radiation. The model incorporated a lifetime horizon to estimate outcomes in terms of quality-adjusted life-years (QALYs) and costs from the perspective of the NHS. RESULTS: Three studies met the inclusion criteria for the review. Two studies compared EOS with film X-ray and one study compared EOS with CR. The three included studies were small and of limited quality. One study used an earlier version of the technology, the Charpak system. Both studies comparing EOS with film X-ray found image quality to be comparable or better with EOS overall. Radiation dose was considerably lower with EOS: ratio of means for posteroanterior spine was 5.2 (13.1 for the study using the Charpak system); ratio of means for the lateral spine was 6.2 (15.1 for the study using the Charpak system). The study comparing EOS with CR found image quality to be comparable or better with EOS. Radiation dose was considerably lower with EOS than CR; ratio of means for the centre of the back was 5.9 and for the proximal lateral point 8.8. The lowest ratio of means was at the nape of the neck, which was 2.9. No other outcomes were assessed in the included studies, such as implications for patient management from the nature and quality of the image. Patient throughput is the major determinant of the cost-effectiveness of EOS. The average cost per procedure of EOS decreases with utilisation. Using estimates of patient throughput at national level from Hospital Episode Statistics data suggests that EOS is not cost-effective for the indications considered. Throughput in the region of 15,100 to 26,500 (corresponding to a workload of 60 to 106 patient appointments per working day) for EOS compared with a throughput of only 7530 for CR (30 patient appointments per working day) is needed to achieve an incremental cost-effectiveness ratio of £30,000 per QALY. EOS can be shown to be cost-effective only when compared with CR if the utilisation for EOS is about double the utilisation of CR. LIMITATIONS: The main limitation of the systematic review of the clinical effectiveness of EOS was the limited number and quality of the data available. In particular, there were no studies assessing the potential health benefits arising from the quality and nature of the image, over and above those associated with reduced radiation exposure. Uncertainty in the model inputs was not fully explored owing to a lack of reporting of standard deviations or confidence intervals in the published literature for most of the parameters. As a result, uncertainty in the cost-effectiveness results was not presented. CONCLUSIONS: Radiation dose is considerably lower with EOS than standard X-ray, whereas image quality remains comparable or better with EOS. However, the long-term health benefits from reduced radiation exposure with EOS are very small and there was a lack of data on other potential patient health benefits. The implications of any changes in the quality and nature of the EOS image compared with standard X-ray, for patient health outcomes, needs to be assessed. Given the higher cost of an EOS machine, utilisation is the major determinant of cost-effectiveness. Estimates of patient throughput at national level suggest that EOS is not cost-effective. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Omalizumab for the treatment of severe persistent allergic asthma in children aged 6-11 years.

This paper presents a summary of the evidence review group report into the clinical effectiveness and cost-effectiveness of omalizumab for the treatment of severe persistent asthma in children aged 6-11 years, based upon the evidence submission from Novartis Pharmaceutical UK Ltd to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal process. The manufacturer's submission was generally considered to be of good quality. The submission was based primarily on a preplanned subgroup IA-05 EUP (European Union Population) from the IA-05 trial, with outcomes including the number of clinically significant (CS) and clinically significant severe (CSS) exacerbations. Omalizumab therapy was associated with a statistically significant reduction in the rate of CS exacerbations, but the reduction in the rate of CSS exacerbations was not statistically significant. The benefit in terms of CS exacerbations was achieved mainly in patients with more than three exacerbations per year at baseline. The manufacturer found no previous published cost-effectiveness studies of omalizumab in children aged 6-11 years, so their de novo economic evaluation formed the basis of the submitted economic evidence. The economic model was considered appropriate for the decision problem. The results from the model indicated that omalizumab in addition to standard therapy compared with standard therapy alone did not appear cost-effective in either the overall population or a subgroup of patients hospitalised in the year prior to enrollment, with incremental cost-effectiveness ratios of £ 91,169 and £ 65,911 per quality-adjusted life-year, respectively. These findings were found to be robust across a wide range of alternative assumptions through one-way sensitivity analyses. The guidance issued by NICE states that omalizumab is not recommended for the treatment of severe persistent allergic asthma in children aged 6-11 years.

