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Primary liver tumours and liver metastases from colorectal carcinoma are the two most common malignant tumours to affect the liver. The liver is second only to the lymph nodes as the most common site for metastatic disease. More than half of the patients with metastatic liver disease will die from metastatic complications. Chemoembolisation is based on the concept that the blood supply to hepatic tumours originates predominantly from the hepatic artery. Therefore, embolisation of the hepatic artery can lead to selective necrosis of the liver tumour while it may leave normal parenchyma virtually unaffected.To study the beneficial and harmful effects of transarterial (chemo)embolisation compared with no intervention or placebo intervention in patients with liver metastases.We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, LILACS, and CINAHL up to November 2011.We included all randomised clinical trials assessing beneficial and harmful effects of transarterial (chemo)embolisation compared with no intervention or placebo intervention in patients with liver metastases, no matter the location of the primary tumour.We extracted relevant information on participant characteristics, interventions, study outcome measures, and data on the outcome measures for our review as well as information on the design and methodology of the studies. Bias risk assessment of the trials, fulfilling the inclusion criteria, and data extraction from the retrieved final evaluation trials were done by one author and checked by a second author.One randomised clinical trial fulfilled the inclusion criteria of the review. Sixty-one patients with colorectal liver metastases were randomised into three intervention groups: 22 received hepatic artery embolisation, 19 received hepatic artery infusion chemotherapy, and 20 were randomised to control, described as "no active therapeutic intervention, although symptomatic treatment was provided whenever necessary". As hepatic artery infusion chemotherapy is not in the scope of this review, we have not included the data from this intervention group. In the remaining two groups that were of interest to the review, 43 of the participants were men and 18 women. Most tumours were synchronous metastases involving up to 75% of the liver and non-resectable. The risk of bias in the trial was judged to be high.Patients were followed-up for a minimum of seven months. Mortality at last follow-up was 86% (19/22) in the hepatic artery embolisation group versus 95% (19/20) in the control group (RR 0.91; 95% CI 0.75 to 1.1), that is, no statistically significant difference was observed. Median survival after trial entry was 7.0 months (range 2 to 44) in the hepatic artery embolisation group and 7.9 months (range 1 to 26) in the control group. Nine out of 22 (41%) in the hepatic artery embolisation group and five out of 20 (25%) in the control group developed evidence of extrahepatic disease (RR 1.64; 95% CI 0.60 to 4.07). Local recurrence was reported for 10 patients in the trial without details about the trial group. Most patients in the embolisation group experienced post-embolic syndrome (82%), and one patient had local haematoma. No other adverse events were reported. The authors did not report if there were any adverse events in the control group.On the basis of one small randomised trial that did not describe sequence generation, allocation concealment or blinding, it can be concluded that in patients with liver metastases no significant survival benefit or benefit on extrahepatic recurrence was found in the embolisation group in comparison with the palliation group. The probability for selective outcome reporting bias in the trial is high. At present, transarterial (chemo)embolisation cannot be recommended outside randomised clinical trials.

Background: Third-generation aromatase inhibitors (letrozole, anastrozole) have shown superior efficacy in early and advanced breast cancer compared with tamoxifen. For HR+, HER2+ MBC, combination of an AI with an anti-HER2 agent (lapatinib or trastuzumab) has shown clinical benefit. Methods: Six databases were searched until January 2009 for randomized controlled clinical trials, assessing the safety and efficacy of first-line treatments for postmenopausal women with HR+ and HER2 (ErbB2) positive MBC, who have not received prior therapy for advanced or metastatic disease. Relevant interventions were lapatinib, aromatase inhibitors, tamoxifen, and trastuzumab. Outcomes included overall survival (OS), progression-free-survival (PFS), time-to-progression (TTP), and objective response rate (ORR). Results: Eighteen studies (62 papers) were included. Lapatinib + letrozole was significantly superior to letrozole alone based on a direct head-to-head study in terms of PFS/TTP and ORR. Using a network meta-analysis, compared with lapatinib+letrozole, tamoxifen (HR 0.45 (95% CI: 0.32, 0.65) and anastrozole (HR 0.53 (0.36, 0.80)) scored significantly worse in terms of PFS/TTP and ORR (tamoxifen: OR 0.25 (0.12, 0.53), anastrozole: OR 0.27 (0.12, 0.58). The combination also seemed significantly superior to exemestane in terms of PFS/TTP (HR 0.52 (0.34, 0.79)). Lapatinib + letrozole also seemed better, although not significantly, in terms of OS versus tamoxifen: HR 0.74 (0.49, 1.12), anastrozole: HR 0.71 (0.45, 1.14) and exemestane: HR 0.65 (0.39, 1.11). When compared with trastuzumab + anastrozole, lapatinib + letrozole seemed to be better in terms of OS (HR 0.85 (0.47, 1.54)), PFS/TTP (HR 0.89 (0.54, 1.47)) and ORR (OR 0.92 (0.24, 3.48)), although, none of these results were significant. Discussion: Lapatinib + letrozole was significantly superior to letrozole in terms of PFS/TTP and ORR based on a direct head-to-head study. Indirect comparisons appeared to favor lapatinib + letrozole versus other first-line treatments used in this patient population in terms of three main outcomes: OS, PFS/TTP and ORR. Indirect comparison results are based on a network analysis for which the basic assumptions of homogeneity, similarity and consistency were not fulfilled. Therefore, despite the fact that these are the best available data, the results need to be interpreted with caution.

Objective: To systematically assess efficacy and safety of buprenorphine patch versus fentanyl patch in patients with chronic moderate to severe pain. Methods: Fifteen databases were searched up to December 2010. Randomised and quasi-randomised trials assessing the efficacy in patients with chronic pain were included. Quantitative methods for data synthesis were used and two network meta-analyses were conducted. Results: Fourteen unique trials (17 publications) were included. No head-to-head randomised trials of buprenorphine patch compared with fentanyl patch were identified. Therefore, less robust evidence from indirect comparisons was used. Results from a network meta-analysis of non-enriched designs (eight trials), using trials versus placebo and trials versus morphine for indirect comparisons, indicated that transdermal fentanyl, in comparison with transdermal buprenorphine, showed significantly more nausea (odds ratio [OR] 4.66, 95% confidence interval (CI) 1.07 to 20.39), a significantly higher number of treatment discontinuations due to adverse events (OR 5.94, 95% CI 1.78 to 19.87), and non-significant differences on all other outcomes, including pain measures. In comparison with morphine, transdermal buprenorphine had a significantly higher decrease of pain intensity (MD [mean difference] -16.20, 95% CI -28.92 to -3.48) while morphine caused more cases of constipation (OR 7.50, 95% CI 1.45 to 38.85) and a significantly higher number of treatment discontinuations due to adverse events (OR 5.80, 95% CI 1.68 to 20.11). All other outcomes showed non-significant differences between transdermal buprenorphine and morphine. The results were similar when also including six trials using enriched designs with the exception of more cases of vomiting for fentanyl (OR 17.32, 95% CI 4.43 to 67.71) and morphine (OR 15.85, 95% CI 3.92 to 64.13) compared to buprenorphine. Conclusions: The findings indicate comparability of transdermal buprenorphine and transdermal fentanyl for pain measures with significantly fewer adverse events (nausea and treatment discontinuation due to adverse events) caused by transdermal buprenorphine.

