MSR105 Tackling Rare Events in Network Meta-Analysis: Comparative Performance of Methods for Sparse Safety Outcomes

Background/Objective: Systematic reviews (SRs) with network meta-analysis (NMA) support evidence-based decision-making by enabling both direct and indirect comparisons across multiple interventions. Given the expanding use of Janus kinase (JAK) inhibitors in rheumatoid arthritis (RA), the methodological rigor of SRs with NMA is essential for trustworthy conclusions. This study is aimed at evaluating the methodological quality of SRs with NMA assessing the efficacy and/or safety of JAK inhibitors in RA. Methods: PubMed and Embase were searched for full-text SRs with NMAs evaluating JAK inhibitors as a therapeutic class in RA. Eligible publications were English-language articles reporting efficacy and/or safety outcomes. Narrative reviews, letters, duplicates, reviews focused on a single JAK inhibitor, and reviews without quantitative synthesis were excluded. Three independent reviewers assessed methodological quality using AMSTAR 2. Descriptive statistics were used to summarize findings. Results: Of the 222 records identified, 18 SRs with NMA met the inclusion criteria: 5 focused on efficacy, 5 on safety, and 8 assessed both. The most consistently fulfilled AMSTAR 2 items were a clearly defined PICO question (100%), duplicate study selection (100%), and reporting of conflicts of interest (100%). Common shortcomings included lack of protocol registration (44%), incomplete reporting of the search strategy (39%), and absence of publication bias assessment (50%). Risk-of-bias assessment varied by review focus: all safety reviews complied (100%), compared with 20% of efficacy reviews and 37% of mixed reviews. Conclusions: Most SRs with NMA of JAK inhibitors in RA present relevant methodological limitations, particularly in protocol registration, search reporting, and risk-of-bias assessment. Methodological standards were generally higher in safety-focused reviews, underscoring the need for more consistent and rigorous conduct and reporting, especially in efficacy and mixed reviews, to strengthen confidence in NMA-derived conclusions.

ObjectiveWe compared the effectiveness and safety of polidocanol 1% endovenous microfoam ablation vs endovenous thermal ablation with radiofrequency or laser energy for treatment of venous insufficiency caused by lower extremity truncal vein incompetence via network meta-analysis of published comparative evidence. MethodsWe conducted a systematic literature review following best practices, including a prospective protocol. We screened studies published in English from 2000 to 2023 for randomized and nonrandomized studies reporting direct or indirect comparisons between polidocanol 1% endovenous microfoam and endovenous thermal ablation. Thirteen studies met our eligibility criteria for the network meta-analysis. The co-primary effectiveness outcomes were the closure rate ≥3 months after procedure and the average change in the Venous Clinical Severity Score. For the subgroup of venous ulcer patients, the ulcer healing rate was the primary effectiveness outcome. The secondary outcomes included safety and patient-reported outcomes. Network meta-analyses were conducted on outcomes having sufficient data. Categorical outcomes were summarized using odds ratios (ORs) with 95% confidence intervals (CIs). Sensitivity tests and estimates of network inconsistency were used to investigate the robustness of our meta-analysis. ResultsWe found that polidocanol 1% endovenous microfoam was not significantly different statistically from endovenous thermal ablation for venous closure (OR, 0.65; 95% CI, 0.36-1.18; P = .16). Although not the primary aim of the study, the network meta-analysis also provided evidence to confirm our supposition that polidocanol 1% endovenous microfoam was significantly differentiated statistically from physician-compounded foam, with higher odds for vein closure (OR, 2.91; 95% CI, 1.58-5.37; P < .01). A sensitivity analysis using the longest available time point for closure in each study, with a minimum of 12 months of follow-up (median, 48 months; range, 12-72 months), showed results similar to those of the main analysis. No association was found between the risk of deep vein thrombosis and the treatment received. The available data were insufficient for a network meta-analysis of Venous Clinical Severity Score improvement and ulcer healing rates. ConclusionsPolidocanol 1% endovenous microfoam was not significantly different statistically from endovenous thermal ablation for venous closure and deep vein thrombosis risk for chronic venous insufficiency treatment, based on a network meta-analysis of published evidence. Polidocanol 1% endovenous microfoam was significantly differentiated statistically from physician-compounded foam, with higher odds of vein closure. A sensitivity analysis found venous closure findings were robust at follow-up intervals of 12 months or greater and for up to 6 years. New evidence meeting the inclusion criteria for this review will be incorporated at regular intervals into a living network meta-analysis.