Golimumab for the treatment of psoriatic arthritis.

This paper presents a summary of the evidence review group (ERG) report into the use of golimumab for the treatment of psoriatic arthritis (PsA). The main clinical effectiveness data were derived from a single phase III randomised controlled trial (RCT: GO-REVEAL) that compared golimumab with placebo for treating patients with active and progressive PsA who were symptomatic despite the use of previous disease-modifying antirheumatic drugs or non-steroidal anti-inflammatory drugs. The 14-week data showed that, compared with placebo, golimumab 50 mg significantly improved joint disease response as measured by American College of Rheumatology (ACR) 20 [relative risk (RR) 5.73, 95% confidence interval (CI) 3.24 to 10.56] and Psoriatic Arthritis Response Criteria (PsARC) (RR 3.45, 95% CI 2.49 to 4.87), and skin disease response as measured by the Psoriasis Area and Severity Index (PASI) 75 (RR 15.95, 95% CI 4.62 to 59.11). The 24-week absolute data showed that these treatment benefits were maintained. There was a significant improvement in patients' functional status as measured by the Health Assessment Questionnaire (HAQ) change from baseline at 24 weeks (-0.33, p < 0.001). The open-label extension data showed that these beneficial effects were also maintained at 52 and 104 weeks. However, PASI 50 and PASI 90 at 14 weeks, and all of the PASI outcomes at 24 weeks, were not performed on the basis of intention-to-treat analysis. Furthermore, analyses of the 24-week data were less robust, failing to adjust for treatment contamination due to patient crossover at week 16. The manufacturer conducted a mixed treatment comparison (MTC) analysis. The ERG considered the assumption of exchangeability between the trials for the purpose of the MTC analysis to be acceptable, and the statistical approach in the MTC analysis to be reliable. Regarding the safety evaluation of golimumab, the manufacturer failed to provide longer-term data or to consider adverse event data of golimumab from controlled studies in other conditions, such as rheumatoid arthritis and ankylosing spondylitis. Although the adverse effect profile of golimumab appears similar to other anti-tumour necrosis factor (TNF) agents, the longer-term safety profile of golimumab remains uncertain. The manufacturer's submission presented a decision model to compare etanercept, infliximab, golimumab and adalimumab versus palliative care for patients with PsA. In the base-case model, 73% of the cohort of patients were assumed to have significant psoriasis (> 3% of body surface area). Estimates of the effectiveness of anti-TNF agents in terms of PsARC, HAQ change and PASI change were obtained from an MTC analysis of RCT data. The manufacturer failed to calculate incremental cost-effectiveness ratios (ICERs) correctly by comparing golimumab with palliative care instead of the most cost-effective alternative (etanercept). Despite the manufacturer's claim that golimumab is a cost-effective treatment option, the manufacturer's own model showed that golimumab is not cost-effective compared with other biologics when the ICERs are correctly calculated. None of the sensitivity analyses carried out by the manufacturer or the ERG regarding uncertainty in the estimates of clinical effectiveness, the acquisition and administration cost of drugs, the cost of treating psoriasis and the utility functions estimated to generate health outcomes changed this conclusion. However, a key area in determining the cost-effectiveness of anti-TNF agents is whether they should be treated as a class. If all anti-TNF agents are considered equally effective then etanercept, adalimumab and golimumab have very nearly equal costs and equal quality-adjusted life-years (QALYs), and all have an ICER of about £ 15,000 per QALY versus palliative care, whereas infliximab with a higher acquisition cost is dominated by the other biologics.