Introduction. Estimates on the epidemiology of chronic pain vary widely throughout Europe. It is unclear whether this variation reflects true differences between populations or methodological factors. Information on the epidemiology of chronic pain can support decision makers in allocating adequate health care resources. Methods. In order to obtain epidemiological data on chronic pain in Denmark and Sweden, we conducted a literature review of epidemiological data primarily on chronic noncancer pain, prioritising studies of highest quality, recency, and validity by conducting a systematic search for relevant studies. Following quality assessment, data were summarised and assigned to the research questions. Results. The prevalence of moderate to severe noncancer pain was estimated at 16% in Denmark and 18% in Sweden. Chronic pain impacts negatively on perceived health status, quality of life and is associated with increased cost. Despite using pain medications, a large proportion of chronic pain sufferers have inadequate pain control. There was a lack of high-quality and low-bias studies with clear inclusion criteria. Conclusions. In both Denmark and Sweden, chronic pain is a common health problem which is potentially undertreated and warrants attention of health care workers, policy makers and researchers. Future research should utilise clear reporting guidelines to assist decision and policy makers, in this important area.

BACKGROUND Primary liver tumours and liver metastases from colorectal carcinoma are the two most common malignant tumours to affect the liver. The liver is second only to the lymph nodes as the most common site for metastatic disease. More than half of the patients with metastatic liver disease will die from metastatic complications. Chemoembolisation is based on the concept that the blood supply to hepatic tumours originates predominantly from the hepatic artery. Therefore, embolisation of the hepatic artery can lead to selective necrosis of the liver tumour while it may leave normal parenchyma virtually unaffected. OBJECTIVES To study the beneficial and harmful effects of transarterial (chemo)embolisation compared with no intervention or placebo intervention in patients with liver metastases. SEARCH METHODS We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, LILACS, and CINAHL up to December 2012. SELECTION CRITERIA We included all randomised clinical trials assessing beneficial and harmful effects of transarterial (chemo)embolisation compared with no intervention or placebo intervention in patients with liver metastases, no matter the location of the primary tumour. DATA COLLECTION AND ANALYSIS We extracted relevant information on participant characteristics, interventions, study outcome measures, and data on the outcome measures for our review as well as information on the design and methodology of the studies. Bias risk assessment of the trials, fulfilling the inclusion criteria, and data extraction from the retrieved final evaluation trials were done by one author and checked by a second author. MAIN RESULTS One randomised clinical trial fulfilled the inclusion criteria of the review. Sixty-one patients with colorectal liver metastases were randomised into three intervention groups: 22 received hepatic artery embolisation, 19 received hepatic artery infusion chemotherapy, and 20 were randomised to control, described as "no active therapeutic intervention, although symptomatic treatment was provided whenever necessary". As hepatic artery infusion chemotherapy is not in the scope of this review, we have not included the data from this intervention group. In the remaining two groups that were of interest to the review, 43 of the participants were men and 18 women. Most tumours were synchronous metastases involving up to 75% of the liver and non-resectable. The risk of bias in the trial was judged to be high.Patients were followed-up for a minimum of seven months. Mortality at last follow-up was 86% (19/22) in the hepatic artery embolisation group versus 95% (19/20) in the control group (RR 0.91; 95% CI 0.75 to 1.1), that is, no statistically significant difference was observed. Median survival after trial entry was 7.0 months (range 2 to 44) in the hepatic artery embolisation group and 7.9 months (range 1 to 26) in the control group. Nine out of 22 (41%) in the hepatic artery embolisation group and five out of 20 (25%) in the control group developed evidence of extrahepatic disease (RR 1.64; 95% CI 0.60 to 4.07). Local recurrence was reported for 10 patients in the trial without details about the trial group. Most patients in the embolisation group experienced post-embolic syndrome (82%), and one patient had local haematoma. No other adverse events were reported. The authors did not report if there were any adverse events in the control group. AUTHORS' CONCLUSIONS On the basis of one small randomised trial that did not describe sequence generation, allocation concealment or blinding, it can be concluded that in patients with liver metastases no significant survival benefit or benefit on extrahepatic recurrence was found in the embolisation group in comparison with the palliation group. The probability for selective outcome reporting bias in the trial is high. At present, transarterial (chemo)embolisation cannot be recommended outside randomised clinical trials.

Aim: A systematic review of chronic pain treatment with strong opioids (step 3 WHO pain ladder) and a comparison to a new drug recently approved for the treatment of severe chronic pain in Europe, tapentadol (Palexia, Nucynta*), were performed. Methods: Thirteen electronic databases were searched as well as a number of other sources from 1980 up to November 2010 for relevant randomized controlled clinical trials in chronic moderate and severe pain investigating at least one step 3 opioid. Chronic pain could be nociceptive or neuropathic, malignant or non-malignant, all systemic administrations were considered as well as trials of different lengths. Two separate analyses were performed, one only for trials which reported (at least as sub-groups) the outcome in patients with severe pain, the other including both moderate and severe pain conditions. With the exception of the direct comparison between tapentadol, oxycodone and placebo, indirect comparisons were performed based on a network analysis. Trials with an enriched or an enriched withdrawal design were excluded. Primary (pain intensity) and a number of secondary endpoints were evaluated, including pain relief (30% and 50%), patient global impression of change, quality of life, quality of sleep, discontinuations, as well as serious adverse events and selected adverse events. Results: Only 10 trials were eligible for analysis of patients with severe pain (eight investigating tapentadol and two trials comparing buprenorphine patch vs placebo). For moderate and severe pain, 42 relevant trials were identified and indirect comparisons with transdermal buprenorphine, transdermal fentanyl, hydromorphone, morphine, and oxymorphone were performed. This report focuses on the network analysis. Tapentadol showed statistically favourable results over oxycodone for pain intensity, 30% and 50% pain relief, patient global impression of change (PGIC), and quality of life. Furthermore, some of the most important adverse events of chronic opioid treatment were significantly less frequent with tapentadol as compared to oxycodone, i.e. constipation, nausea, and vomiting; discontinuations due to these adverse events were found significantly reduced with tapentadol. Similar results were obtained for the network analysis, i.e. tapentadol was superior for the primary outcome (pain intensity) to hydromorphone and morphine, whereas fentanyl and oxymorphone showed trends in favour of these treatments. Significantly less frequent gastrointestinal adverse events of tapentadol were observed in comparison with fentanyl, hydromorphone, morphine, and oxymorphone, apparently leading to significantly reduced treatment discontinuations (for any reason). Conclusions: Taken together, the benefit-risk ratio of tapentadol appears to be improved compared to step 3 opioids.

Patients with rheumatoid arthritis must learn to adjust their exercise, rest and medication to the varying activity of the disease. Patient education can help patients in making the right decisions about adjustments in their treatment regimen and in attaining ¿self-management¿ behaviors. We developed a group education program based on social learning theory and the `Arthritis Self Management Course¿ developed in the USA by Lorig. Goal of the program is the strengthening of self-efficacy, outcome expectations and self-management behaviors of RA patients which may lead to better health status. The program has been evaluated in an experimental design. We established significant positive effects of the group training on functional disability, joint tenderness, practice of relaxation and physical exercises, self-management behavior, outcome expectations, self-efficacy function and knowledge. After 14 months we still found effects on practice of physical exercises, self-efficacy function and knowledge.