Clinical management for unexplained infertility includes expectant management as well as active treatments, including ovarian stimulation (OS), intrauterine insemination (IUI), OS-IUI, and in vitro fertilisation (IVF) with or without intracytoplasmic sperm injection (ICSI).Existing systematic reviews have conducted head-to-head comparisons of these interventions using pairwise meta-analyses. As this approach allows only the comparison of two interventions at a time and is contingent on the availability of appropriate primary evaluative studies, it is difficult to identify the best intervention in terms of effectiveness and safety. Network meta-analysis compares multiple treatments simultaneously by using both direct and indirect evidence and provides a hierarchy of these treatments, which can potentially better inform clinical decision-making. To evaluate the effectiveness and safety of different approaches to clinical management (expectant management, OS, IUI, OS-IUI, and IVF/ICSI) in couples with unexplained infertility. We performed a systematic review and network meta-analysis of relevant randomised controlled trials (RCTs). We searched electronic databases including the Cochrane Gynaecology and Fertility Group Specialised Register of Controlled Trials, the Cochrane Central Register of Studies Online, MEDLINE, Embase, PsycINFO and CINAHL, up to 6 September 2018, as well as reference lists, to identify eligible studies. We also searched trial registers for ongoing trials. We included RCTs comparing at least two of the following clinical management options in couples with unexplained infertility: expectant management, OS, IUI, OS-IUI, and IVF (orcombined with ICSI). Two review authors independently screened titles and abstracts identified by the search strategy. We obtained the full texts of potentially eligible studies to assess eligibility and extracted data using standardised forms. The primary effectiveness outcome was a composite of cumulative live birth or ongoing pregnancy, and the primary safety outcome was multiple pregnancy. We performed a network meta-analysis within a random-effects multi-variate meta-analysis model. We presented treatment effects by using odds ratios (ORs) and 95% confidence intervals (CIs). For the network meta-analysis, we used Confidence in Network Meta-analysis (CINeMA) to evaluate the overall certainty of evidence. We included 27 RCTs (4349 couples) in this systematic review and 24 RCTs (3983 couples) in a subsequent network meta-analysis. Overall, the certainty of evidence was low to moderate: the main limitations were imprecision and/or heterogeneity.Ten RCTs including 2725 couples reported on live birth. Evidence of differences between OS, IUI, OS-IUI, or IVF/ICSI versus expectant management was insufficient (OR 1.01, 95% CI 0.51 to 1.98; low-certainty evidence; OR 1.21, 95% CI 0.61 to 2.43; low-certainty evidence; OR 1.61, 95% CI 0.88 to 2.94; low-certainty evidence; OR 1.88, 95 CI 0.81 to 4.38; low-certainty evidence). This suggests that if the chance of live birth following expectant management is assumed to be 17%, the chance following OS, IUI, OS-IUI, and IVF would be 9% to 28%, 11% to 33%, 15% to 37%, and 14% to 47%, respectively. When only including couples with poor prognosis of natural conception (3 trials, 725 couples) we found OS-IUI and IVF/ICSI increased live birth rate compared to expectant management (OR 4.48, 95% CI 2.00 to 10.1; moderate-certainty evidence; OR 4.99, 95 CI 2.07 to 12.04; moderate-certainty evidence), while there was insufficient evidence of a difference between IVF/ICSI and OS-IUI (OR 1.11, 95% CI 0.78 to 1.60; low-certainty evidence).Eleven RCTs including 2564 couples reported on multiple pregnancy. Compared to expectant management/IUI, OS (OR 3.07, 95% CI 1.00 to 9.41; low-certainty evidence) and OS-IUI (OR 3.34 95% CI 1.09 to 10.29; moderate-certainty evidence) increased the odds of multiple pregnancy, and there was insufficient evidence of a difference between IVF/ICSI and expectant management/IUI (OR 2.66, 95% CI 0.68 to 10.43; low-certainty evidence). These findings suggest that if the chance of multiple pregnancy following expectant management or IUI is assumed to be 0.6%, the chance following OS, OS-IUI, and IVF/ICSI would be 0.6% to 5.0%, 0.6% to 5.4%, and 0.4% to 5.5%, respectively.Trial results show insufficient evidence of a difference between IVF/ICSI and OS-IUI for moderate/severe ovarian hyperstimulation syndrome (OHSS) (OR 2.50, 95% CI 0.92 to 6.76; 5 studies; 985 women; moderate-certainty evidence). This suggests that if the chance of moderate/severe OHSS following OS-IUI is assumed to be 1.1%, the chance following IVF/ICSI would be between 1.0% and 7.2%. There is insufficient evidence of differences in live birth between expectant management and the other four interventions (OS, IUI, OS-IUI, and IVF/ICSI). Compared to expectant management/IUI, OS may increase the odds of multiple pregnancy, and OS-IUI probably increases the odds of multiple pregnancy. Evidence on differences between IVF/ICSI and expectant management for multiple pregnancy is insufficient, as is evidence of a difference for moderate or severe OHSS between IVF/ICSI and OS-IUI.