Paracetamol and selective and non-selective non-steroidal anti-inflammatory drugs for the reduction in morphine-related side-effects after major surgery: a systematic review.

Non-opioid analgesics, paracetamol, non-steroidal anti-inflammatory drugs (NSAIDs), or cyclo-oxygenase 2 (COX-2) inhibitors are often given along with morphine as part of multimodal analgesia after major surgery. We have undertaken a systematic review and a mixed treatment comparison (MTC) analysis in order to determine explicitly which class of non-opioid analgesic, paracetamol, NSAIDs, or COX-2 inhibitors is the most effective in reducing morphine consumption and morphine-related adverse effects. Sixty relevant studies were identified. The MTC found that when paracetamol, NSAIDs, or COX-2 inhibitors were added to patient-controlled analgesia (PCA) morphine, there was a statistically significant reduction in morphine consumption: paracetamol [mean difference (MD) -6.34 mg; 95% credibility interval (CrI) -9.02, -3.65], NSAIDs (MD -10.18; 95% CrI -11.65, -8.72), and COX-2 inhibitors (MD -10.92; 95% CrI -12.77, -9.08). There was a significant reduction in nausea and postoperative nausea and vomiting with NSAIDs compared with placebo (odds ratio 0.70; 95% CrI 0.53, 0.88) but not for paracetamol or COX-2 inhibitors, nor for NSAIDs compared with paracetamol or COX-2 inhibitors. There was no statistically significant difference in sedation between any intervention and comparator. On the basis of six trials (n=695), 2.4% of participants receiving an NSAID experienced surgical-related bleeding compared with 0.4% with placebo. The MTC found that there is a decrease in 24 h morphine consumption when paracetamol, NSAID, or COX-2 inhibitors are given in addition to PCA morphine after surgery, with no clear difference between them. Similarly, the benefits in terms of reduction in morphine-related adverse effects do not strongly favour one of the three non-opioid analgesics.

Etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis: a systematic review and economic evaluation.

BACKGROUND: Etanercept, infliximab and adalimumab are licensed in the UK for the treatment of active and progressive psoriatic arthritis (PsA) in adults who have an inadequate response to standard treatment. OBJECTIVE: To determine the clinical effectiveness, safety and cost-effectiveness of these biologic agents in the treatment of active and progressive PsA. DATA SOURCES: Systematic reviews were performed, with data sought from 10 electronic databases (MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Science Citation Index, Conference Proceedings Citation Index - Science, ClinicalTrials.gov, metaRegister of Current Controlled Trials, NHS Economic Evaluation Database, Health Economic Evaluations Database and EconLit) up to June 2009. REVIEW METHODS: Full paper manuscripts of titles/abstracts considered relevant were obtained and assessed for inclusion by two reviewers according to criteria on study design, interventions, participants and outcomes. Data on study and participant characteristics, efficacy outcomes, adverse effects, costs to the health service and cost-effectiveness were extracted, along with baseline data where reported. The primary efficacy outcomes were measures of anti-inflammatory response, skin lesion response and functional status, and the safety outcome was the incidence of serious adverse events. The primary measure of cost-effectiveness was incremental cost per additional quality-adjusted life-year (QALY). Standard meta-analytic techniques were applied to efficacy data. Published cost-effectiveness studies and the economic analyses submitted to the National Institute for Health and Clinical Excellence (NICE) by the biologic manufacturers were reviewed. An economic model was developed by updating the model produced by the York Assessment Group for the previous NICE appraisal of biologics in PsA. RESULTS: Pooled estimates of effect demonstrated a significant improvement in patients with PsA for all joint disease and functional status outcomes at 12-14 weeks' follow-up. The biologic treatment significantly reduced joint symptoms for etanercept [relative risk (RR) 2.60, 95% confidence interval (CI) 1.96 to 3.45], infliximab (RR 3.44, 95% CI 2.53 to 4.69) and adalimumab (RR 2.24, 95% CI 1.74 to 2.88), with 24-week data demonstrating maintained treatment effects. Trial data demonstrated a significant effect of all three biologics on skin disease at 12 or 24 weeks. Evidence synthesis found that infliximab appeared to be most effective across all outcomes of joint and skin disease. The response in joint disease was greater with etanercept than with adalimumab, whereas the response in skin disease was greater with adalimumab than with etanercept, although these differences are not statistically significant. Under base-case assumptions, etanercept was the most likely cost-effective strategy for patients with PsA and mild-to-moderate psoriasis if the threshold for cost-effectiveness was £20,000 or £30,000 per QALY. All biologics had a similar probability of being cost-effective for patients with PsA and moderate-to-severe psoriasis at a threshold of £20,000 per QALY. LIMITATIONS: Limited available efficacy data and difficulty in assessing PsA activity and its response to biologic therapy. CONCLUSIONS: The data indicated that etanercept, infliximab and adalimumab were efficacious in the treatment of PsA compared with placebo, with beneficial effects on joint symptoms, functional status and skin. Short-term data suggested that these biologic agents can delay joint disease progression and evidence to support their use in the treatment of PsA is convincing. Future research would benefit from long-term observational studies with large sample sizes of patients with PsA to demonstrate that beneficial effects are maintained, along with further monitoring of the safety profiles of the biologic agents. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Dronedarone for the treatment of atrial fibrillation and atrial flutter.

