Comparative efficacy and safety of bimekizumab in axial spondyloarthritis: a systematic literature review and network meta-analysis.

OBJECTIVES: To compare the efficacy and safety of bimekizumab 160 mg every 4 weeks, a selective inhibitor of interleukin­17F and 17A, with biologic/targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs) in non-radiographic axial spondyloarthritis (nr-axSpA) and ankylosing spondylitis (AS). METHODS: A systematic literature review identified randomised controlled trials until January 2023 for inclusion in Bayesian network meta-analyses (NMAs), including three b/tsDMARDs exposure networks: predominantly-naïve, naïve, and experienced. Outcomes were Assessment of SpondyloArthritis international Society (ASAS)20, ASAS40, and ASAS partial remission (PR) response rates at 12-16 weeks. A safety NMA investigated discontinuations due to any reason and serious adverse events at 12-16 weeks. RESULTS: The NMA included 36 trials. The predominantly-naïve network provided the most comprehensive results. In the predominantly-naïve nr-axSpA analysis, bimekizumab had significantly higher ASAS20 response rates vs secukinumab 150 mg (with loading dose [LD]/without LD), and comparable response rates vs other active comparators. In the predominantly-naïve AS analysis, bimekizumab had significantly higher ASAS40 response rates vs secukinumab 150 mg (without LD), significantly higher ASAS-PR response rates vs secukinumab 150 mg (with LD), and comparable response rates vs other active comparators. Bimekizumab demonstrated similar safety to other b/tsDMARDs. CONCLUSION: Across ASAS outcomes, bimekizumab was comparable to most b/tsDMARDs, including ixekizumab, TNF inhibitors and upadacitinib, and achieved higher response rates vs secukinumab for some ASAS outcomes in predominantly b/tsDMARD-naïve nr-axSpA and AS patients at 12-16 weeks. In a pooled axSpA network, bimekizumab demonstrated comparable safety vs other b/tsDMARDs.

Systematic Review with Meta-Analysis: Efficacy and Safety of Lusutrombopag for Severe Thrombocytopenia in Patients with Chronic Liver Disease Undergoing Invasive Procedures.

INTRODUCTION: Lusutrombopag is an oral thrombopoietin receptor agonist (TPO-RA). Clinical trials have shown lusutrombopag's efficacy in reducing need for preoperative platelet transfusion in patients with chronic liver disease (CLD) and severe thrombocytopenia. This analysis assessed efficacy and safety of lusutrombopag in patients with severe thrombocytopenia and CLD undergoing planned invasive procedures. METHODS: An electronic database search (through 1 December 2020) identified three randomised, placebo-controlled, double-blind clinical trials comparing lusutrombopag with placebo in patients with CLD and platelet count below 50 × 109/L scheduled to undergo a procedure with a perioperative bleeding risk. A random-effects meta-analysis examined treatment effect, with Cochrane Collaboration's tool assessing risk of bias. RESULTS: The meta-analysis included 343 (lusutrombopag 3 mg, n = 173; placebo, n = 170) patients. More patients met the criteria for treatment response (platelet count at least 50 × 109/L and increase of at least 20 × 109/L from baseline anytime during the study) with lusutrombopag versus placebo (risk ratio [RR] 6.39; 95% confidence interval [CI] 3.69, 11.07; p < 0.0001). The primary efficacy outcome, proportion of patients requiring no platelet transfusion and no rescue therapy for bleeding for at least 7 days post procedure, was achieved by more patients treated with lusutrombopag versus placebo (RR 3.42; 95% CI 1.86, 6.26; p = 0.0001). The risk of any bleeding event was significantly lower with lusutrombopag compared to placebo (RR 0.55; 95% CI 0.32, 0.95; p = 0.03); conversely, thrombosis event rates were similar between lusutrombopag and placebo (RR 0.79; 95% CI 0.19, 3.24; p = 0.74). CONCLUSION: This meta-analysis showed that treatment of severe thrombocytopenia with lusutrombopag in patients with CLD prior to a planned invasive procedure was efficacious and safe in increasing platelet counts, avoiding the need for platelet transfusions, and reducing risk of bleeding, thereby enhancing the certainty of evidence supporting the efficacy and safety of lusutrombopag.

Anti-dsDNA Testing Specificity for Systemic Lupus Erythematosus: A Systematic Review.