The current gold standard for sentinel lymph node biopsy in breast cancer patients is the dual modality technique (radioisotope and blue dye). Owing to the limitations inherent to the use of radioisotopes, the uptake of this method is limited to approximately 50-60% of breast cancer patients in developed countries. In most centers worldwide with no access to radioisotopes, blue dye is the most commonly employed technique as it is relatively cheap, easy to administer with no radiation exposure risk. However, the use of blue dye is associated with a high false negative rate. We performed a systematic review and network meta-analysis to compare the performance of blue dye and radioisotope against three novel techniques, namely indocyanine green fluorescence (ICG), superparamagnetic iron oxide (SPIO) nanoparticles and contrast enhanced ultrasound (CEUS) using microbubbles. This is the first network meta-analysis synthesizing direct as well as indirect comparisons of performance among different techniques in terms of sentinel lymph node detection and false negative rate, thereby allowing a more robust quantitative analysis. In comparison to a published systematic review on this topic in 2014, the current review had almost double the number of patients and trials included with a total of 35 cohort studies and 4,244 patients. Our systematic review suggested that two of the techniques, indocyanine green fluorescence (ICG) and superparamagnetic iron oxide (SPIO) nanoparticles have consistently performed better than the blue dye technique and similar to gold standard dual modality. Hence, in centres where blue dye was used as a single modality, perhaps ICG and SPIO can offer a viable alternative with improved performance. Future research should focus on the economic evaluations of various techniques as well as to explore the cost-effectiveness and cost-utility of adopting new techniques in the clinical setting. Table 2Pooled estimates of RR and averages on detection rate and false negative rate from network meta-analysis (RR)ICG1.03 (0.96, 1.11)1.08 (1.00, 1.15)1.03 (0.99, 1.06)1.05 (0.96, 1.14)1.12 (1.07, 1.16)*0.67 (0.21, 2.08)SPIO1.03 (0.95, 1.12)0.99 (0.93, 1.06)1.01 (0.95, 1.07)1.09 (1.01, 1.18)*0.16 (0.52, 0.05)0.24 (0.05, 1.08)CEUS0.96 (0.89, 1.02)0.98 (0.90, 1.06)1.03 (0.98, 1.11)0.64 (0.36, 1.13)0.96 (0.34, 2.75)4.00 (1.17, 13.7)*Tc1.00 (0.91, 1.10)1.09 (1.04, 1.15)*0.56 (0.14, 2.23)0.84 (0.36, 1.93)3.49 (0.67, 18.2)0.87 (0.24, 3.23)Tc/BD1.09 (0.98, 1.16)0.29 (0.16, 0.54)*0.45 (0.14, 1.45)1.85 (0.68, 6.06)0.44 (0.20, 0.96)*0.57 (0.13, 2.51)BDBD: Blue dye; CEUS: Contrast-enhanced ultrasound; ICG: Indocyanine green; SPIO: Superparamagnetic iron oxide; Tc: Technetium-99; Tc/BD: Combined used of Technetium-99 and blue dye Top right panel reported the pooled RRs of detection rate from network meta-analysis, and the technique name below each RR was the reference group; Bottom left panel reported the pooled RRs of false negative rate from network meta-analysis, and the technique name to the right of each RR was the reference group; *: Statistical significant with P value &amp;lt; 0.05 Citation Format: Mok CW, Zheng Q, Shi L, Tan S-M. Challenging dual modality as the gold standard for sentinel lymph node biopsy in breast cancer: A systematic review and network meta-analysis of novel and conventional techniques [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-03-26.