This paper presents a summary of the evidence review group (ERG) report on the clinical effectiveness and cost-effectiveness of dronedarone for the treatment of atrial fibrillation (AF) or atrial flutter based upon a review of the manufacturer's submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal process. The population considered in the submission were adult clinically stable patients with a recent history of or current non-permanent AF. Comparators were the current available anti-arrhythmic drugs: class 1c agents (flecainide and propafenone), sotalol and amiodarone. Outcomes were AF recurrence, all-cause mortality, stroke, treatment discontinuations (due to any cause or due to adverse events) and serious adverse events. The main evidence came from four phase III randomised controlled trials, direct and indirect meta-analyses from a systematic review, and a synthesis of the direct and indirect evidence using a mixed-treatment comparison. Overall, the results from the different synthesis approaches showed that the odds of AF recurrence appeared statistically significantly lower with dronedarone and other anti-arrhythmic drugs than with non-active control, and that the odds of AF recurrence are statistically significantly higher for dronedarone than for amiodarone. However, the results for outcomes of all-cause mortality, stroke and treatment discontinuations and serious adverse events were all uncertain. A discrete event simulation model was used to evaluate dronedarone versus antiarrhythmic drugs and standard therapy alone. The incremental cost-effectiveness ratio of dronedarone was relatively robust and less than 20,000 pounds per quality-adjusted life-year. Exploratory work undertaken by the ERG identified that the main drivers of cost-effectiveness were the benefits assigned to dronedarone for all-cause mortality and stroke. Dronedarone is not cost-effective relative to its comparators when the only effect of treatment is a reduction in AF recurrences. In conclusion, uncertainties remain in the clinical effectiveness and cost-effectiveness of dronedarone. In particular, the clinical evidence for the major drivers of cost-effectiveness (all-cause mortality and stroke), and consequently the additional benefits attributed in the economic model to dronedarone compared to other anti-arrhythmic drugs are highly uncertain. The final guidance, issued by NICE on 25 August 2010, states that: Dronedarone is recommended as an option for the treatment of non-permanent atrial fibrillation only in people: whose atrial fibrillation is not controlled by first-line therapy (usually including beta-blockers), that is, as a second-line treatment option, and who have at least one of the following cardiovascular risk factors: - hypertension requiring drugs of at least two different classes, diabetes mellitus, previous transient ischaemic attack, stroke or systemic embolism, left atrial diameter of 50 mm or greater, left ventricular ejection fraction less than 40% (noting that the summary of product characteristics [SPC] does not recommend dronedarone for people with left ventricular ejection fraction less than 35% because of limited experience of using it in this group) or age 70 years or older, and who do not have unstable New York Heart Association (NYHA) class III or IV heart failure. Furthermore, 'People who do not meet the criteria above who are currently receiving dronedarone should have the option to continue treatment until they and their clinicians consider it appropriate to stop'.

