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.

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.

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.

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 cost effectiveness of tacrolimus versus microemulsified cyclosporin: a 10-year model of renal transplantation outcomes.

INTRODUCTION AND OBJECTIVE: In 1983, the launch of cyclosporin was a significant clinical advance for organ transplant recipients. Subsequent drug research led to further advances with the introduction of cyclosporin microemulsion (cyclosporin ME) and tacrolimus. This paper presents the results from a long-term model comparing the clinical and economic outcomes associated with cyclosporin ME and tacrolimus immunosuppression for the prevention of graft rejection following renal transplantation. STUDY DESIGN: A model was developed to project the costs and outcomes over a 10-year period following transplantation. The model was based on the results of a prospective, randomised study of 179 renal transplantation recipients receiving either cyclosporin ME or tacrolimus, which was conducted by the Welsh Transplantation Research Group (median follow-up: 2.7 years). METHODS: The short-term costs and outcomes were the averages from the actual head-to-head trial data. From this, the long-term costs and outcomes were extrapolated based on the rate of change in patient and graft survival at 3, 5 and 10 years post transplant, as reported in the 1995 United Kingdom Transplant Support Service Authority Renal Transplant Audit. PERSPECTIVE AND YEAR OF COST DATA: The analysis was conducted from the perspective of a UK transplant unit. Costs were at 1999 prices (pounds sterling 1 = dollars US 1.42 = Euro 1.5) and costs and outcomes were discounted at 6% and 1.5%, respectively. RESULTS: The model estimated that 10 years after transplantation, the proportion of patients surviving was 56% of the cyclosporin ME cohort and 64% of the tacrolimus cohort. The cumulative cost of maintenance therapy at 10 years was pounds sterling 23204 per patient maintained on cyclosporin ME versus pounds sterling 23803 per patient on tacrolimus. The cost per survivor at 10 years was pounds sterling 37000 (tacrolimus) versus pounds sterling 41000 (cyclosporin ME) and the cost per patient with a functioning graft was pounds sterling 39000 versus pounds sterling 45000. A Monte Carlo simulation of the model (10000 simulations) gave an average cost at 10 years of pounds sterling 23279 (SD pounds sterling 3457) for cyclosporin ME and pounds sterling 22841 (SD pounds sterling 3590) for tacrolimus. A (second order) probabilistic sensitivity analysis was also performed. The average cost at 10 years from a simulated cohort of 1000 was pounds sterling 23473 (SD pounds sterling 2154) for cyclosporin ME and pounds sterling 24087 (SD pounds sterling 2025) for tacrolimus. CONCLUSION: Renal transplant recipients maintained on tacrolimus have better short- and long-term outcomes than patients maintained on cyclosporin ME. The long-term use of tacrolimus is a more cost-effective solution in terms of the number of survivors, patients with a functioning graft and rejection-free patients.

Cost-effectiveness of the AMOArray multifocal intraocular lens in cataract surgery.

PURPOSE: To compare the cost and outcomes of bilateral cataract surgery with the foldable AMOArray multifocal intraocular lens (MIOL) versus the foldable monofocal intraocular lens from the health care payer perspective. METHODS: A cost-effectiveness analysis was used to evaluate treatment with the MIOL compared to monofocal lens, using data from clinical trials, literature, expert opinion, and a review of the German health care funding and reimbursement system. RESULTS: The average total direct medical cost per patient (per procedure) with the MIOL was DM 1,774 compared to DM 1,716 with the monofocal lens (1DM = US$0.558 in April 1998). The MIOL was more cost-effective than the monofocal lens in terms of cost per patient (spectacle-free). Cost per patient without overall limitation in vision-related function and cost per patient without limited night vision were similar for both patient groups. The incremental cost of the MIOL for a one-point increase was DM 52 in the self-rated score "quality of vision," DM 82 in "satisfaction with day vision," and DM 115 in "satisfaction with night vision." CONCLUSION: The small additional cost of the MIOL was outweighed by the increased satisfaction with vision experienced by MIOL patients.