Background To undertake a systematic review of the available data for oral and intravenous topotecan in adults with relapsed small cell lung cancer (SCLC) for whom re-treatment with the first line regimen is not considered appropriate. Methods We searched six databases from 1980 up to March 2009 for relevant trials regardless of language or publication status. Relevant studies included any randomised trial of any chemotherapeutic treatment against any comparator in this licensed indication. Where possible we used apposite quantitative methods. Where meta-analysis was considered unsuitable for some or all of the data, we employed a narrative synthesis method. For indirect comparisons we used the method of Bucher et al., where available data allowed it, otherwise we used narrative descriptions. Results Seven unique studies met the inclusion criteria, four of which could be used in our analyses. These included one study comparing oral topotecan plus best supportive care (BSC) to BSC alone, one study comparing intravenous topotecan to cyclophosphamide, adriamycin and vincristine (CAV), and two studies comparing oral topotecan with intravenous topotecan. All four studies appear to be well conducted and with low risk of bias. Oral topotecan plus BSC has advantages over BSC alone in terms of survival (hazard ratio = 0.61; 95% CI, 0.43 to 0.87) and quality of life (EQ-5 D difference: 0.15; 95% CI, 0.05 to 0.25). Intravenous topotecan was at least as effective as CAV in the treatment of patients with recurrent small-cell lung cancer and resulted in improved quality-of-life with respect to several symptoms. CAV was associated with significantly less grade 4 thrombocytopenia compared with IV topotecan (risk ratio = 5.83; 95% CI, 2.35 to 14.42). Survival (hazard ratio = 0.98; 95% CI, 0.77 to 1.25) and response (pooled risk ratio = 1.04; 95% CI, 0.58 to 1.85) data were similar for the oral and IV topotecan groups. Symptom control was also very similar between the trials and between the oral and IV groups. Toxicity data showed a significant difference in favour of oral topotecan for neutropenia (pooled risk ratio = 0.65; 95% CI, 0.47 to 0.89). Indirect evidence showed that oral topotecan was at least as good as or better than CAV on all outcomes (survival, response rates, toxicities, and symptoms) that allowed indirect comparisons, with the only exception being grade four thrombocytopenia which occurred less often on CAV treatment. Conclusions Concerning topotecan both the oral and intravenous options have similar efficacy, and patient preference may be a decisive factor if the choice would be between the two formulations. The best trial evidence for decision making, because it was tested versus best supportive care, exists for oral topotecan. Indirectly, because we have two head-to-head comparisons of oral versus intravenous topotecan, and one comparison of intravenous topotecan versus CAV in similar patients as in the trial against best supportive care, one might infer that IV topotecan and CAV could also be superior to best supportive care, and that oral topotecan has similar effects to CAV with possibly better symptom control. From the evidence discussed above, it is evident that oral topotecan has similar efficacy to IV topotecan (direct comparison) and CAV (indirect comparison). There is no further evidence base of direct or possible indirect comparisons for other comparators than CAV of either oral or IV topotecan.

This systematic review evaluates the diagnostic accuracy of preschool vision screening tests for the detection of amblyopia and its risk factors. The literature searches were conducted in nine bibliographic databases. No limitation to a specific study design, year of publication or language was applied. Studies were included if they compared a vision screening test with a reference test (gold standard) in children from the general population. In addition, the studies had to provide sufficient data to calculate diagnostic accuracy (sensitivity and specificity). Full-text articles were assessed for studies that satisfied the inclusion criteria using the “Quality of Diagnostic Accuracy Studies (QUADAS)” checklist. Two studies with a longitudinal design and 25 cross-sectional studies met the inclusion criteria. One of the longitudinal studies compared a screening programme in children between 1 and 2 years of age with a re-examination at the age of 8. The sensitivity for the screening programme was 86% (range: 64–97%) and the specificity 99% (range: 98–99%). The second longitudinal study compared screening examinations at 8, 12, 18, 25 and 31 months, with a re-examination at the age of 37 months. In this study, the sensitivity of the screening examination increased with age, while the specificity remained unchanged. The cross-sectional studies evaluated different screening settings, visual acuity tests, auto- or photorefractors and stereo tests. A large variety of reference tests, differing criteria for defining amblyopia and its risk factors and methodological limitations of the studies prevented a valid data interpretation. Diagnostic test accuracy of preschool vision screening tests can only be sufficiently investigated after establishing age-related values defining amblyopia, refractive errors and binocular disorders. To address these questions, we recommend a controlled longitudinal study design.

Patient education shows short-term benefits for adults with rheumatoid arthritis. The purpose was to examine the effectiveness of patient education interventions on health status (pain, functional disability, psychological well-being and disease activity) in patients with rheumatoid arthritis (RA). Patient education had a small beneficial effect at first follow-up for disability, joint counts, patient global assessment, psychological status, and depression. At final follow-up (3-14 months) no evidence of significant benefits was found.

Background If the spine is unstable following traumatic spinal cord injury (SCI), surgical fusion and bracing may be necessary to obtain vertical stability and prevent re-injury of the spinal cord from repeated movement of the unstable bony elements. It has been suggested that this spinal fixation surgery may promote early rehabilitation and mobilisation. Objectives To answer the question: is there a difference in functional outcome and other commonly measured outcomes between people who have a spinal cord injury and have had spinal fixation surgery and those who have not? Search methods The following databases were searched: AMED, CCTR, CINAHL, DARE, EMBASE, HEED, HMIC, MEDLINE, NRR, NHS EED. Searches were updated in May 2003 and MEDLINE was searched again in May 2007. The reference lists of retrieved articles were checked. Selection criteria Randomised controlled trials and controlled trials that compared surgical spinal fixation, with or without decompression, to any other treatment, in patients with a traumatic SCI. Data collection and analysis Two reviewers independently selected studies. One reviewer assessed the quality of the studies and extracted data. Main results No randomised controlled trials or controlled trials were identified that compared surgical spinal fixation surgery to other treatments in patients with a traumatic SCI. All of the studies identified were retrospective observational studies and of poor quality. Authors' conclusions The current evidence does not enable conclusions to be drawn about the benefits or harms of spinal fixation surgery in patients with traumatic SCI. Well-designed, prospective experimental studies with appropriately matched controls are needed.

OBJECTIVES: A systematic review was undertaken and an economic model constructed to evaluate the clinical effectiveness and cost-effectiveness of docetaxel (Taxotere, Sanofi-Aventis) in combination with prednisone/prednisolone for the treatment of metastatic hormone-refractory prostate cancer (mHRPC). The main comparators considered were other established chemotherapy regimens and best supportive care. DATA SOURCES: Twenty-one resources (including MEDLINE, EMBASE and the Cochrane Library) were searched to April 2005. REVIEW METHODS: Two reviewers independently assessed studies for inclusion. Data from included studies were extracted and quality assessed. Where appropriate, outcomes were synthesised using formal analytic approaches. A new economic model was developed in order to establish the cost-effectiveness of docetaxel compared with a range of potential comparators. A separate review was undertaken to identify sources of utility data required to estimate quality-adjusted life-years (QALYs). Sensitivity analyses were also undertaken to explore the robustness of the main analysis to alternative assumptions related to quality of life. Monte Carlo simulation was used to propagate uncertainty in input parameters through the model in such a way that the results of the analysis could be presented with their uncertainty. The impact of uncertainty surrounding the decision was established using value of information and implementation approaches. RESULTS: Seven randomised controlled trials were identified that met the inclusion criteria. A direct comparison of docetaxel plus prednisone versus mitoxantrone plus prednisone in an open-label randomised trial showed improved outcomes for docetaxel plus prednisone in terms of overall survival, quality of life, pain and prostate-specific antigen decline. Two other chemotherapy regimens that included docetaxel: docetaxel plus estramustine and docetaxel plus prednisone plus estramustine, also showed improved outcomes in comparison with mitoxantrone plus prednisone. Indirect comparison suggested that docetaxel plus prednisone seems to be superior to corticosteroids alone in terms of overall survival. Conclusions on cost-effectiveness were primarily informed by the results of the in-house model. This indicated that mitoxantrone plus a corticosteroid is probably cheaper and more effective than corticosteroid alone. Compared with mitoxantrone plus prednisone/prednisolone, the use of docetaxel plus prednisone/prednisolone (3-weekly) appears cost-effective only if the NHS is prepared to pay 33,000 pounds per QALY. The incremental cost-effectiveness ratio associated with docetaxel plus prednisone (3-weekly) remained fairly robust to these variations with estimates ranging from 28,000 pounds to 33,000 pounds per QALY. Value of information analysis revealed that further research is potentially valuable. Given a maximum acceptable ratio of 30,000 pounds per QALY, the expected value of information was estimated to be approximately 13 million pounds. CONCLUSIONS: This systematic review of the research suggests that docetaxel plus prednisone seems to be the most effective treatment for men with mHRPC. The economic model suggests that treatment with docetaxel plus prednisone/prednisolone is cost-effective in patients with mHRPC provided the NHS is prepared to pay 33,000 pounds per additional QALY. Future research should include the direct assessment of quality of life and utility gain associated with different treatments, including the effect of adverse events of treatment, using generic instruments, which are suitable for the purposes of cost-effectiveness analyses.

