This Meta-Analysis Evaluates the Optimal Timing for Initiating and Discontinuing Eltrombopag for Aplastic Anemia

This Meta-Analysis Evaluates the Optimal Timing for Initiating and Discontinuing Eltrombopag for Aplastic Anemia | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article This Meta-Analysis Evaluates the Optimal Timing for Initiating and Discontinuing Eltrombopag for Aplastic Anemia Shuai Tan, Mingyue Shang, Yixian Guo, Li Su, Huanyuan Wang, Qiang Ma, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7631623/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Aplastic anemia (AA) is a bone marrow failure syndrome. How to achieve better efficacy of Eltrombopag (EPAG) and IST in the treatment of AA is still unclear. This meta-analysis compares the efficacy of EPAG+IST verses IST alone, and assesses the optimal timing and duration for starting EPAG in different ages of AA patients. Methods: The literature was retrieved from Chinese and English databases up to July 1, 2025. The analysis was conducted using RevMan 5.4 software, employing a fixed effects model to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the outcomes. The I² statistic was used to assess heterogeneity among included studies. Results: 21 studies involving 2,239 patients were included. The overall response rate in the EPAG+IST group was higher at 3 months (OR = 2.13, 95% CI 1.65–2.74, p < 0.00001) and 6 months (OR = 2.13, 95% CI 1.73–2.61, p < 0.00001). There was no significant difference between two groups at 12 months (OR = 1.14, 95% CI 0.86–1.51, p = 0.36, I² = 35%). For adults, it is recommended the concurrent therapy of EPAG and IST, and continue for a period of 3 months to achieve significant hematological improvement (HI). If EPAG was added after 7 days, patients will achieve HI for about 6 months. For children, regardless of the concurrent or nonconcurrent therapy, it is recommended to continue for about 6 months to achieve better HI. Conclusion: Eltrombopag should be used as early as possible, as it shows a better HI compared with simply IST treatment within 3-6 months, with no significant difference in risk. Concurrent therapy of EPAG should be performed and extending EPAG treatment beyond 12 months may not yield significantly enhanced benefits. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42024604778 Aplastic anemia (AA) Bone marrow failure (BMF) Eltrombopag(EPAG) Immunosuppressive therapy (IST) Thrombopoietin receptor agonists (TPO-RA) Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Highlights Our study indicates that Eltrombopag should be used as early as possible, as it shows better hematological improvements (HIs) compared with simply IST treatment within 3-6 months, with no significant difference in risk. For adults, it is recommended the concurrent therapy of EPAG and IST (EPAG was added within 7 days of the start of IST treatment), and continue for a period of 3 months to achieve significant HI. If EPAG was added after 7 days, patients will achieve HI for about 6 months. For children, regardless of the concurrent or nonconcurrent therapy, there was no significant difference compared with IST alone in 3 months. It is recommended to continue for about 6 months to achieve better HI. For all AA patients, the HIs of additional Eltrombopag for more than 12 months were not significantly different from those of simply IST. Introduction Aplastic anemia (AA), a bone marrow failure (BMF) syndrome, is characterized by marrow hypoplasia and peripheral blood cytopenia[ 1 ]. The pathophysiology of BMF can arise from chemical or physical damage, a compromised immune system (primarily due to T cells), or constitutional genetic defects affecting immune regulation[ 2 ]. The incidence of AA ranges from 0.6 to 7 cases per million people per year, with a higher rate observed in adolescents and older adults[ 3 ]. Frontline treatment of AA depends on disease severity, donor availability, and patient age, primarily involving immunosuppressive therapy (IST) and hematopoietic stem cell transplantation (HSCT). Standard IST, including anti-thymocyte globulin (ATG) and cyclosporine A (CSA), yields a hematologic response rate and transfusion independence of 60 to 70%[ 4 ],[ 5 ]. Nonetheless, about one-third of patients relapse, and 10 to 15% may develop cytogenetic abnormalities in the long term[ 5 ]. Eltrombopag (EPAG), an oral thrombopoietin-receptor agonist, is effective in patients with aplastic anemia refractory to immunosuppression[ 6 ],[ 7 ]. Recent studies indicate that adding EPAG to IST is associated with significantly higher rates of hematologic response in patients with severe aplastic anemia compared to standard IST[ 6 ],[ 8 ]. However, response rates with EPAG combined with IST vary between adults and children[ 8 ],[ 9 ], and also depend on different EPAG maintenance durations[ 10 ]. In clinical practice, there are no conclusive guidelines regarding the optimal timing for initiating and discontinuing eltrombopag for different populations. Therefore, we conducted this systematic review and meta-analysis to compare the efficacy of EPAG + IST with that of standard IST in patients with AA and to assess the optimal initiation and maintenance timing of EPAG in both adults and children. Methods The recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines[11] were used to formulate the systematic review and meta-analysis eligibility criteria. Search