Sugammadex for reversal of neuromuscular block after rapid sequence intubation: a systematic review and economic assessment.

Sugammadex 16 mg kg⁻¹ can be used for the immediate reversal of neuromuscular block 3 min after administration of rocuronium and could be used in place of succinylcholine for emergency intubation. We have systematically reviewed the efficacy and cost-effectiveness and made an economic assessment of sugammadex for immediate reversal. The economic assessment investigated whether sugammadex appears cost-effective under various assumptions about the value of any reduction in recovery time with sugammadex, the likelihood of a 'can't intubate, can't ventilate' (CICV) event, the age of the patient, and the length of the procedure. Three trials were included in the efficacy review. Sugammadex administered 3 or 5 min after rocuronium produced markedly faster recovery than placebo or spontaneous recovery from succinylcholine-induced block. No published economic evaluations were found. Our economic analyses showed that sugammadex appears more cost-effective, where the value of any reduction in recovery time is greater, where the reduction in mortality compared with succinylcholine is greater, and where the patient is younger, for lower probabilities of a CICV event and for long procedures which do not require profound block throughout. Because of the lack of evidence, the value of some parameters remains unknown, which makes it difficult to provide a definitive assessment of the cost-effectiveness of sugammadex in practice. The use of sugammadex in combination with high-dose rocuronium is efficacious. Further research is needed to clarify key parameters in the analysis and to allow a fuller economic assessment.

Sugammadex compared with neostigmine/glycopyrrolate for routine reversal of neuromuscular block: a systematic review and economic evaluation.

The cost-effectiveness of sugammadex for the routine reversal of muscle relaxation produced by rocuronium or vecuronium in UK practice is uncertain. We performed a systematic review of randomized controlled trials of sugammadex compared with neostigmine/glycopyrrolate and an economic assessment of sugammadex for the reversal of moderate or profound neuromuscular block (NMB) produced by rocuronium or vecuronium. The economic assessment aimed to establish the reduction in recovery time and the 'value of time saved' which would be necessary for sugammadex to be potentially cost-effective compared with existing practice. Three trials indicated that sugammadex 2 mg kg⁻¹ (4 mg kg⁻¹) produces more rapid recovery from moderate (profound) NMB than neostigmine/glycopyrrolate. The economic assessment indicated that if the reductions in recovery time associated with sugammadex in the trials are replicated in routine practice, sugammadex would be cost-effective if those reductions are achieved in the operating theatre (assumed value of staff time, £4.44 per minute), but not if they are achieved in the recovery room (assumed value of staff time, £0.33 per minute). However, there is considerable uncertainty in these results. Sugammadex has the potential to be cost-effective compared with neostigmine/glycopyrrolate for the reversal of rocuronium-induced moderate or profound NMB, provided that the time savings observed in trials can be achieved and put to productive use in clinical practice. Further research is required to evaluate the effects of sugammadex on patient safety, predictability of recovery from NMB, patient outcomes, and efficient use of resources.

Sugammadex for the reversal of muscle relaxation in general anaesthesia: a systematic review and economic assessment.