BACKGROUND: Autoantibody specificity in autoimmune diseases is variable due to each patient's individual spectrum of autoantibodies and the inherent differences between detection methods and tests. Since false-positive results have downstream consequences, we conducted a comprehensive assessment of anti-double stranded DNA (anti-dsDNA) specificity from published studies of systemic lupus erythematosus (SLE). METHODS: A systematic review (MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and Database of Abstracts of Reviews of Effects) identified cross-sectional or case-control studies published January 2004 to August 2019, reporting anti-dsDNA test accuracy data in SLE. Study quality was assessed using Quality Assessment Tool for Diagnostic Accuracy Studies, version 2. A meta-analysis was conducted to estimate specificity by test method or named test where feasible. RESULTS: Thirty studies were included covering 43 different tests. The Crithidia luciliae indirect immunofluorescence test (CLIFT) and fluorescence enzyme immunoassay methods are likely to be ≥ 90% specific (Euroimmun 97.8% (95% CI 96.2%-98.7%) 4 studies; EliA 94.7% (95% CI 91.7%-96.7%), 6 studies; CLIFT 98.7% (95% CI 96.7%-99.5%), 8 studies/7 tests]. For other test methods, specificity was not fully demonstrated to be ≥ 90% and/or the control group included healthy patients possibly overestimating specificity. More studies are required for NOVA Lite [96.0% (95% CI 87.2%-98.9%), 5 studies], chemiluminescence immunoassays [92.3% (95% CI 83.6%-96.6%), 6 studies/4 tests], multiplex immunoassays [89.3% (95% CI 86.1%-91.8%), 4 studies/2 tests], and Farr fluorescent immunoassays (no estimate, 2 studies). Specificity data reported for Farr radioimmunoassays [93.8% (95% CI 85.4-97.5%), 11 studies, 9 tests] and enzyme-linked immunosorbent assays [93.4% (95% CI 89.9%-95.7%), 15 studies/16 tests] lacked consistency. CONCLUSION: Anti-dsDNA testing shows considerable variation in test specificity, with potential impact on the management of SLE patients. This review may help laboratory specialists and clinicians choose and interpret the appropriate anti-dsDNA test for their setting.

Systematic review of anti-dsDNA testing for systemic lupus erythematosus: A meta-analysis of the diagnostic test specificity of an anti-dsDNA fluorescence enzyme immunoassay.

BACKGROUND AND AIMS: The objective of this meta-analysis was to review the diagnostic performance of anti-dsDNA testing, to determine whether test specificity meets the revised 2019 EULAR/ACR classification criteria for systemic lupus erythematosus (SLE). The new criteria state that anti-dsDNA testing should be conducted using "an immunoassay with demonstrated ≥ 90% specificity for SLE against relevant disease controls". MATERIALS AND METHODS: A systematic review (MEDLINE, Embase, CENTRAL and DARE) identified cross-sectional or case-control studies published January 2004 to August 2019, reporting anti-dsDNA test accuracy data. Studies included cases of SLE (confirmed using one or more of three validated SLE classification criteria sets) and a disease control group. Data were adjusted to exclude healthy controls. A hierarchical, bivariate mixed-effect meta-analysis of eligible quantitative studies was conducted in STATA MP v16.1 to produce a pooled estimate of sensitivity and specificity. RESULTS: The review identified six fluorescence immunoassay (FEIA) dsDNA studies (1977 total patients, of whom 47% had SLE) eligible to be included in quantitative meta-analysis and all reported a point estimate >90% for specificity. The meta-analysis estimated a pooled specificity of 94.7% (95% CI 91.67%-96.67%). CONCLUSION: The meta-analysis has demonstrated that the specificity of FEIA dsDNA is ≥90% for SLE, against relevant disease controls, and therefore performs in accordance with the 2019 classification criteria.

Once-Daily Oral Semaglutide Versus Injectable GLP-1 RAs in People with Type 2 Diabetes Inadequately Controlled on Basal Insulin: Systematic Review and Network Meta-analysis.

INTRODUCTION: The relative efficacy and safety of once-daily oral semaglutide vs. injectable glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in subjects with type 2 diabetes (T2D) inadequately controlled on basal insulin were assessed using network meta-analysis (NMA). METHODS: A systematic literature review (SLR) was performed to identify randomised controlled trials of GLP-1 RAs in this population. Data at 26 ± 4 weeks were extracted for efficacy and safety outcomes feasible for the NMA: change from baseline in glycated haemoglobin (HbA1c), weight and blood pressure; HbA1c target levels (< 7.0% and ≤ 6.5%); composite endpoint; incidence of nausea, vomiting or diarrhoea. Comparators of interest were all licensed doses of dulaglutide, exenatide, liraglutide, lixisenatide and once-weekly injectable semaglutide. RESULTS: The NMA included seven trials. Once-daily oral semaglutide 14 mg was associated with significantly greater HbA1c reductions vs. most comparators (treatment differences: - 0.42 to - 1.32%); differences vs. once-weekly injectable semaglutide (0.5 mg and 1 mg doses) were not statistically significant. Once-daily oral semaglutide 14 mg was associated with significantly greater weight reductions vs. exenatide 2 mg and lixisenatide 20 µg (- 2.21 and - 2.39 kg respectively); non-statistically significant weight reductions in favour of once-daily oral semaglutide 14 mg were observed vs. all other comparators except once-weekly injectable semaglutide 1 mg. Similar trends were observed for the proportion of subjects achieving HbA1c < 7.0% and ≤ 6.5% and the composite endpoint. Once-daily oral semaglutide 14 mg was associated with similar odds of experiencing nausea, vomiting or diarrhoea vs. all comparators. CONCLUSION: Once-daily oral semaglutide 14 mg, as an add-on to basal insulin, is an efficacious treatment for reducing HbA1c and weight and meeting glycaemic targets at 26 ± 4 weeks. Once-daily oral semaglutide 14 mg also offers the option of an oral treatment with similar or better efficacy and similar tolerability vs. most injectable GLP-1 RAs.