strategy Eligible studies published before July 1, 2025, were retrieved by two independent authors (S. Tan and MY. Shang) from PubMed, EMBASE, Web of Science, the Cochrane Library, LILACS, CNKI, WANFANG, VIP, and the Chinese Biomedical Literature Database (CBM). The search terms used to retrieve relevant studies included "Aplastic Anemia" , "Eltrombopag" and "immunosuppressive therapy". Additional studies were identified from the bibliographies of screened articles as appropriate. Outcomes and study selection The primary outcomes were overall response (defined as either complete or partial response) and complete response (defined as an absolute neutrophil count [ANC] ≥ 1.0 × 10 9 /L, hemoglobin [Hb] levels ≥ 100 g/L, and a platelet count ≥ 100 × 10 9 /L) at 3, 6, and 12 months. The secondary outcome was partial response (as defined in each included study) at the same time points. Two authors (YX. Guo and L. Su) independently screened the titles and abstracts of all studies and subsequently examined the full texts of eligible studies. In cases of disagreement during the study selection process, consensus was reached through group discussion with a third author (HY. Wang). Data extraction Two authors (Q. Ma and WH. Hui) independently collated the baseline characteristics of each included study using a standardized Excel table. The baseline characteristics were as follows: (1) study data, including the first author, publication year, and study design; (2) patient data, encompassing the number of patients, age categories, and gender distribution; (3) grouping information, detailing the initiation time of EPAG and immunosuppressive therapy programs; and (4) primary and secondary outcomes. Quality assessment and bias risk assessment Two authors (J. Ni and ZH. Cai) independently evaluated the quality of non-randomized controlled trials (non-RCTs) using the Newcastle-Ottawa Scale (NOS). This assessment utilized nine items in three main categories: selection (score 3), comparability (score 3), and outcome assessment (score 3). Each study received a total score of 9, with a score of ≥ 6 indicating high quality. For randomized controlled trials (RCTs), the Cochrane Collaboration tool was employed. Assessments were categorized as “low risk of bias,” “unclear risk of bias,” or “high risk of bias” based on seven criteria: Random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other biases. Any disagreements in this process were resolved through discussion or adjudication by a third author (HZ. He). Statistical analysis All statistical tests were conducted using RevMan 5.4 software. A fixed-effects model was employed to calculate odds ratios (ORs) with 95% confidence intervals (CIs) for both primary and secondary outcomes. I² statistics were used to assess the heterogeneity of the included studies. The fixed-effects model was applied when p > 0.1 and I² < 50%, while the random-effects model was used when p 50%. Subgroup analyses were performed based on the initiation time of EPAG (0–7 days vs. > 7 days), age (< 18 years vs. ≥ 18 years), and region (Asia vs. North America). Results Outcomes of the search process The initial search yielded a total of 2,609 records among all databases, from which 596 duplicates were detected and removed. After reviewing the titles and abstracts of the remaining 2,013 studies according to the exclusion criteria, 1,949 studies were excluded. We then examined the full texts of the remaining 64 articles, resulting in 21 studies that met the inclusion criteria and were ultimately included in our meta-analysis (Figure 1). Study Characteristics and Quality Evaluation The characteristics of the included studies are summarized in Table 1. In total, 2,239 patients were included in our meta-analysis, with 1,059 treated with EPAG + IST and 1,180 treated with IST alone. Of the 21 included studies, 7 were prospective (4 were RCTs) and 14 were retrospective. The quality assessments of the 17 cohort studies are shown in Table 2: 6 studies had a NOS score of 9, 5 studies had a score of 8, 4 studies had a score of 7, and 3 studies had a score of 6, all meeting the study criteria. The Cochrane risk of bias assessment for the three RCTs indicated low risk of bias and high quality, as presented in Supplemental Figure 1. Outcomes of this Meta‑Analysis Overall Response The overall response after 3 months was evaluated in 14 studies, encompassing 1,159 patients with AA (Fig. 2A). The results indicated that the overall response rate in the EPAG combined with IST group was higher than in the IST group (OR=2.13, 95% CI 1.65–2.74, p < 0.00001), with no heterogeneity among these studies ( p = 0.10, I² = 34%). At 6 months, 18 studies including 1,990 patients with AA were evaluated (Fig. 2B), showing a similar trend: The overall response rate in the EPAG combined with IST group was higher than in the IST group (OR=2.13, 95% CI 1.73–2.61, p < 0.00001), again with no heterogeneity ( p = 0.24, I² = 18%). At 12 months, 10 studies with 953 patients were assessed (Fig. 2C), revealing no significant difference between the EPAG + IST and IST alone groups according to the pooled results (OR=1.14, 95% CI 0.86–1.51, p = 0.36, I² = 35%). Complete Response The complete response at 3 months was evaluated in 13 studies involving 1,124 patients with AA (Fig. 3A). Our analysis suggested that the complete response rate in the EPAG combined with IST group was higher