To review the evidence on the clinical effectiveness of etanercept and infliximab for the treatment of active and progressive psoriatic arthritis (PsA) in patients with an inadequate response to standard treatment (including DMARD therapy).A systematic review was conducted. The literature search covered a range of 13 medical databases and submissions were provided by the manufacturers of etanercept and infliximab. Randomised controlled trials (RCTs) of etanercept or infliximab that reported outcomes of disease activity in PsA were reviewed.There were two good quality double-blind, placebo-controlled RCTs each for etanercept and infliximab. The results demonstrated that after initial treatment (12 weeks for etanercept and 14 or 16 weeks for infliximab) both drugs had statistically significant beneficial effects compared with placebo on ACR 20, 50 and 70, PsARC and HAQ scores. Efficacy was not dependent upon concomitant methotrexate. Results at 24 weeks indicated that the response to treatment is maintained. Effects on psoriasis were beneficial, particularly with infliximab. Uncontrolled radiographic assessment data at one year indicated a beneficial effect of both etanercept and infliximab on the progression of joint disease.Our review indicates that both etanercept and infliximab are efficacious in the treatment of PsA with beneficial effects on both joint and psoriasis symptoms and on functional status. There are limited data indicating that etanercept and infliximab can delay joint disease progression. Further long-term data are required to confirm and consolidate the evidence base for both drugs.

OBJECTIVES: To evaluate the clinical effectiveness, safety, tolerability and cost-effectiveness of etanercept and efalizumab for the treatment of moderate to severe chronic plaque psoriasis. DATA SOURCES: Major electronic databases and several Internet resources were searched up to April 2004. REVIEW METHODS: Systematic reviews were undertaken of the efficacy, safety and economic reviews of etanercept and efalizumab. An existing systematic review of the efficacy and safety of other treatments was also updated. Economic models supplied by the manufacturers of etanercept and efalizumab were critiqued. An economic model was then developed of etanercept and efalizumab in the treatment of moderate to severe chronic plaque psoriasis. RESULTS: The review of the clinical evidence identified a total of 39 published and three unpublished studies: eight randomised controlled trials (RCTs) of the efficacy of etanercept (three trials) and efalizumab (five); 10 studies of the adverse effects of the interventions; and 24 RCTs of the efficacy of the other treatments for moderate to severe psoriasis. The trials of the efficacy of the interventions were all double-blind and placebo-controlled trials and generally of good quality, but three of the five efalizumab trials were poorly reported. A total of 1347 patients were included in the etanercept trials and 2963 in the efalizumab trials. Data on the efficacy of etanercept 25 mg twice a week for 12 weeks were available from three RCTs. On average, active treatment resulted in 62% of patients achieving a Psoriasis Area and Severity Index (PASI) 50, 33% achieving a PASI 75, 11% achieving a PASI 90 and 40% were assessed as clear or almost clear. These figures are not adjusted for changes relative to placebo. Improvement in quality of life as assessed by mean percentage change in Dermatology Life Quality Index (DLQI) was around 59% with etanercept 25 mg twice a week compared with 9% with placebo, and all mean differences that could be calculated were statistically significantly in favour of etanercept. Data on the efficacy of etanercept 50 mg twice a week for 12 weeks were available from two RCTs. Across the two trials, the proportion of patients achieving PASI 50, 75 and 90 was 76, 49 and 21%, respectively; the pooled relative risks were all statistically significantly in favour of etanercept. The findings for mean PASI after treatment, mean percentage change in PASI from baseline and mean percentage change in DLQI also demonstrated the efficacy of etanercept treatment. Evidence from one RCT indicates that the response to etanercept is maintained post-treatment, at least in the medium term, and data from uncontrolled follow-up phases reflect and extend these findings. Efalizumab at a dose of 1 mg/kg once a week subcutaneously was studied in five RCTs. Across these trials, 12 weeks of active treatment resulted in an average of 55% of patients achieving PASI 50, 27% PASI 75, 4.3% PASI 90 and 27% clear or minimal psoriasis status. These figures are not adjusted for changes relative to placebo. There is no evidence from RCTs that the response to efalizumab 1 mg/kg once a week is maintained when treatment continues beyond 12 weeks, and long-term follow-up data relate to a range of doses and are poorly reported and so cannot be used to draw even tentative conclusions regarding the long-term efficacy of efalizumab. Uncontrolled data from trial follow-up suggest that time to relapse may be around 60 days. No data indicating the existence or absence of any rebound in psoriasis after discontinuation of efalizumab were identified. There is no evidence relating to the efficacy of efalizumab upon retreatment. A mixed treatment comparison analysis found a higher response rate in terms of PASI 50, 75 and 90 with etanercept than with efalizumab. Injection site reactions appear to be the most common adverse effects of etanercept. Overall, etanercept appears to be well tolerated in short- and long-term use, although many of the long-term data are not from patients with psoriasis. Headache, chills and, to a lesser extent, nausea, myalgia, pain and fever are the common adverse events associated with efalizumab. Overall, withdrawal rates due to adverse events are low. Longer term data for efalizumab are not readily available for evaluation, but the adverse events data up to 3 years appear to reflect those over 12 weeks and to remain stable. Unfortunately, few data for serious infections and serious adverse events with efalizumab are available. For the primary analysis comparing etanercept, efalizumab and supportive care, the results of the York Model suggest that the biological therapies would only be cost-effective for all patients with moderate to severe psoriasis if the NHS were willing to pay over pound 60,000 per QALY gained. In patients with poor baseline quality of life (fourth quartile DLQI), efalizumab, etanercept 25 mg (intermittent), etanercept 25 mg (continuous) and etanercept 50 mg (intermittent) would be cost-effective as part of a treatment sequence if the NHS were willing to pay pound 45,000, pound 35,000, pound 45,000 and pound 65,000 per QALY gained, respectively. In patients who are also at high risk of inpatient hospitalisation (21 days per annum), these therapies would be cost-effective as part of a sequence as long as the NHS were willingness to pay pound 25,000, pound 20,000, pound 25,000 and pound 45,000 per QALY gained, respectively. As part of a secondary analysis including a wider range of systemic therapies as comparators, the York Model found that it would only be cost-effective to use etanercept and efalizumab in a sequence after methotrexate, ciclosporin and Fumaderm. CONCLUSIONS: Clinical trial data indicate that both etanercept and efalizumab are efficacious in patients who are eligible for systemic therapy, but the economic evaluation demonstrates that these biological therapies are likely to be cost-effective only in patients with poor baseline QoL and who are at risk of hospitalisation. Efficacy trials conducted in the specific population for which etanercept and efalizumab are licensed are required, as are long-term comparisons of etanercept and efalizumab with other treatments for moderate to severe psoriasis. Long-term efficacy trials and safety/tolerability data for patients treated with etanercept or efalizumab are required, as are trials on the response of specific subtypes of psoriasis to different drugs. Research on the rate of inpatient hospitalisation in patients with moderate to severe psoriasis is warranted, and the effect of treatment on this rate.