BACKGROUND: Sugammadex (Bridion) is a newly developed agent for the reversal of neuromuscular blockade (NMB) induced by rocuronium or vecuronium. Sugammadex can reverse profound blockade and can be given for immediate reversal and its use would avoid the potentially serious adverse effects of the currently used agent, succinylcholine. Also, sugammadex can reverse NMB more quickly and predictably than existing agents. OBJECTIVES: To determine the clinical effectiveness and cost-effectiveness of sugammadex for the reversal of muscle relaxation after general anaesthesia in UK practice following routine or rapid induction of NMB. DATA SOURCES: Medical databases [including MEDLINE, EMBASE, CINAHL, Science Citation Index, BIOSIS and Cochrane Central Register of Controlled Trials (CENTRAL), conference proceedings, internet sites and clinical trials registers] were searched to identify published and unpublished studies. The main searches were carried out in May 2008 and supplemented by current awareness updates up until November 2008. REVIEW METHODS: For the clinical effectiveness review, randomised controlled trials of sugammadex against placebo or an active comparator (neostigmine + glycopyrrolate) for the reversal of moderate or profound NMB and for immediate reversal (spontaneous recovery from succinylcholine-induced blockade) were included. The primary effectiveness outcome was speed of recovery from NMB, as measured by objective monitoring of neuromuscular function. For the cost-effectiveness review, a de novo economic assessment considered the routine induction of NMB and the rapid induction and/or reversal of NMB, and threshold analyses were carried out on a series of pairwise comparisons to establish how effective sugammadex needs to be to justify its cost. RESULTS: The review of clinical effectiveness included four randomised active-control trials of sugammadex, nine randomised placebo-controlled trials and five studies in special populations. A total of 2132 titles and abstracts and 265 full-text publications were screened. The included trials indicated that sugammadex produces more rapid recovery from moderate or profound NMB than placebo or neostigmine. Median time to recovery from moderate blockade was 1.3-1.7 minutes for rocuronium + sugammadex, 21-86 minutes for rocuronium + placebo and 17.6 minutes for rocuronium + neostigmine. In profound blockade, median time to recovery was 2.7 minutes for rocuronium + sugammadex, 30 to > 90 minutes for rocuronium + placebo, and 49 minutes for rocuronium + neostigmine. Results for vecuronium were similar. In addition, recovery from NMB was faster with rocuronium reversed by sugammadex 16 mg/kg after 3 minutes (immediate reversal) than with succinylcholine followed by spontaneous recovery (median time to primary outcome 4.2 versus 7.1 minutes). The evidence base for modelling cost-effectiveness is very limited. However, assuming that the reductions in recovery times seen in the trials can be achieved in routine practice and can be used productively, sugammadex [2 mg/kg (4 mg/kg)] is potentially cost-effective at its current list price for the routine reversal of rocuronium-induced moderate (profound) blockade, if each minute of recovery time saved can be valued at approximately 2.40 pounds (1.75 pounds) or more. This is more likely to be achieved if any reductions in recovery time are in the operating room (estimated value of 4.44 pounds per minute saved) rather than the recovery room (estimated value of 0.33 pounds per minute saved). The results were broadly similar for rocuronium- and vecuronium-induced blockade. For rapid reversal of NMB it appeared that any reduction in morbidity from adopting sugammadex is unlikely to result in significant cost savings. LIMITATIONS: The evidence base was not large and many of the published trials were dose-finding and safety studies with very small sample sizes. Also, some relevant outcomes, in particular patient experience/quality of life and resources/costs used, were either not investigated or not reported. In addition, it is likely that the patients included in the efficacy trials were relatively young and in good general health compared with the overall surgical population. Regarding the economic evaluation, there appears to be no evidence linking measures of clinical efficacy to patients' health-related quality of life and mortality risks. CONCLUSIONS: Sugammadex may be a cost-effective option compared with neostigmine + glycopyrrolate for reversal of moderate NMB and also provides the facility to recover patients from profound blockade. Rocuronium + sugammadex could be considered as a replacement for succinylcholine for rapid induction (and reversal) of NMB, although this may not be a cost-effective option in some types of patient at current list prices for sugammadex. Considerable uncertainties remain about whether the full benefits of sugammadex can be realised in clinical practice.

Alitretinoin for the treatment of severe chronic hand eczema.