Thrombopoietin receptor agonists (TPO-RAs) play a crucial role in stimulating thrombopoiesis. However, conventional meta-analyses have shown inconsistent results regarding the efficacy of thrombopoietin receptor agonists versus placebo. Therefore, we performed a network meta-analysis to assess the effects of five TPO-RAs via indirect comparison. For this network meta-analysis, we considered randomized trials that included any of the following interventions: avatrombopag, lusutrombopag, eltrombopag, romiplostim, recombinant human thrombopoietin (rhTPO). We searched the Medline, PubMed, Embase, the Cochrane Library, and Web of Science databases for randomized controlled clinical trials from inception to January 31, 2021. We use randomized controlled clinical trials of TPO-RAs for treatment of immune thrombocytopenia in adults. The primary outcome was the number of patients achieving platelet response which was defined as the achievement of a platelet count of more than 30 or 50 cells × 109/L in the absence of rescue therapy, and the secondary outcome was the therapy-related serious adverse events and incidence of bleeding episodes. To obtain the estimates of efficacy and safety outcomes, we performed a random-effects network meta-analysis. These estimates were presented as odds ratios with 95% confidence intervals. We use surface under the cumulative ranking probabilities to rank the comparative effects and safety of all drugs against the placebo. In total, 2,207 patients were analyzed in 20 clinical trials. All preparations improved the point estimates of platelet response when compared with the placebo. Avatrombopag and lusutrombopag had the best platelet response compared to the placebo, the former had a non-significant advantage compared to the latter [odds ratio (OR) = 1.91 (95% confidence interval: 0.52, 7.05)]. The treatments were better than eltrombopag, romiplostim, rituximab, and rhTPO + rituximab, with corresponding ORs of 3.10 (1.01, 9.51), 9.96 (2.29, 43.29), 33.09 (8.76, 125.02), and 21.31 (3.78, 119.98) for avatrombopag and 1.62 (0.63, 4.17), 5.21 (1.54, 17.62), 17.34 (5.15, 58.36), and 11.16 (2.16, 57.62) for lusutrombopag. Regarding bleeding, the placebo group had the highest probability of bleeding, whereas lusutrombopag had the lowest risk of bleeding when compared to the placebo. Adverse events were slightly higher in patients receiving rituximab than in those receiving placebo or other treatments. Overall, this meta-analysis showed that avatrombopag may yield the highest efficacy because it has the most favorable balance of benefits and acceptability.

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To compare the efficacy and safety of different prophylactic pharmacological interventions (antiemetic drugs) either against no treatment, placebo or against each other (as mono- or combination prophylaxis) for the prevention of postoperative nausea and vomiting in adults undergoing any type of surgery under general anaesthesia. To explore the best dose or dose range of the antiemetic drugs in terms of efficacy and safety. To generate a clinically useful ranking of antiemetic drugs (mono- and combination prophylaxis) according to efficacy and safety.