A systematic review was performed to evaluate the clinical effectiveness of docetaxel in combination with prednisolone (docetaxel is licensed in the UK for use in combination with prednisone or prednisolone for the treatment of patients with metastatic hormone-refractory prostate cancer. Prednisone is not used in the UK, but it is reasonable to use docetaxel plus prednisone data in this review of docetaxel plus prednisolone) for the treatment of metastatic hormone-refractory prostate cancer. A scoping search identified a trial of docetaxel plus prednisone vs mitoxantrone plus prednisone, but did not identify any trials comparing docetaxel plus prednisolone/prednisone with any other treatments. Therefore, we considered additional indirect evidence that would enable a comparison of docetaxel plus prednisolone/prednisone with other chemotherapy regimens and active supportive care. Systematic searching (upto April 2005) identified seven randomised controlled trials. One large well-conducted trial assessed docetaxel plus prednisone vs mitoxantrone plus prednisone; this showed statistically significant improvements with 3-weekly docetaxel in terms of overall survival, quality of life, pain response and PSA decline. Two other chemotherapy regimens that included docetaxel with estramustine also showed improved outcomes in comparison with mitoxantrone plus prednisone. Three trials that compared mitoxantrone plus corticosteroids with corticosteroids alone were identified and their results for overall survival combined, which showed very little difference between the two groups. The addition of clodronate to mitoxantrone plus prednisone showed no significant differences in comparison with mitoxantrone plus prednisone alone. The evidence suggests that chemotherapy regimens containing 3-weekly docetaxel are superior to mitoxantrone or corticosteroids alone.

Objectives: To study the burden as experienced by informal caregivers for people with Rheumatoid Arthritis (RA) in Egypt and the Netherlands and to determine which factors are related to this burden. Methods: A total of 99 Dutch and 30 Egyptian females with RA and their caregivers participated in the study. Data were collected by means of questionnaires including the amount of help provided, mental health and subjective burden as experienced by the caregiver, patient demographic and health status, social support, self-efficacy expectations and caregiver characteristics. Differences between Egypt and the Netherlands were analysed with ANCOVA, controlled for age and disease duration. Variables related to subjective burden and mental health were analyzed by multiple regression. Results: The objective burden as measured in the hours spent on helping the patients was less in Egypt (24 hours) compared to the Netherlands (35 hours). But the number of ADL tasks performed by the caregiver was higher in Egypt (4.3 vs 2.4). Subjective burden of the Egyptian caregivers was higher (32.4 vs 14.2) and their mental health was worse (61.5 vs 78.6) than those of the Dutch caregivers.In Egypt 34% of the subjective burden of caregivers could be explained by negative attitude towards help (β = −0.47), worse affect (β = 0.31), and the fact that the caregivers felt that the patients were heavily dependent upon them (β = 0.26). Whereas, in the Netherlands 27% could be explained by negative attitude towards help (β = −0.45), the fact that the caregivers felt that the patients were heavily dependant upon them (β = 0.30), and higher patient income (β = 0.27). Poor mental health among Egyptian caregivers could for 33% be explained by higher level of education (β = −0.47), and more pain (β = −0.47) of patients. Among the Dutch caregivers 45% could be explained by positive attitude towards help (β = −0.53), less negative social support for patients (β = −0.34), high self efficacy of caregivers for giving help (β = 0.27), and good physical health of the caregivers (β = 0.19). Conclusion: Egyptian caregivers for RA patients have higher subjective burden than the Dutch and worse mental health. In both countries negative attitude towards help and high caregiver estimation of dependency of their care-receivers were consistent variables for predicting subjective burden. In Egypt patient variables are the most important variables in predicting poor mental health of the caregivers whereas in the Netherlands caregiver variables are.

OBJECTIVES To assess the clinical effectiveness of treatments for childhood retinoblastoma. DATA SOURCES Electronic databases were searched from inception to April 2004. REVIEW METHODS Studies of participants diagnosed with childhood retinoblastoma, any interventions and all clinical outcomes were eligible for inclusion. Randomised and non-randomised controlled trials and cohort studies with clear comparisons between treatment groups were included. Methodological quality was assessed. A narrative synthesis was conducted. Where possible, studies assessing common interventions were grouped together, with prospective and retrospective studies grouped separately. Emphasis was placed on prospective studies. RESULTS Thirty-one individual studies, from 42 publications, were included in the review. Apart from one non-randomised controlled trial, only comparative studies of observational design were available for any of the treatments. Four of the included studies were prospective and the remaining 27 were retrospective. Most of the studies were of radiotherapy or chemotherapy, with few studies available on enucleation or focal treatments such as brachytherapy, photocoagulation, cryotherapy and thermotherapy. The methodological quality was generally poor, with a high risk of bias in all included studies. The main problems were in relation to how treatment was allocated and lack of consideration of potentially confounding factors, such as initial disease severity, in the study design and data analysis. The evidence base for effectiveness of treatments for childhood retinoblastoma is extremely limited. Owing to the considerable limitations of the evidence identified, it was not possible to make meaningful and robust conclusions about the relative effectiveness of different treatment approaches for childhood retinoblastoma. CONCLUSIONS In the authors' opinion, the evidence base for the effectiveness of treatments for childhood retinoblastoma is not sufficiently robust to provide clear guidance for clinical practice. Ideally, good-quality randomised controlled trials (RCTs) assessing the effectiveness of different treatment options for childhood retinoblastoma are required. Research is required on all the treatments currently used for this condition. Where RCTs are not feasible, for ethical or practical reasons, only high-quality, prospective, non-randomised studies should be given consideration, owing to the generally higher risk of bias in retrospective studies. To reduce the risk of confounding due to allocation by clinical indication, studies should compare patients with similar disease severity rather than compare patients of mixed disease severities. Standardised outcomes should be agreed for use in studies assessing the effectiveness of treatment. These outcomes should encompass potential important adverse effects of treatment such as loss of visual acuity and cosmetic outcome, as well as beneficial effects.

Objective: To examine sensitivity to change of Dutch versions of AIMS2 (arthritis impact measurement scales-2) and AIMS2-SF (short form) components, in comparison with M-HAQ (modified health assessment questionnaire) and the 100 mm visual analogue scale for pain (VAS-pain) in patients with rheumatoid arthritis. Methods: 218 patients participated in a study on patient education. Participants completed the Dutch AIMS2, M-HAQ, and VAS-pain at baseline and after one year; 165 completed both assessments. The education programme did not have any effect on health status. Patients were classified according to change over one year in their responses to the AIMS2 question about general health perception: improved health (n = 32), no change (n = 101), and poorer health (n = 32). Changes in scores over one year were tested with paired t tests, and standardised response means were calculated for AIMS2 and AIMS2-SF components, M-HAQ total score, and VAS-pain in the three classifications of change in health perception. Results: AIMS2 and AIMS2-SF physical, symptom, and affect components showed similar sensitivity to change. The physical and symptom components performed better than M-HAQ and VAS-pain. AIMS2 and AIMS2-SF social interaction and role components were not sensitive to changes in general health perception. The role component was only applicable in 63 patients, because the others were unemployed, disabled, or retired. Conclusions: AIMS2-SF is a good alternative to the AIMS2 long form for the assessment of health status in rheumatoid arthritis, and is preferable to M-HAQ and VAS-pain. Use of the AIMS2-SF makes it easier and less costly to collect data and reduces the burden on patients.