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of alitretinoin for the treatment of adults with severe chronic hand eczema refractory to topical steroid treatment in accordance with the licensed indication, based upon the evidence submission from Basilea Pharmaceuticals Ltd to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal process. The clinical evidence came from a single placebo-controlled randomised controlled trial of daily treatment with alitretinoin for 12-24 weeks, with follow-up for a further 24 weeks, in patients with severe chronic hand eczema (CHE) unresponsive to topical steroids. A statistically significantly greater proportion of patients using alitretinoin achieved the primary end point of clear or almost clear hands by week 24 than did those with placebo. Dose-dependent headache was the most commonly reported adverse event in patients treated with alitretinoin. Serious adverse events were rare, but alitretinoin was associated with increases in both total cholesterol and triglycerides, which has implications for risks of future cardiovascular events. The manufacturer submitted a de novo decision analytic model to estimate, over a time horizon of 3 years, the cost-effectiveness of alitretinoin versus the other relevant comparators identified by NICE. In response to the points of clarification put to it by the ERG regarding the initial submission, the manufacturer provided additional evidence and a revised decision analytic model with a 'placebo' arm. In the manufacturer's original submission to NICE, the base-case incremental cost-effectiveness ratios (ICERs) reported for alitretinoin were 8614 pounds per quality-adjusted life-year (QALY) versus ciclosporin, -469 pounds per QALY versus psoralen + UVA (with alitretinoin dominant) and 10,612 pounds per QALY versus azathioprine. These ICERs decreased as the time horizon was extended in sensitivity analyses. In patients with hyperkeratotic CHE and in women of child-bearing potential, the ICER remained below 20,000. pounds When the health-related quality of life (HRQoL) values used in the model were replaced with those derived from an alternative study, these ICERs increased significantly (to 22,312 pounds per QALY for alitretinoin versus azathioprine). In the revised model, alitretinoin was reported to have an ICER of 12,931 pounds per QALY gained versus supportive care (placebo). However, the model underestimates the costs of treatment associated with alitretinoin. The manufacturer assumed that patients receiving alitretinoin visited the dermatologist every 4 weeks and ceased treatment as soon as they responded to it. If, in practice, patients would receive treatment for longer than this, then the manufacturer's model will have significantly underestimated the costs to the NHS. Additional analyses undertaken by the ERG produced ICERs close to 30,000 pounds per QALY gained for alitretinoin versus supportive care. This was largely due to uncertainty surrounding the impact of alitretinoin on HRQoL. The placebo-controlled trials conducted to date have established that alitretinoin can be efficacious for the treatment of severe CHE refractory to topical steroids, but longer term follow-up of trials or the implementation of registries is required to better establish the longer term efficacy or safety of alitretinoin. NICE recommended the use of alitretinoin for patients with severe CHE and a Dermatology Life Quality Index (DLQI) score of at least 15. Treatment was recommended to be stopped as soon as an adequate response was observed, or if CHE remained severe at 12 weeks, or if response was inadequate at 24 weeks.

A systematic review and economic evaluation of the clinical effectiveness and cost-effectiveness of aldosterone antagonists for postmyocardial infarction heart failure.