Endovascular revascularization of below-the-knee lesions is a crucial treatment for patients with chronic limb-threatening ischemia (CLTI). However, the optimal approach to revascularizing infrapopliteal arteries remains uncertain. This study aims to compare the safety and efficacy outcomes of various endovascular treatment modalities for infrapopliteal artery disease and provide an evidence-based update through a network meta-analysis. We performed a systematic literature search in MEDLINE, EMBASE, and the Cochrane Database for randomized controlled trials published between January 01, 2005, and January 12, 2025. The study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and was prospectively registered in PROSPERO database (CRD42022323480). The primary safety outcome was major adverse events defined as a composite of all-cause death, major amputation, and any re-intervention of the target limb at 30 days. The primary efficacy outcomes included freedom from composite of major amputation, target lesion occlusion, and clinically driven target lesion revascularization (CD-TLR) and primary patency defined as freedom from binary restenosis and CD-TLR at 6 months. The network meta-analysis was conducted in the frequentist framework using random effects model and conventional percutaneous transluminal angioplasty (PTA) as the reference intervention. Treatment effects were reported as odds ratio (OR) with 95% confidence interval (CI) compared with conventional PTA and interventions were ranked using P-scores. Twenty-three studies including 3091 patients treated with PTA, paclitaxel drug-coated balloons (DCB), drug-eluting stents (DES), bare metal stents (BMS), bioresorbable vascular scaffold (BVS), and atherectomy were included. There were no significant differences in the primary safety outcome between different treatment modalities. At 6 months, DCB, atherectomy with DCB, and DES produced the largest benefit for primary efficacy outcomes. DCB (OR, 3.68; 95% CI, 1.37-9.92) had a higher freedom from the primary composite, and atherectomy with DCB (OR, 7.65; 95% CI, 1.03-56.98) and DES (OR, 5.48; 95% CI, 1.54-19.49) had higher primary patency compared with PTA. At 12 months, the benefit of atherectomy with DCB was sustained for primary patency, and BVS was ranked first for freedom from the primary composite. There was no benefit of BMS compared with PTA at any timepoint. This network meta-analysis evaluating 7 endovascular treatment modalities provides evidence of improved efficacy outcomes with DCB, atherectomy with DCB, DES, and BVS compared with PTA for treating infrapopliteal lesions in patients with CLTI.Clinical ImpactLocal antiproliferative drug delivery, whether by balloon-expandable sirolimus/everolimus DES or paclitaxel DCB or everolimus BVS, is necessary to improve patency and efficacy outcomes for the treatment of infrapopliteal artery disease. Furthermore, combining atherectomy with drug delivery shows promising potential. Emerging endovascular targeted drug delivery therapies with limus-based DCB or scaffolds promise to provide greater drug transfer efficiency and a more effective therapeutic alternative that overcomes the limitations of metallic stents in one of the most challenging vascular beds.

Anti-VEGF drugs are effective at improving vision in people with DMO with three to four in every 10 people likely to experience an improvement of 3 or more lines VA at one year. Aflibercept may confer some advantage over ranibizumab and bevacizumab in people with DMO at one year in visual and anatomic terms but it is unclear whether this applies to the long-term. There is a need for more evidence on the long-term (greater than two years) comparative effects of these anti-VEGF agents. Evidence from RCTs may not apply to real-world practice, where people in need of antiangiogenic treatment are often under-treated and under-monitored.We found no signals of differences in overall safety between the three antiangiogenic drugs that are currently available to treat DMO, but our estimates are imprecise for cardiovascular events and death.