A hierarchical bivariate meta-analysis of diagnostic test accuracy to provide direct comparisons of immunoassays vs. indirect immunofluorescence for initial screening of connective tissue diseases.

OBJECTIVES: To compare indirect immunofluorescence (IIF) for antinuclear antibodies (ANA) against immunoassays (IAs) as an initial screening test for connective tissue diseases (CTDs). METHODS: A systematic literature review identified cross-sectional or case-control studies reporting test accuracy data for IIF and enzyme-linked immunosorbent assays (ELISA), fluorescence enzyme immunoassay (FEIA), chemiluminescent immunoassay (CLIA) or multiplex immunoassay (MIA). The meta-analysis used hierarchical, bivariate, mixed-effect models with random-effects by test. RESULTS: Direct comparisons of IIF with ELISA showed that both tests had good sensitivity (five studies, 2321 patients: ELISA: 90.3% [95% confidence interval (CI): 80.5%, 95.5%] vs. IIF at a cut-off of 1:80: 86.8% [95% CI: 81.8%, 90.6%]; p = 0.4) but low specificity, with considerable variance across assays (ELISA: 56.9% [95% CI: 40.9%, 71.5%] vs. IIF 1:80: 68.0% [95% CI: 39.5%, 87.4%]; p = 0.5). FEIA sensitivity was lower than IIF sensitivity (1:80: p = 0.005; 1:160: p = 0.051); however, FEIA specificity was higher (seven studies, n = 12,311, FEIA 93.6% [95% CI: 89.9%, 96.0%] vs. IIF 1:80 72.4% [95% CI: 62.2%, 80.7%]; p < 0.001; seven studies, n = 3251, FEIA 93.5% [95% CI: 91.1%, 95.3%] vs. IIF 1:160 81.1% [95% CI: 73.4%, 86.9%]; p < 0.0001). CLIA sensitivity was similar to IIF (1:80) with higher specificity (four studies, n = 1981: sensitivity 85.9% [95% CI: 64.7%, 95.3%]; p = 0.86; specificity 86.1% [95% CI: 78.3%, 91.4%]). More data are needed to make firm inferences for CLIA vs. IIF given the wide prediction region. There were too few studies for the meta-analysis of MIA vs. IIF (MIA sensitivity range 73.7%-86%; specificity 53%-91%). CONCLUSIONS: FEIA and CLIA have good specificity compared to IIF. A positive FEIA or CLIA test is useful to support the diagnosis of a CTD. A negative IIF test is useful to exclude a CTD.

Allergen components in diagnosing childhood hazelnut allergy: Systematic literature review and meta-analysis.

BACKGROUND: Hazelnut-specific IgE antibodies (sIgEs) in serum support the diagnosis of hazelnut allergy, but extract-based tests have low diagnostic specificity, commonly leading to over-diagnosis. Measuring sensitization to individual allergen components may enhance the diagnosis of hazelnut allergy. We systematically examined data on diagnostic accuracy of sIgE to commercially available hazelnut components to compare their individual contributions in diagnosing hazelnut allergy. METHODS: Seven databases were searched for diagnostic studies on patients suspected of having hazelnut allergy. Studies employing component-specific IgE testing on patients whose final diagnosis was determined by oral food challenges were included in the meta-analysis. Study quality was assessed as recommended by Cochrane. RESULTS: Seven cross-sectional studies and one case-control study were identified, seven presenting data on children (N = 635), and one on a mixed age population. Overall, the diagnostic accuracies of sIgE to both Cor a 9 and Cor a 14 were significantly higher than for Cor a 1-sIgE (P < .05). In children, the specificity of Cor a 14-sIgE at 0.35 kUA /L cutoff was 81.7% (95% CI 77.1, 85.6), and 67.3% (60.3, 73.6) for Cor a 9-sIgE. The specificities for Cor a 1-sIgE and hazelnut-sIgE were 22.5% (7.4, 51.2) and 10.8% (3.4, 29.8), respectively. The sensitivity of Cor a 1-sIgE (60.2% [46.9, 72.2]) was lower than for hazelnut extract-sIgE (95.7% [88.7, 98.5]), while their specificities did not differ significantly. CONCLUSION: sIgE to Cor a 14 and Cor a 9 hazelnut storage proteins increases diagnostic specificity in assessing hazelnut allergy in children. The combined use of hazelnut extract and hazelnut storage proteins may improve diagnostic value.