OBJECTIVES: To review systematically the clinical effectiveness and the cost-effectiveness of clopidogrel used in combination with standard therapy including aspirin, compared with standard therapy alone for the treatment of non-ST-segment elevation acute coronary syndromes (ACS). DATA SOURCES: Electronic databases. Manufacturers' submissions. REVIEW METHODS: Studies were selected using rigorous criteria. The quality of randomised controlled trials (RCTs) was assessed according to criteria based on NHS CRD Report No. 4, and the quality of systematic reviews was assessed according to the guidelines for the Database of Reviews of Effect (DARE) criteria. The quality of economic evaluations was assessed according to a specifically tailored checklist. The clinical effectiveness and cost-effectiveness of clopidogrel in combination with standard therapy compared with standard therapy alone were synthesised through a narrative review with full tabulation of the results of the included studies. In the economic evaluations, a cost-effectiveness model was constructed using the best available evidence to determine cost-effectiveness in a UK setting. RESULTS: One RCT (the CURE trial) was a randomised, double-blind, placebo-controlled trial of high quality and showed that clopidogrel in addition to aspirin was significantly more effective than placebo plus aspirin in patients with non-ST-segment elevation ACS for the composite outcome of death from cardiovascular causes, non-fatal myocardial infarction or stroke over the 9-month treatment period. However, clopidogrel was associated with a significantly higher number of episodes of both major and minor bleeding. The results from the five systematic reviews that assessed the adverse events associated with long-term aspirin use showed that aspirin was associated with a significantly higher incidence of haemorrhagic stroke, extracranial haemorrhage and gastrointestinal haemorrhage compared with placebo. Of the cost-effectiveness evidence reviewed, only the manufacturer's submission was considered relevant from the perspective of the NHS. The review of this evidence highlighted potential limitations within the submission in its use of data and in the model structure used. These limitations led to the development of a new model with the aim of providing a more reliable estimate of the cost-effectiveness from the perspective of the UK NHS. This model indicated that clopidogrel appears cost-effective compared with standard care alone in patients with non-ST-elevation ACS as long as the NHS is willing to pay GBP6078 per quality of life year (QALY). The results were most sensitive to the inclusion of additional strategies that assessed alternative treatment durations with clopidogrel. Although treatment with clopidogrel for 12 months remained cost-effective for the overall cohort, provisional findings indicate that the shorter treatment durations may be more cost-effective in patients at low risk. CONCLUSIONS: The results of the CURE trial indicate that clopidogrel in combination with aspirin was significantly more effective than placebo combined with aspirin in a wide range of patients with ACS. This benefit was largely related to a reduction in Q-wave myocardial infarction. There was no statistically significant benefit in relation to mortality. The trial data suggested that a substantial part of the benefit derived from clopidogrel is achieved by 3 months, with a further small benefit over the remaining 9 months of chronic treatment. The results from the base-case model suggest that treatment with clopidogrel as an adjunct to standard therapy (including aspirin) for 12 months, compared with standard therapy alone, is cost-effective in non-ST elevation ACS patients as long as the health service is willing to pay GBP6078 per additional QALY. However, although treatment with clopidogrel for 12 months remained cost-effective for the overall cohort, provisional findings indicate that the shorter treatment durations may be more cost-effective in patients at low risk. To estimate the exact length of time that clopidogrel in addition to standard therapy should be prescribed for patients with non-ST-segment ACS would require a prospective trial that randomised patients to various durations of therapy. This would accurately assess whether a 'rebound' phenomenon occurs in patients if clopidogrel were stopped after 3 months of treatment.

OBJECTIVES: To examine the clinical effectiveness and cost-effectiveness of two alternative antiplatelet agents, clopidogrel and modified-release (MR)-dipyridamole, relative to prophylactic doses of aspirin for the secondary prevention of occlusive vascular events. DATA SOURCES: Electronic databases. REVIEW METHODS: A total of 2906 titles and abstracts were rigorously screened and 441 studies were assessed in detail. Two RCTs were identified. For the assessment of cost-effectiveness, eight reviews were identified. The results were presented in structured tables and as a narrative summary. No additional clinical effectiveness data were presented in either of two company submissions. All economic evaluations (including accompanying models) included in the company submissions were assessed. Following this analysis, if the existing models (company or published) were not sufficient, a de novo model or modified versions of the models were developed. RESULTS: In the CAPRIE trial the point estimate for the primary outcome, i.e. ischaemic stroke, myocardial infarction (MI) or vascular death, favoured clopidogrel over aspirin, but the boundaries of the confidence intervals raise the possibility that clopidogrel is not more beneficial than aspirin. In terms of the secondary outcomes reported, there was a non-significant trend in favour of clopidogrel over aspirin but the boundaries of the confidence intervals on the relative risks all crossed unity. There was no difference in the number of patients ever reporting any bleeding disorder in the clopidogrel group compared with the aspirin group. The incidences of rash and diarrhoea were statistically significantly higher in the clopidogrel group than the aspirin group. Patients in the aspirin group had a higher incidence of indigestion/nausea/vomiting than patients in the clopidogrel group. Haematological adverse events were rare in both the clopidogrel and aspirin groups. No cases of thrombotic thrombocytopenic purpura were reported in either group. Treatment with MR-dipyridamole alone did not significantly reduce the risk of any of the primary outcomes reported in ESPS-2 compared with treatment with aspirin. ASA-MR-dipyridamole was significantly more effective than aspirin alone in patients with stroke or transient ischaemic attacks (TIAs) at reducing the outcome of stroke and marginally more effective at reducing stroke and/or death. Treatment with ASA-MR-dipyridamole did not statistically significantly reduce the risk of death compared to treatment with aspirin. The number of strokes was statistically significantly reduced in the ASA-MR-dipyridamole group compared with the MR-dipyridamole group. In terms of the other primary outcomes, stroke and/or death and death, the results favoured treatment with ASA-MR-dipyridamole but the findings were not statistically significant. There was no difference in the number of bleeding complications between the ASA-MR-dipyridamole and aspirin groups. The incidence of bleeding complications was significantly lower in the MR-dipyridamole treatment group. More patients in the MR-dipyridamole treatment groups experienced headaches compared to patients receiving treatment with aspirin alone. The York model assessed the cost-effectiveness of differing combinations of treatment strategies in four patient subgroups, under a number of different scenarios. The results of the model were sensitive to the assumptions made in the alternative scenarios, in particular the impact of therapy on non-vascular deaths. CONCLUSIONS: Clopidogrel was marginally more effective than aspirin at reducing the risk of ischaemic stroke, MI or vascular death in patients with atherosclerotic vascular disease, however, it did not statistically significantly reduce the risk of vascular death or death from any cause compared with aspirin. There was no statistically significant difference in the number of bleeding complications experienced in the clopidogrel and aspirin groups. MR-dipyridamole in combination with aspirin was superior to aspirin alone at reducing the risk of stroke and marginally more effective at reducing the risk of stroke and/or death. Compared with treatment with MR-dipyridamole alone, MR-dipyridamole in combination with aspirin significantly reduced the risk of stroke. Treatment with MR-dipyridamole in combination with aspirin did not statistically significantly reduce the risk of death compared with aspirin. Compared with treatment with MR-dipyridamole alone, bleeding complications were statistically significantly higher in patients treated with aspirin and MR-dipyridamole in combination with aspirin. Due to the assumptions that have to be made, no conclusions could be drawn about the relative effectiveness of MR-dipyridamole, alone or in combination with aspirin, and clopidogrel from the adjusted indirect comparison. The following would apply for a cost of up to GBP20,000-40,000 per additional quality-adjusted life-year. For the stroke and TIA subgroups, ASA-MR-dipyridamole would be the most cost-effective therapy given a 2-year treatment duration as long as all patients were not left disabled by their initial (qualifying) stroke. For a lifetime treatment duration, ASA-MR-dipyridamole would be considered more cost-effective than aspirin as long as treatment effects on non-vascular deaths are not considered and all patients were not left disabled by their initial stroke. In patients left disabled by their initial stroke, aspirin is the most cost-effective therapy. Clopidogrel and MR-dipyridamole alone would not be considered cost-effective under any scenario. For the MI and peripheral arterial disease subgroups, clopidogrel would be considered cost-effective for a treatment duration of 2 years. For a lifetime treatment duration, clopidogrel would be considered more cost-effective than aspirin as long as treatment effects on non-vascular deaths are not considered. It is suggested that the combination of clopidogrel and aspirin should be evaluated for the secondary prevention of occlusive vascular events. Also randomised, direct comparisons of clopidogrel and MR-dipyridamole in combination with aspirin are required to inform the treatment of patients with a history of stroke and TIA, plus trials that compare treatment with clopidogrel and MR-dipyridamole for the secondary prevention of vascular events in patients who demonstrate a genuine intolerance to aspirin.