BACKGROUND: Two aldosterone inhibitors are currently licensed for heart failure (HF) in the UK: spironolactone and eplerenone. Recent clinical guidelines recommend eplerenone after an acute myocardial infarction (MI) for patients with symptoms and/or signs of HF and left ventricular dysfunction. OBJECTIVES: The primary objective was to evaluate relative clinical effectiveness and cost-effectiveness of spironolactone and eplerenone in patients with postMI HF and explore the possibility of conducting an indirect comparison of spironolactone and eplerenone. A second objective was to undertake value-of-information (VOI) analyses to determine the need for further research to identify research questions critical to decision-making and to help inform the design of future studies. DATA SOURCES: Relevant databases including MEDLINE, EMBASE and CENTRAL were searched between September and December 2008. Randomised controlled trials (RCTs) of spironolactone, eplerenone, canrenone or potassium canrenoate were included if conducted in a postMI HF population. Trials of general HF patients with a subgroup of postMI HF patients were considered if they had at least 100 ischaemic participants per arm and the authors provided subgroup data when contacted. Adverse events summary data were sought from recognised reference sources and RCTs or observational studies in any population that recruited more than 100 participants. REVIEW METHODS: The comparative clinical effectiveness and cost-effectiveness of spironolactone and eplerenone was derived using Bayesian meta-regression drawing on a wider 'network' of aldosterone trials to those considered in the main clinical effectiveness review. An alternative scenario was also considered assuming a 'class effect' for the aldosterone antagonists in terms of major clinical events, but allowing for potential differences in side effect profiles. Cost-effectiveness was assessed using incremental cost-effectiveness ratios (ICERs) where appropriate. Uncertainty in cost-effectiveness results was also presented and used to inform future research priorities using VOI analyses based on expected value of perfect information (EVPI). A probabilistic decision analytic model was developed to estimate cost-effectiveness of spironolactone, eplerenone and standard care for management of postMI HF, provide estimates relevant to the NHS and explore alternative approaches to an indirect comparison between spironolactone and eplerenone. The model incorporated a lifetime horizon to estimate outcomes in terms of quality-adjusted life-years (QALYs) and costs from the NHS persepctive. In the base-case analysis, 2-year treatment duration was assumed, consistent with the follow-up in the main RCTs. Other scenarios were explored to examine the robustness of alternative assumptions including impact of different treatment durations. RESULTS: Searches yielded five RCTs: two spironolactone trials of poor methodological quality and three trials of which only one (of eplerenone) specifically examined postMI HF (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study, EPHESUS). One trial of spironolactone (Randomised Aldactone Evaluation Study, RALES) and one of canrenone (Antiremodelling Effect of Aldosterone receptors blockade with canrenone In mild Chronic Heart Failure, AREA IN-CHF) comprised general HF, but data were available for an ischaemic subgroup. Structural similarity of spironolactone and eplerenone suggests that they may be interchangeable, but formal indirect comparison between the three trials was severely limited by trial differences. Relative safety data were limited from RCTs and observational sources. Hyperkalaemia rates varied, but were generally higher than for placebo; data were insufficient to assess discontinuation because of hyperkalaemia.Gynaecomastia rates were higher with spironolactone. Adverse event data were sparse. Systematic review of economic evidence identified three main published studies but none used a UK perspective or attempted to compare cost-effectiveness in postMI HF. The new decision model indicated that eplerenone was the most cost-effective strategy for postMI HF (ICER of eplerenone compared with standard care was 4457 pounds per QALY, increasing to 7893 pounds per QALY if treatment continued over the patient's lifetime); in neither scenario did spironolactone appear cost-effective. The ICER of eplerenone was consistently under the 20,000-30,000 pounds per QALY threshold used to establish value for money in the NHS. Uncertainty resulted in EVPI estimates between 820M pounds (base-case) and 1265M pounds (lifetime treatment duration scenario). When class effect for mortality and hospitalisations was assumed spironolactone emerged as the most cost-effective treatment and EVPI estimates were negligible. If class effect is considered more plausible than the results of the evidence synthesis model then there would be limited value in additional research. LIMITATIONS: Exchangeability between trials was poor and there was a lack of robust data in RCTs. CONCLUSIONS: Only two good-quality trials of aldosterone inhibitors in the postMI HF population were found, but lack of exchangeability with respect to study populations, meant that a comparison between these drugs could not be done. It consistently emerged that, compared with usual care, use of an aldosterone antagonist appears to be a highly cost-effective strategy for the management of postMI HF patients in the NHS. An adequately powered, well-conducted RCT that directly compares spironolactone and eplerenone is required to provide more robust evidence on the optimal management of postMI HF patients.