Accuracy of component-resolved diagnostics in peanut allergy: Systematic literature review and meta-analysis.

BACKGROUND: Peanut allergy diagnosis relies on clinical reactivity to peanut supported by detection of specific IgE (sIgE) antibodies. Extract-based sIgE tests have low specificity, so component-resolved diagnostics may complement whole-extract testing. METHODS: We systematically collected peanut allergen component data in seven databases and studied the diagnostic accuracy of peanut storage proteins (Arah1, 2, 3) and cross-reactive peanut proteins (Arah8 PR-10 and Arah9 lipid transfer protein) through meta-analyses. The systematic literature review included studies employing peanut components and oral food challenge (OFC) as reference standard in patients suspected of peanut allergy. Data for component sIgE at pre-defined detection thresholds were extracted and combined in random-effects bivariate meta-analyses. Risk of bias was assessed as recommended by Cochrane, with two additional quality items of importance for this review. RESULTS: Nineteen eligible studies presented data suitable for meta-analysis. In cross-sectional pediatric studies, the pooled sensitivity of Arah2-sIgE at 0.35 kUA /L cutoff was 83.3% [95% CI 75.6, 88.9] and specificity in diagnosing objective peanut allergy was 83.6% [95% CI 77.4, 88.4]. Compared with 0.1 and 1.0 kUA /L, this threshold provided the best diagnostic accuracy. At 0.35 kUA /L, Arah1 and Arah3 had comparable specificity (86.0% and 88.0%, respectively) but significantly lower sensitivity compared with Arah2 (37.0% and 39.1%, respectively; P < .05). CONCLUSION: sIgE to Arah2 can enhance the certainty of diagnosis and reduce the number of OFC necessary to rule out clinical peanut allergy in unclear cases.

A comparative evaluation of gemtuzumab ozogamicin + daunorubicin-cytarabine and other treatments for newly diagnosed acute myeloid leukemia.

AIM: To evaluate the comparative efficacy and safety of gemtuzumab ozogamicin + daunorubicin-cytarabine (GO + DA) versus common induction therapies for newly diagnosed acute myeloid leukemia. Materials & methods: A network meta-analysis following a systematic literature review. RESULTS: In base-case analyses, GO + DA was associated with significantly greater overall survival and relapse-free survival versus most comparators, and similar rates of complete remission versus all evaluated comparators. Similar findings were seen in the subgroup analyses. Grade 3+ bleeding and hepatic events were higher with GO + DA versus some comparators, consistent with GO's profile. No differences were found for other evaluated outcomes. CONCLUSION: GO + DA provides significant overall survival and relapse-free survival benefit versus evaluated induction regimens for newly diagnosed acute myeloid leukemia.

A Network Meta-Analysis Comparing Semaglutide Once-Weekly with Other GLP-1 Receptor Agonists in Japanese Patients with Type 2 Diabetes.

INTRODUCTION: Semaglutide once-weekly (QW) is a novel glucagon-like peptide-1 (GLP-1) analogue administered at a 0.5 or 1.0 mg dose. In the absence of head-to-head trials between semaglutide QW and other GLP-1 receptor agonists (GLP-1 RAs) in a Japanese population, a network meta-analysis (NMA) was performed. The objective was to assess the relative efficacy and safety of semaglutide QW vs GLP-1 RAs in Japanese patients with type 2 diabetes (T2DM), with a specific focus on the comparison between semaglutide 0.5 mg QW and dulaglutide 0.75 mg QW. METHODS: A systematic review (SR) and supplementary Japanese searches were conducted to identify trials of GLP-1 RAs in Japanese patients on diet and exercise, who have previously received 0-1 oral antidiabetic drugs (OADs). Data at 52-56 weeks were extracted for the following outcomes (feasible for analysis in an NMA): glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), weight, systolic blood pressure (SBP), and overall hypoglycemia. The data were synthesized using an NMA and a Bayesian framework. RESULTS: Four trials, identified from the SR and Japanese-specific searches, were relevant for inclusion in the NMA. When compared to dulaglutide 0.75 mg QW, semaglutide 0.5 mg QW was shown to provide significant reductions in HbA1c [- 0.61% (12.3 mmol/mol)], weight (- 1.45 kg), SBP (- 5.03 mmHg), and FPG (- 1.26 mmol/L). No significant differences in the proportion of patients achieving a HbA1c level < 7% (53 mmol/mol) or the risk of overall hypoglycemia were observed between semaglutide 0.5 mg QW and dulaglutide 0.75 mg QW. CONCLUSION: Overall, semaglutide 0.5 mg QW was associated with significant reductions from baseline in HbA1c, weight, SBP, and FPG compared with dulaglutide 0.75 mg QW in Japanese patients with T2DM. These data may provide valuable evidence for clinical decision-making, cost-effectiveness analyses, and health technology appraisal (HTA) requirements. FUNDING: Novo Nordisk Pharma Ltd.