To identify existing guidelines and develop a synthesised guideline plus accompanying checklist. In addition to provide guidance on key theoretical, methodological and practical issues and consider the implications of this research for what might be expected of future decision-analytic models.Electronic databases.A systematic review of existing good practice guidelines was undertaken to identify and summarise guidelines currently available for assessing the quality of decision-analytic models that have been undertaken for health technology assessment. A synthesised good practice guidance and accompanying checklist was developed. Two specific methods areas in decision modelling were considered. The first method's topic is the identification of parameter estimates from published literature. Parameter searches were developed and piloted using a case-study model. The second topic relates to bias in parameter estimates; that is, how to adjust estimates of treatment effect from observational studies where there are risks of selection bias. A systematic literature review was conducted to identify those studies looking at quantification of bias in parameter estimates and the implication of this bias.Fifteen studies met the inclusion criteria and were reviewed and consolidated into a single set of brief statements of good practice. From this, a checklist was developed and applied to three independent decision-analytic models. Although the checklist provided excellent guidance on some key issues for model evaluation, it was too general to pick up on the specific nuances of each model. The searches that were developed helped to identify important data for inclusion in the model. However, the quality of life searches proved to be problematic: the published search filters did not focus on those measures specific to cost-effectiveness analysis and although the strategies developed as part of this project were more successful few data were found. Of the 11 studies meeting the criteria on the effect of selection bias, five concluded that a non-randomised trial design is associated with bias and six studies found 'similar' estimates of treatment effects from observational studies or non-randomised clinical trials and randomised controlled trials (RCTs). One purpose of developing the synthesised guideline and checklist was to provide a framework for critical appraisal by the various parties involved in the health technology assessment process. First, the guideline and checklist can be used by groups that are reviewing other analysts' models and, secondly, the guideline and checklist could be used by the various analysts as they develop their models (to use it as a check on how they are developing and reporting their analyses). The Expert Advisory Group (EAG) that was convened to discuss the potential role of the guidance and checklist felt that, in general, the guidance and checklist would be a useful tool, although the checklist is not meant to be used exclusively to determine a model's quality, and so should not be used as a substitute for critical appraisal.The review of current guidelines showed that although authors may provide a consistent message regarding some aspects of modelling, in other areas conflicting attributes are presented in different guidelines. In general, the checklist appears to perform well, in terms of identifying those aspects of the model that should be of particular concern to the reader. The checklist cannot, however, provide answers to the appropriateness of the model structure and structural assumptions, as these may be seen as a general problem with generic checklists and do not reflect any shortcoming with the synthesised guidance and checklist developed here. The assessment of the checklist, as well as feedback from the EAG, indicated the importance of its use in conjunction with a more general checklist or guidelines on economic evaluation. Further methods research into the following areas would be valuable: the quantification of selection bias in non-controlled studies and in controlled observational studies; the level of bias in the different non-RCT study designs; a comparison of results from RCTs with those from other non-randomised studies; assessment of the strengths and weaknesses of alternative ways to adjust for bias in a decision model; and how to prioritise searching for parameter estimates.

Objectives: To evaluate the clinical and cost-effectiveness of quetiapine, olanzapine and valproate semisodium in the treatment of mania associated with bipolar disorder. Data sources: Electronic databases; industry submissions made to the National Institute for Clinical Excellence. Review methods: Randomised trials and economic evaluations that evaluated the effectiveness of quetiapine, olanzapine or valproate semisodium in the treatment of mania associated with bipolar disorder were selected for inclusion. Data were extracted by one reviewer into a Microsoft Access database and checked for quality and accuracy by a second. The quality of the cost-effectiveness studies was assessed using a checklist updated from that developed by Drummond and colleagues. Relative risk and mean difference data were presented as Forest plots but only pooled where this made sense clinically and statistically. Studies were grouped by drug and, within each drug, by comparator used. I? 2 tests of heterogeneity were performed for the outcomes if pooling was indicated. A probabilistic model was developed to estimate costs from the perspective of the NHS, and health outcomes in terms of response tare, based on an improvement of at least 50 in a patient's baseline manic symptoms derived from an interview-based mania assessment scale. The model evaluated the cost-effectiveness of the alternative drugs when used as part of treatment for the acute manic episode only. Results: Eighteen randomised trials met the inclusion criteria. Aspects of three of the quetiapine studies were commercial-in-confidence. The quality of the included trials was limited and overall, key methodological criteria were not met in most trials. Quetiapine, olanzapine and valproate semisodium appear superior to placebo in reducing manic symptoms, but may cause side-effects. There appears to be little difference between these treatments and lithium in terms of effectiveness, but quetiapine is associated with somnolence and weight gain, whereas lithium is associated with tremor. Olanzapine as adjunct therapy to mood stabilisers may be more effective than placebo in reducing mania and improving global health, but it is associated with more dry mouth, somnolence, weight gain, increased appetite, tremor and speech disorder. There was little difference between these treatments and haloperidol in reducing mania, but haloperidol was associated with more extrapyramidal side-effects and negative implications for health-related quality of life. Intramuscular olanzapine and lorazepam were equally effective and safe in one very short (24 hour) trial. Valproate semisodium and carbamazepine were equally effective and safe in one small trial in children. Olanzapine may be more effective than valproate semisodium in reducing mania, but was associated with more dry mouth, increased appetite, oedema, somnolence, speech disorder, Parkinson-like symptoms and weight gain. Valproate semisodium was associated with more nausea than olanzapine. The results from the base-case analysis demonstrate that choice of optimal strategy is dependent on the maximum that the health service is prepared to pay per additional responder. For a figure of less than £7179 per additional responder, haloperidol is the optimal decision; for a spend in excess of this, it would be olanzapine. Under the most favourable scenario in relation to the costs of responders and non-responders beyond the 3-week period considered in the base-case analysis, the incremental cost-effectiveness ratio of olanzapine is reduced to £1236. Conclusions: In comparison with placebo, quetiapine, olanzapine and valproate semisodium appear superior in reducing manic symptoms, but all drugs are associated with adverse events. In comparison with lithium, no significant differences were found between the three drugs in terms of effectiveness, and all were associated with adverse events. Several limitations of the cost-effectiveness analysis exist, which inevitably means that the results should be treated with some caution. There remains a need for well-conducted, randomised, double-blind head-to-head comparisons of drugs used in the treatment of mania associated with bipolar disorder and their cost-effectiveness. Participant demographic, diagnostic characteristics, the treatment of mania in children, the use of adjunctive therapy and long-term safety issues in the elderly population, and acute and long-term treatment are also subjects for further study. © Queen's Printer and Controller of HMSO 2004. All rights reserved.