A systematic literature review and network meta-analysis of effectiveness and safety outcomes in advanced melanoma

It is crucial that the safety profiles of biosimilars are similar to those of the original biologics. A better understanding of biosimilars and their relative safety and immunogenicity profiles are required for healthcare providers to prescribe them to patients with life-threatening cancer diseases who receive chemotherapies with potentially serious adverse events (AEs). The purpose of this study was to collate and analyze currently available safety and immunogenicity outcomes of biosimilars used in oncology and compare their safety information with those of the original biologics. The MEDLINE and Cochrane Library databases were searched as at 28 February 2022. Four anti-cancer biosimilar molecules were considered: bevacizumab, trastuzumab, rituximab, and (peg)filgrastim. Through a systematic review, we selected the randomized controlled trials (RCTs) comparing safety outcomes between the biosimilars and original biologics of the four molecules. As safety outcomes, various treatment-emergent adverse events (TEAEs) were collated, such as any TEAE, serious AE, and TEAE higher than grade 3. A risk ratio (RR) per category of TEAE was estimated through a meta-analysis. A network meta-analysis (NMA) was also conducted to compare the safety among the biosimilar brands for TEAEs over 25% with higher variability in addition to the serious AE cases. Forty-nine RCTs were identified. The results from the meta-analysis showed that the safety and immunogenicity profiles of all four biosimilar molecules are comparable with that of the original biologics at the TEAE level without statistically significant differences, except for diarrhea for (peg)filgrastim. The incidence of diarrhea with (peg)filgrastim was less than that with the original biologic (RR 0.66, 95% confidence interval 0.50-0.89). The NMA results showed similar safety profiles among the biosimilar brands for all four biosimilar molecules, except for the serious adverse event of a trastuzumab biosimilar (RR 0.296, 95% credible interval 0.109-0.840). The meta-analysis and NMA for all four biosimilars showed that the safety and immunogenicity profiles of biosimilar products in oncology are generally comparable with that of the original biologics at the TEAE level. However, additional evidence needs to be collected since several TEAEs of specific biosimilars were out of the equivalent range. The results of this study provide comparative safety information and a better understanding of oncology biosimilars for healthcare providers to prescribe them to patients.

Background:Cerebral infarction is a commonly dangerous disease also with high morbidity and mortality. Thrombolytic agent is an effective method to treat it, but their relative efficacy and safety are unclear. A network meta-analysis (NMA) will be conducted to resolve this urgent problem.Methods:The PubMed, Embase, and Cochrane library will be systematically search from their inception to November 2018. All randomized controlled trials (RCTs) will be included this NMA and their risk of bias will be assessed using Cochrane handbook tool. The outcomes of efficacy and safety including: Modified Rankin Scale scores, reperfusion rate, incidence of symptomatic intracerebral hemorrhage and all-cause mortality. A network meta-analysis will be performed using R x64 3.5.1 software and pairwise meta-analysis will be conducted using Stata 12.0 software (Stata Corp., College Station, Texas). Grading of Recommendations Assessment, Development and Evaluation (GRADE) will be used to assess quality of outcomes.Results:The results of NMA will be published in a peer-reviewed journal.Conclusion:The NMA will provide a comprehensive evidence summary on thrombolytic agents for patients with cerebral infarction.

BackgroundBehavioral and psychological symptoms of dementia (BPSD) are highly prevalent in patients with dementia. Both pharmacological and non-pharmacological strategies are commonly used to treat these symptoms, but their comparative safety and efficacy is unknown.MethodsWe will conduct a systematic review of the published and unpublished literature to retrieve all articles pertaining to outcomes of safety and efficacy associated with pharmacological and non-pharmacological treatments of BPSD for patients living in the community and institutionalized care settings. Our primary outcome of efficacy is a change in aggression. Our primary outcome of safety will be risk of fracture. These primary outcomes were chosen by stakeholders involved in the care of patients experiencing BPSD. Possible secondary outcomes of efficacy will include a change in agitation, depressive symptoms, and night-time behaviors. Possible secondary outcomes of safety will include the risk of stroke, falls, and mortality. All article screening, data abstraction, and risk of bias appraisal will be completed independently by two reviewers. If the assumption of transitivity is valid and the evidence forms a connected network, Bayesian random-effects pairwise and network meta-analyses (NMAs) will be conducted. Relative treatment rankings will be reported with mean ranks and the surface under the cumulative ranking curve.DiscussionWe will identify the safest and most efficacious treatment strategies for patients with BPSD from among our most highly ranked treatments. The results of this study will be used to guide decision-making and improve patient care.Systematic review registrationPROSPERO registry number CRD42017050130.