A comparison of a fluorescence enzyme immunoassay versus indirect immunofluorescence for initial screening of connective tissue diseases: Systematic literature review and meta-analysis of diagnostic test accuracy studies.

The aim was to compare indirect immunofluorescence (IIF) and fluorescence enzyme immunoassay (FEIA) for initial screening of connective tissue diseases (CTDs) and to evaluate whether combining IIF with FEIA adds value. A comprehensive systematic literature review was conducted to identify fully paired, cross-sectional or case-control studies on ANA screening of CTD reporting results for IIF and FEIA. Study quality was assessed using the QUADAS-2 checklist. The reference standard was assessed against established classification criteria. The meta-analysis used hierarchical, bivariate and mixed-effects models to allow test results to vary within and across studies. Eighteen studies of good to fair quality were included in the review. IIF had a higher sensitivity than FEIA [cut-off 1:160, 7 studies, 3251 patients, 0.83 (95% CI 0.75-0.89) versus 0.73 (95% CI 0.64-0.80); cut-off 1:80, 7 studies, 12,311 patients, 0.89 (95% CI 0.84-0.93) versus 0.78 (95% CI 0.71-0.84)] but lower specificity [1:160, 0.81 (95% CI 0.73-0.87) versus 0.94 (95% CI 0.91-0.95); 1:80, 0.72 (95% CI 0.62-0.81) versus 0.94 (95% CI 0.90-0.96)]. A double-positive test had a higher likelihood ratio (LR) for CTD (26.2 (95% CI 23.0-29.9)) than a single positive test (14.4 (95% CI 13.1-15.9) FEIA+, 5.1 (95% CI 4.8-5.4) IIF+). A double-negative test result had more clinical value for ruling out CTD than a single negative test (LR 0.15 (95% CI 0.12-0.18) versus 0.21 (95% CI 0.18-0.25) IIF; 0.33 (95% CI 0.29-0.37) FEIA-). A FEIA+/IIF- discordant result had a higher LR than an IIF+/FEIA- discordant result (LR 2.4 (95% CI 1.7-3.4) versus 1.4 (95% CI 1.2-1.7)). Because of the comparatively higher specificity of FEIA and higher sensitivity of IIF, the combination of FEIA and IIF increases the diagnostic value. Clinicians should be acquainted with the clinical presentation of CTD and aware of the advantages and disadvantages of FEIA and IIF to avoid misinterpretation.

Comparative effectiveness of glycemic control in patients with type 2 diabetes treated with GLP-1 receptor agonists: a network meta-analysis of placebo-controlled and active-comparator trials.

BACKGROUND: Clinical studies of patients with type 2 diabetes show that GLP-1 receptor agonists (GLP-1 RAs) improve glycemic control and promote weight loss. We conducted a Bayesian network meta-analysis (NMA) of placebo- and active-controlled randomized trials to assess the comparative effectiveness of liraglutide, albiglutide, dulaglutide, and exenatide twice daily and once weekly, with a focus on glycemic control. MATERIALS AND METHODS: We searched Medline, Embase, and the Cochrane Library (up to December 2014) for core registration programs for US-approved GLP-1 RAs. Patients reaching an A1C target of <7% were analyzed with a binomial model and change in A1C from baseline with a normal model. A covariate analysis assessed the impact of baseline A1C and treatment background on outcomes. RESULTS: The base-case NMA used 23 trials reporting A1C outcomes at ~6 month follow-up. The results, unadjusted and adjusted for baseline A1C, indicated that all GLP-1 RAs resulted in statistically significantly lower A1C at follow-up compared with placebo. The odds of reaching the <7% target were also significantly better compared with placebo. With dulaglutide, exenatide once weekly, and liraglutide, the absolute reduction in A1C at 6 months was 0.9%-1.4%, and was significantly better than exenatide twice daily. Albiglutide was not significantly different from exenatide twice daily. We estimate that ~50% of patients will meet the <7% A1C target within 6 months of commencing GLP-1 RAs. CONCLUSION: This was a comprehensive assessment of the comparative effectiveness of GLP-1 RAs and A1C outcome. GLP-1 RAs are a viable addition to oral antidiabetes therapy, and dulaglutide, exenatide once weekly, and liraglutide are the most effective.