Objective To examine the clinical effectiveness and cost-effectiveness of oral capecitabine for locally advanced and metastatic breast cancer in relation to its licensed indications. Data sources Twenty-three electronic databases and other databases of ongoing research and Internet resources, bibliographies of retrieved articles and industry submissions. Review methods Two reviewers independently screened and assessed all titles and/or abstracts including economic evaluations. Randomised controlled trials (RCTs) and observational studies that investigated capecitabine monotherapy, in patients pretreated with an anthracycline-containing regimen or a taxane, or capecitabine in combination with docetaxel, in patients pretreated with an anthracycline-containing regimen, were included. The economic evaluation was based on data reported in the manufacturer's submission. Results For capecitabine monotherapy, 12 uncontrolled observational studies were identified. The methodological quality of the studies was low. Capecitabine demonstrated antitumour activity, but was associated with a particular risk of hand-foot syndrome and diarrhoea. Economic evaluation was hampered by the poor quality of the published studies, but compared indirectly with vinorelbine, capecitabine was associated with lower costs and improved patient outcomes. For capecitabine in combination with docetaxel, one RCT was identified. Combination therapy was superior to single-agent docetaxel in terms of survival, time to disease progression and overall response. Adverse events occurred more frequently with combination therapy. The economic evaluation demonstrated an overall improved QALY score for combination therapy with a slight reduction in costs. Conclusions No conclusions could be drawn regarding the therapeutic benefit of capecitabine monotherapy; RCTs are required. Capecitabine appeared cost-effective compared with vinorelbine, but serious doubts remain; the poor quality of the trials may invalidate this conclusion. Based on limited evidence, combination therapy was more effective than single-agent docetaxel and likely to be cost-effective, but was associated with higher incidences of hand-foot syndrome, nausea, diarrhoea and stomatitis.

Objective: To examine sensitivity to change of Dutch versions of AIMS2 (arthritis impact measurement scales–2) and AIMS2-SF (short form) components, in comparison with M-HAQ (modified health assessment questionnaire) and the 100 mm visual analogue scale for pain (VAS-pain) in patients with rheumatoid arthritis. Methods: 218 patients participated in a study on patient education. Participants completed the Dutch AIMS2, M-HAQ, and VAS-pain at baseline and after one year; 165 completed both assessments. The education programme did not have any effect on health status. Patients were classified according to change over one year in their responses to the AIMS2 question about general health perception: improved health (n = 32), no change (n = 101), and poorer health (n = 32). Changes in scores over one year were tested with paired t tests, and standardised response means were calculated for AIMS2 and AIMS2-SF components, M-HAQ total score, and VAS-pain in the three classifications of change in health perception. Results: AIMS2 and AIMS2-SF physical, symptom, and affect components showed similar sensitivity to change. The physical and symptom components performed better than M-HAQ and VAS-pain. AIMS2 and AIMS2-SF social interaction and role components were not sensitive to changes in general health perception. The role component was only applicable in 63 patients, because the others were unemployed, disabled, or retired. Conclusions: AIMS2-SF is a good alternative to the AIMS2 long form for the assessment of health status in rheumatoid arthritis, and is preferable to M-HAQ and VAS-pain. Use of the AIMS2-SF makes it easier and less costly to collect data and reduces the burden on patients.

The aim of this paper is to assess the clinical effectiveness of orlistat used for the management of obesity. Nineteen electronic databases were searched for randomized controlled trials evaluating the effectiveness of orlistat for weight loss or maintenance of weight loss in overweight or obese patients. Each included trial was assessed for methodological quality. Statistical pooling was performed when trials were considered to be sufficiently similar. Twenty-three trials were eligible for inclusion. Placebo-controlled trials recruiting patients with uncomplicated obesity reported statistically significant differences in favour of orlistat for weight loss and changes in obesity-related risk factors at all time points. Trials in obese patients with defined risk factors at baseline showed similar results, however, smaller effect sizes were observed in patients with type 2 diabetes. The effectiveness of orlistat relative to other anti-obesity drugs is currently unclear. When orlistat was added to simvastatin, this proved to be more effective for weight loss than either drug used individually. Orlistat use is associated with a higher incidence of gastrointestinal adverse events compared with placebo. In conclusion, orlistat is more effective than placebo in promoting weight loss, maintenance of weight loss, and improving cardiovascular risk factor profiles. Baseline parameters of patients seen in clinical practice should be taken into account when considering treatment

In this study we examined the differences in perceptions of the patient's health status between rheumatoid arthritis (RA) patients and their spouses, and correlates of these differences with patients' and spouses' well-being.A sample of 188 couples with one member receiving treatment for RA were selected from the rheumatology clinics in Twente, The Netherlands. The mean age of both RA patients and spouses was 56 years. Respondents completed questionnaires, including estimations of both patients and spouses on the patient's functional disabilities and pain, and scales on affect and marital commitment for patients and spouses.Differences in estimations of patients and spouses were considerable. Both over- and underestimations of the patient's functional disabilities by the spouse were associated with the patient's poorer mental health status. Overestimations of the patient's functional disabilities were associated with poorer mental health among spouses.It is essential that any support intended by the spouse is in accordance with the patient's needs. If the patient's condition is misperceived by the spouse, this can lead to ineffective and inappropriate support being given.

Objectives To examine four key areas: (1) the effectiveness and cost-effectiveness of spinal fixation surgery, (2) the consequences of immediate versus delayed referral to a spinal injuries unit (SIU), (3) the number of people with a new spinal cord injury (SCI) who are discharged from hospital without ever being transferred to an SIU, and (4) the effectiveness and cost-effectiveness of steroids for people with SCI. Data sources Searches were carried out on several databases and also on the Internet. Specialist SCI and spinal injury related websites were searched, specifically the Spinal Injuries Association, the British Association of Spinal Cord Injury Specialists and the National Spinal Cord Injury Association. Review methods Three separate search strategies were devised to find studies relating to the four key areas. Two reviewers independently screened all study citations for inclusion. The lists of all retrieved studies were scanned for additional studies. Quality of studies was assessed and data were extracted by one reviewer then checked by the second. Data from included studies were summarised within each key area. For dichotomous data, relative risks were calculated with 95% confidence intervals. Pooled relative risks were calculated as appropriate. For continuous data, mean differences with 95% confidence intervals were calculated and, if data were pooled, weighted mean differences were calculated. Searches were carried out to identify economic evaluations, details of these together with a critical appraisal of quality are presented in structured tables. Quality was assessed using a checklist supplemented with additional comments on the adequacy of methodology where appropriate. Results For spinal fixation versus no fixation, 68 retrospective observational studies were found that suggested some benefits of fixation surgery. Only four studies were found on fixation surgery in SIUs compared with non-SIU hospitals and no significant differences were seen. All 28 studies concerning delayed referral to a SIU were retrospective observational studies. In most, study details were poorly reported and there was doubt over the comparability of groups at baseline and on confounding factors. Times of referral and transfer were not reported separately. Evidence suggested an effect in favour of the SIU group for neurological improvement. No relevant published studies of any design were found regarding how many people with a new SCI are discharged from hospital without ever being transferred to an SIU. Two systematic reviews were found that assessed the effectiveness of steroids. No studies were identified that considered both costs and the impact on patient outcomes of a given intervention. Conclusions Although there was evidence to suggest some benefits of fixation surgery and also a benefit of immediate referral to SIUs compared with delayed or no referral, owing to the limitations of the data these should be interpreted with caution. Not enough data were found to assess whether surgery is more beneficial when carried out in SIUs and further research is required in this area. Well-designed prospective observational studies with appropriately matched controls are needed. High-dose methylprednisolone steroid therapy may be effective in promoting some degree of neurological recovery if given within 8 hours of injury. There is a need for more randomised controlled trials (RCTs) of pharmacological therapy for acute SCI. No published studies of any design were found to answer the question of how many people with acute SCI are discharged from hospital without ever being transferred to an SIU. Primary research involving audit of selected hospital records should be commissioned and published. The search strategy did not identify any full economic evaluations. Future research should include full economic evaluations, possibly alongside a large RCT, which fully consider the costs and consequences of implementing interventions.