BackgroundMultiple novel oral anticoagulants and left atrial appendage closure devices (WATCHMAN) have been tested against dose-adjusted vitamin K antagonists in randomized controlled trials for stroke prophylaxis in non-valvular atrial fibrillation. No direct comparisons of these strategies are available from randomized controlled trials. We conducted the current analyses by combining efficacy and safety characteristics of all FDA approved stroke prophylaxis treatment strategies for patients with non-valvular atrial fibrillation.Materials and MethodsWe searched SCOPUS from 1945 till October 2015 for randomized controlled trials comparing these strategies and reporting efficacy and safety outcomes. Six randomized controlled trials were identified and included in the final analyses and review. We followed PRISMA guidelines for network meta-analyses while reporting the current analyses. We collected data on ischemic stroke, major bleeding, and the composite primary safety endpoint as defined by various randomized controlled trials. Network meta-analyses were conducted using consistency and inconsistency models for efficacy and safety outcomes. Surface under the cumulative ranking curve were then utilized to cluster rank these treatments for safety and efficacy.ResultsSix randomized controlled trials with 59,627 patients comparing six treatment strategies were eligible for the analyses. All prophylaxis strategies had comparable rates of ischemic stroke. Apixaban was associated with the least number of primary safety endpoint events as compared with all other treatments. In the cluster analyses assessing safety and efficacy, apixaban, edoxaban and dabigatran ranked best followed by vitamin K antagonists and rivaroxaban, whereas the WATCHMAN left atrial appendage closure device ranked last.ConclusionsDose-adjusted vitamin K antagonists, novel oral anticoagulants, and the WATCHMAN left atrial appendage closure devices are equally efficacious for ischemic stroke prevention but these treatments have different safety profiles. More randomized controlled trials are needed to directly compare these strategies.

<b>Background:</b> Triple FDC therapy is recommended by GOLD in severe COPD patients experiencing frequent exacerbations and/or symptoms not controlled by dual FDCs. Nevertheless, no RCTs have directly compared the different ICS/LABA/LAMA FDCs. <b>Aim:</b> To compare the approved ICS/LABA/LAMA FDCs on the main functional, clinical, and safety outcomes in COPD. <b>Methods:</b> A network meta-analysis was performed by connecting BDP/FOR/GLY, BUD/GLY/FOR, and FF/UMEC/VI via ICS/LABA or LABA/LAMA FDCs arms. The following outcomes were investigated: risk of exacerbation, trough FEV1, TDI, SGRQ, risk of serious adverse events (SAEs), cardiovascular (CV) SAEs, pneumonia, and all-cause mortality. The surface under the cumulative ranking curve analysis(SUCRA) was also carried out. The study was consistent with PRISMA-P. <b>Results:</b> Data from 21,809 COPD patients were extracted from the ETHOS, IMPACT, KRONOS, and TRILOGY studies. No significant differences were detected across the triple FDCs with respect to the efficacy and safety outcomes (Figure 1A). SUCRA ranked BUD/GLY/FOR the most effective FDC on exacerbation and TDI, and FF/UMEC/VI on FEV1 and SGRQ; no concerns raised on the safety profile, and the protection against mortality was related with the dose of ICS (Figure 1B). <b>Conclusions</b> All triple FDC are effective and safe in COPD regardless of the regimen of administration (twice daily vs. once daily), with no relevant difference on the risk of CV SAEs and pneumonia.