A systematic review and mixed-treatment comparison of dapagliflozin with existing anti-diabetes treatments for those with type 2 diabetes mellitus inadequately controlled by sulfonylurea monotherapy.

BACKGROUND: To compare the first-in-class sodium glucose co-transporter 2 (SGLT2) inhibitor, dapagliflozin, with existing type 2 diabetes mellitus (T2DM) treatment options available within the European Union (EU) for add-on therapy to sulfonylureas (SUs). METHODS: A systematic review was conducted to identify randomised controlled trials (RCTs) in T2DM patients inadequately controlled by SU monotherapy. Direct meta-analysis, Bucher indirect comparisons and Bayesian network meta-analysis (NMA) were conducted on studies meeting predefined inclusion criteria. Sufficient data were available to assess three clinical endpoints at 24 (+/- 6) weeks follow-up: mean change in HbA1c from baseline, mean change in weight from baseline, and the proportion of patients experiencing at least one episode of hypoglycaemia. The effect of confounding baseline factors was explored through covariate analyses. RESULTS: The search identified 1,901 unique citations, with 1,870 excluded based on title/abstract. From reviewing full-texts of the remaining 31 articles, 5 studies were considered eligible for analysis. All studies were comparable in terms of baseline characteristics, including: HbA1c, age and body mass index (BMI). In addition to dapagliflozin, sufficient data for meta-analysis was available for three dipeptidyl peptidase-4 (DPP-4) inhibitors and one glucagon-like peptide-1 (GLP-1) analogue. Based on fixed-effect NMA, all treatment classes resulted in statistically significant decreases in HbA1c at follow-up compared to placebo. Dapagliflozin treatment resulted in significantly decreased weight at follow-up compared to placebo (-1.54 kg; 95% CrI -2.16, -0.92), in contrast to treatment with GLP-1 analogues (-0.65 kg; 95% CrI -1.37, 0.07) and DPP-4 inhibitors (0.57 kg; 95% CrI 0.09, 1.06). The odds of hypoglycaemia were similar to placebo for dapagliflozin and DPP-4 inhibitor add-on treatment, but significantly greater than placebo for GLP-1 analogue add-on treatment (10.89; 95% CrI 4.24, 38.28). Assessment of NMA model heterogeneity was hindered by the small size of the network. CONCLUSIONS: Dapagliflozin, DPP-4 inhibitors and GLP-1 analogues, in combination with SU, all provided better short-term glycaemic control compared to SU monotherapy. Dapagliflozin was the only add-on therapy that had both a favourable weight and hypoglycaemia profile compared to the other classes of treatment evaluated.

Systematic review, network meta-analysis and economic evaluation of biological therapy for the management of active psoriatic arthritis.

BACKGROUND: An updated economic evaluation was conducted to compare the cost-effectiveness of the four tumour necrosis factor (TNF)-α inhibitors adalimumab, etanercept, golimumab and infliximab in active, progressive psoriatic arthritis (PsA) where response to standard treatment has been inadequate. METHODS: A systematic review was conducted to identify relevant, recently published studies and the new trial data were synthesised, via a Bayesian network meta-analysis (NMA), to estimate the relative efficacy of the TNF-α inhibitors in terms of Psoriatic Arthritis Response Criteria (PsARC) response, Health Assessment Questionnaire (HAQ) scores and Psoriasis Area and Severity Index (PASI). A previously developed economic model was updated with the new meta-analysis results and current cost data. The model was adapted to delineate patients by PASI 50%, 75% and 90% response rates to differentiate between psoriasis outcomes. RESULTS: All four licensed TNF-α inhibitors were significantly more effective than placebo in achieving PsARC response in patients with active PsA. Adalimumab, etanercept and infliximab were significantly more effective than placebo in improving HAQ scores in patients who had achieved a PsARC response and in improving HAQ scores in PsARC non-responders. In an analysis using 1,000 model simulations, on average etanercept was the most cost-effective treatment and, at the National Institute for Health and Care Excellence willingness-to-pay threshold of between £20,000 to £30,000, etanercept is the preferred option. CONCLUSIONS: The economic analysis agrees with the conclusions from the previous models, in that biologics are shown to be cost-effective for treating patients with active PsA compared with the conventional management strategy. In particular, etanercept is cost-effective compared with the other biologic treatments.

The efficacy and safety of oral anticoagulants in warfarin-suitable patients with nonvalvular atrial fibrillation: systematic review and meta-analysis.

The novel oral anticoagulants (NOACs) apixaban, dabigatran, and rivaroxaban have been recently indicated for stroke prevention in patients with atrial fibrillation (AF) . Due to a lack of direct head-to-head trials comparing the NOACs, the current systematic review and network meta-analysis (NMA) were conducted to assess their relative efficacy and safety. Three phase III randomized controlled trials enrolling 50 578 patients were included. Results of the NMA show a clear trend favoring NOACs over warfarin with regard to the key outcomes of stroke/systemic embolism and all-cause mortality, with apixaban also showing a favorable response for major bleeding and total discontinuations. Although there were few significant differences among the NOACS with regard to efficacy outcomes, apixaban and dabigatran 110 mg were associated with significantly lower hazards of major bleeding compared with dabigatran 150 mg and rivaroxaban. The NOACs offer a therapeutic advance over standard warfarin treatment in stoke prevention in patients with nonvalvular AF.

Interventions for the treatment of atrial fibrillation: a systematic literature review and meta-analysis.

BACKGROUND: To perform a systematic review/meta-analysis evaluating the efficacy and safety of anti-arrhythmic drugs (AADs) in the treatment of atrial fibrillation (AF). METHODS: Database searches (accessed April 2009) were conducted to identify randomised controlled trials (RCTs). Comparators of interest included all AADs, rate/rhythm strategies or catheter ablation in comparison with AADs. Primary AADs of interest were restricted to Class IC (flecainide and propafenone) and Class III (amiodarone, dofetilide, dronedarone and sotalol). Data were analysed on an intention-to-treat basis and meta-analysis performed using the Peto odds ratio (OR)/fixed-effect model. RESULTS: 113 publications met inclusion criteria. Of these, 74 publications considered an AAD of primary interest. The odds of AF recurrence were generally significantly lower with all active treatments versus non-active control. Dronedarone was the only AAD to show a (non-significant) trend towards reducing the odds of mortality with a narrow CI (OR 0.85 [0.66, 1.09]). Withdrawals due to adverse events (AEs), incidence of serious adverse events (SAEs) and treatment discontinuation were increased following active treatment compared with control, with few significant differences reported between active treatments. Data for other morbidity outcomes such as cardiovascular mortality, hospitalizations or persistence/compliance and health-related quality of life (HRQoL) were limited and meta-analyses were not possible for these outcomes. CONCLUSION: The current meta-analysis confirms the efficacy of AADs in preventing AF recurrence, although their use is associated with a greater incidence of AEs and treatment discontinuation. Further RCTs are required to establish the benefit of AADs in the management of both morbidity outcomes and HRQoL.

Systematic review and network meta-analysis of combination and monotherapy treatments in disease-modifying antirheumatic drug-experienced patients with rheumatoid arthritis: analysis of American College of Rheumatology criteria scores 20, 50, and 70.

BACKGROUND: Biologic disease-modifying antirheumatic drugs (bDMARDs) extend the treatment choices for rheumatoid arthritis patients with suboptimal response or intolerance to conventional DMARDs. The objective of this systematic review and meta-analysis was to compare the relative efficacy of EU-licensed bDMARD combination therapy or monotherapy for patients intolerant of or contraindicated to continued methotrexate. METHODS: Comprehensive, structured literature searches were conducted in Medline, Embase, and the Cochrane Library, as well as hand-searching of conference proceedings and reference lists. Phase II or III randomized controlled trials reporting American College of Rheumatology (ACR) criteria scores of 20, 50, and 70 between 12 and 30 weeks' follow-up and enrolling adult patients meeting ACR classification criteria for rheumatoid arthritis previously treated with and with an inadequate response to conventional DMARDs were eligible. To estimate the relative efficacy of treatments whilst preserving the randomized comparisons within each trial, a Bayesian network meta-analysis was conducted in WinBUGS using fixed and random-effects, logit-link models fitted to the binomial ACR 20/50/70 trial data. RESULTS: The systematic review identified 10,625 citations, and after a review of 2450 full-text papers, there were 29 and 14 eligible studies for the combination and monotherapy meta-analyses, respectively. In the combination analysis, all licensed bDMARD combinations had significantly higher odds of ACR 20/50/70 compared to DMARDs alone, except for the rituximab comparison, which did not reach significance for the ACR 70 outcome (based on the 95% credible interval). The etanercept combination was significantly better than the tumor necrosis factor-α inhibitors adalimumab and infliximab in improving ACR 20/50/70 outcomes, with no significant differences between the etanercept combination and certolizumab pegol or tocilizumab. Licensed-dose etanercept, adalimumab, and tocilizumab monotherapy were significantly better than placebo in improving ACR 20/50/70 outcomes. Sensitivity analysis indicated that including studies outside the target population could affect the results. CONCLUSION: Licensed bDMARDs are efficacious in patients with an inadequate response to conventional therapy, but tumor necrosis factor-α inhibitor combination therapies are not equally effective.