Background: Rheumatoid arthritis (RA) is a wide-spread and debilitating disorder that is becoming increasingly relevant in an aging global population. Identifying and treating RA early in disease course is critical for preventing disability and joint damage. Objectives: The goal of this systematic literature review (SLR) and meta-analysis was to compare the relative efficacy of abatacept (ABA) to other currently recommended therapies for patients with early RA. Methods: We followed Cochrane guidelines for conducting intervention reviews. Population of interest was adult patients with active RA for ≤2 years treated with recommended therapies per the 2015 ACR guidelines as well as targeted synthetic therapies. Studies of interest were randomized controlled trials (RCTs) and observational studies. Outcomes included ACR50, DAS28, radiographic change, and adverse events where available. A search from January 1998 to June 2018 was performed on MEDLINE®, Embase, and the Cochrane CENTRAL databases. Additionally, a hand-search was performed on US and European clinical trials registries from January 2005 to June 2018 and conference proceedings from ACR and EULAR from 2014 to 2018. A Bayesian network meta-analysis (NMA) was performed on the DOC Data™ platform for the RCTs with reported results on ACR50, DAS28 remission, total withdrawal, and withdrawal due to adverse events. Results: We identified 90 publications on 69 unique trials reporting efficacy and safety outcomes in patients with early RA, including 43 RCTs and 26 observational studies. The included studies were low risk as assessed by the Cochrane Collaboration’s tool for assessing risk of bias. The studies were predominantly double-blind phase III or IV trials. Twenty-eight trials were included in the NMA evaluating ABA (n=1 trial), ABA+MTX (n=2), ADA+MTX (n=6), CTZ+MTX (n=2), ETN (n=1), ETN+MTX (n=1), HCQ+SSZ+MTX (n=1), HCQ+SSZ+Pred+MTX (n=1), IFX+MTX (n=4), MTX (n=21), MPred+MTX (n=2), MPred+Pred+MTX (n=1), Pred+SSZ+MTX (n=2), Pred+MTX (n=4), Pred (n=1), SSZ (n=4), SSZ+MTX (n=2), TCZ (n=2), TCZ+MTX (n=2), TOF (n=2), and TOF+MTX (n=2). Abatacept as monotherapy was similar to the combination of ABA and methotrexate for efficacy outcomes, ACR 50 (ABA vs ABA+MTX RR 0.82 [95% CI 0.51-1.35]), and DAS28 Remission (RR 0.76 [95% CI 0.39-1.49]), as well as for all-cause withdrawal (RR 1.8 [95% CI 0.91-3.2]) and withdrawal due to adverse events (RR 2.35 [95% CI 0.69-7.38]). Both ABA as monotherapy and ABA+MTX were similar to all other comparators (as monotherapy or combination therapy) with respect to main efficacy and safety outcomes. Data reported in observational studies was in concert with the RCT analysis. Conclusion: The results of this NMA demonstrate similar efficacy between ABA and other biologics both as monotherapy and in combination with traditional DMARDS in early RA. Further investigation and comparison of different treatment options for early RA is warranted as the growing evidence base evolves in favor of using more novel therapies for RA. ABA=abatacept; ADA=adalimumab; CTZ=certolizumab; ETN= etanercept; HCQ=hydroxychloroquine, IFX= infliximab, MPred= methylprednisolone, MTX=methotrexate; Pred=prednisone, SSZ=sulfasalazine, TCZ= tocilizumab, TOF=tofacitinib Disclosure of Interests: Damemarie Paul Shareholder of: Bristol-Myers Squibb, Employee of: Damemarie Paul is an employee of Bristol-Myers Squibb., Leticia Ferri Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, Grace Crocket Consultant for: Grace Crocket is a consultant for Bristol-Myers Squibb., Lauren Mintzer Grant/research support from: Lauren Mintzer is an employee of Doctor Evidence LLC, and the study was funded by Bristol-Myers Squibb., Mir Sohail Fazeli Grant/research support from: Mir Sohail Fazeli is an employee of Doctor Evidence LLC, and the study was funded by Bristol-Myers Squibb.