The efficacy and safety of pharmacological prophylaxis of venous thromboembolism following elective knee or hip replacement: systematic review and network meta-analysis.

The present systematic review was conducted to assess the efficacy and safety of apixaban versus other anticoagulants, for the prevention of venous thromboembolism (VTE) following total hip replacement (THR) and total knee replacement (TKR) surgery. Electronic databases were interrogated to identify relevant randomized controlled trials. A series of direct/indirect comparisons and a network meta-analysis were conducted. Indirect comparisons found that the odds ratio of "all VTE and all-cause death" were significantly higher for dabigatran than for apixaban in patients with THR (odds ratio [OR], 2.51; 95% confidence interval [CI], 1.50-4.21) and TKR (OR, 1.72; 95% CI, 1.22-2.42). Rivaroxaban showed similar efficacy to apixaban in patients with THR and TKR (OR, 0.69; 95% CI, 0.38-1.25 and OR, 0.83; 95% CI, 0.57-1.19, respectively). No significant differences were observed in bleeding outcomes between treatments. The novel anticoagulants apixaban, rivaroxaban, and dabigatran demonstrated similar or improved efficacy and similar safety compared with current therapies in this indication.

Long-term medical management of primary open-angle glaucoma and ocular hypertension in the UK: optimizing cost-effectiveness and clinic resources by minimizing therapy switches.

PURPOSE: The objective was to assess the long-term economic consequences of the medical management of glaucoma in the UK. METHODS: The economic evaluation was conducted using the results from a 10-year Markov model based around 3 key triggers for a switch in medical therapy for glaucoma, namely: lack of tolerance (using hyperemia as a proxy); intraocular pressure (IOP) not meeting treatment benchmark; and glaucoma progression. Clinical data from a comprehensive systematic literature review and meta-analysis were used. Direct costs associated with glaucoma treatment are considered (at 2008/9 prices) from the perspective of the UK NHS as payer (outpatient/secondary care setting). Using this model, the economic consequences of 3 prostaglandin-based treatment sequences were compared. RESULTS: Drug acquisition costs account for around 8% to 13% of the total cost of glaucoma and, if ophthalmologist visits are included, amount to approximately £0.80 to £0.90 per day of medical therapy. The total long-term costs of all prostaglandin strategies are similar because of a shift in resources: increased drug costs are offset by fewer clinic visits to instigate treatment switches, and by avoiding surgery or costs associated with managing low vision. Under the latanoprost-based strategy, patients would have longer intervals between the need to switch therapies, which is largely due to a reduction in hyperemia, seen as a proxy for tolerance. This leads to a delay in glaucoma progression of 12 to 13 months. For every 1000 clinic appointments, 719 patients can be managed for 1 year with a latanoprost-based strategy compared with 586 or 568 with a bimatoprost or travoprost-based strategy. CONCLUSIONS: Drug acquisition costs are not a key driver of the total cost of glaucoma management and the cost of medical therapy is offset by avoiding the cost of managing low vision. Economic models of glaucoma should include the long-term consequences of treatment as these will affect cost-effectiveness. This analysis supports the hypothesis that the economic and clinical benefits can be optimized by minimizing therapy switches.

Mixed treatment comparison of repeated measurements of a continuous endpoint: an example using topical treatments for primary open-angle glaucoma and ocular hypertension.

Mixed treatment comparison (MTC) meta-analyses estimate relative treatment effects from networks of evidence while preserving randomisation. We extend the MTC framework to allow for repeated measurements of a continuous endpoint that varies over time. We used, as a case study, a systematic review and meta-analysis of intraocular pressure (IOP) measurements from randomised controlled trials evaluating topical ocular hypotensives in primary open-angle glaucoma or ocular hypertension because IOP varies over the day and over the treatment course, and repeated measurements are frequently reported. We adopted models for conducting MTC in WinBUGS (The BUGS Project, Cambridge, UK) to allow for repeated IOP measurements and to impute missing standard deviations of the raw data using the predictive distribution from observations with standard deviations. A flexible model with an unconstrained baseline for IOP variations over time and time-invariant random treatment effects fitted the data well. We also adopted repeated measures models to allow for class effects; assuming treatment effects to be exchangeable within classes slightly improved model fit but could bias estimated treatment effects if exchangeability assumptions were not valid. We enabled all timepoints to be included in the analysis, allowing for repeated measures to increase precision around treatment effects and avoid bias associated with selecting timepoints for meta-analysis.The methods we developed for modelling repeated measures and allowing for missing data may be adapted for use in other MTC meta-analyses.