than in the IST group (OR=2.31, 95% CI 1.63–3.28, p < 0.00001), with no heterogeneity ( p = 0.94, I² = 0%). At 6 months, 17 studies including 1,955 patients were assessed (Fig. 3B), indicating a higher complete response rate in the EPAG combined with IST group (OR=2.37, 95% CI 1.92–2.94, p < 0.00001), with some heterogeneity present ( p = 0.06, I² = 37%). At 12 months, 10 studies with 953 patients were analyzed (Fig. 3C), finding no significant difference between the EPAG + IST and IST alone groups (OR=1.32, 95% CI 0.99–1.75, p = 0.06, I² = 16%). Subgroup Analysis Subgroup analysis based on EPAG initiation time was performed using overall response and complete response after 3 and 6 months as indices (Fig. 4). The start of IST treatment was designated as day 0, with subgroup analyses separating EPAG initiation at day 7 after IST treatment as the cut-off. The results for the 0-7 days EPAG initiation subgroup indicated that IST combined with EPAG improved both overall and complete responses at 3 and 6 months for AA patients. Conversely, the >7 days EPAG initiation subgroup showed improvements in overall and complete responses only at 6 months. Overall, the p -values for interactions were greater than 0.05, indicating that the overall and complete responses were not significantly influenced by the timing of EPAG initiation in AA patients. Subgroup Analysis of Different Ages Subgroup analysis was performed using overall response and complete response at 3, 6, and 12 months as indices, categorized by age (Fig. 5). The results for the subgroup of patients aged <18 years (children) indicated that IST combined with EPAG improved overall and complete response at 6 months. However, there was no effect at 3 and 12 months. For the subgroup of patients aged ≥18 years (adults), IST combined with EPAG improved overall response and complete response at 3 and 6 months. Additionally, it affected overall response at 12 months but did not influence complete response at that time. Overall, the p-value for the interaction of overall response at 3 months was less than 0.05, indicating that the age of AA patients had a significant effect on this response. Subgroup Analysis of Different Regions Using overall response and complete response at 3, 6, and 12 months as indices, subgroup analysis was performed by region (Fig. 6). The analysis for the Asian region revealed that IST combined with EPAG improved overall response and complete response at 3 and 6 months, but had no effect at 12 months. In contrast, the North America (NA) region analysis indicated that IST combined with EPAG had no effect except on complete response after 6 months. Publication Bias Stata 15 was used to evaluate publication bias in overall response and complete response at the 3, 6, and 12 months intervals. Begg’s and Egger’s tests were conducted, revealing no significant publication bias in this study (3 months ORR: Begg’s test p = 0.511, Egger’s test p = 0.669; 3 months CRR: Begg’s test p = 0.502, Egger’s test p = 0.697; 6 months ORR: Begg’s test p = 0.596, Egger’s test p = 0.479; 6 months CRR: Begg’s test p = 0.837, Egger’s test p = 0.879; 12 months ORR: Begg’s test p = 0.592, Egger’s test p = 0.797; 12 months CRR: Begg’s test p = 1.000, Egger’s test p = 0.854). Adverse Events The most common adverse event related to EPAG is liver dysfunction, primarily characterized by increased bilirubin, aspartate aminotransferase, and alanine transaminase levels[8],[10],[12]–[18]. Liver dysfunction led to treatment interruptions[7],[19] or dose reductions[20] in some study patients. Generally, liver function abnormalities in most AA patients were temporary and reversible; however, 10 out of 49 (20%) pediatric patients in Goronkova et al.’s study[19] experienced grade 3 to 4 liver function abnormalities that persisted for more than 21 days after drug discontinuation. In Lesmana et al.’s study, renal insufficiency was more prevalent among patients receiving EPAG. Additionally, gastrointestinal adverse reactions, primarily abdominal distension and mild diarrhea, were noted in Lin et al.’s study[17]. None of these adverse events resulted in dose reduction or discontinuation of EPAG. Other reported adverse events included febrile neutropenia, infection, hypertension, skin hyperpigmentation, rash, myalgia, joint pain, and cardiac disorders. Discussion Many studies have confirmed the efficacy of EPAG + IST versus IST alone for treating AA; however, a unanimous conclusion is still lacking. De Latour et al.’s multicenter trial[ 8 ] showed that complete response at 3 months was 10% in the IST combined with EPAG group and 22% in the IST group (odds ratio, 3.2; 95% confidence interval [CI], 1.3 to 7.8; P = 0.01). There was no significant difference in overall response or complete response at 6 months. Conversely, Jin et al.’s study[ 10 ] demonstrated that the overall response rates (ORR) at 3, 6, and 12 months were higher in the IST combined with EPAG group (p = 0.002, 0.028, 0.006, 0.031), while the complete response rates (CRR) were similar between the two groups. Our meta-analysis indicated that overall response and complete response at 3 and 6 months improved in the IST combined with EPAG group compared to the IST group, with no significant differences at 12 months. This suggests that adding EPAG can increase the rate, rapidity, and strength of hematologic responses in AA patients, maintaining a desirable therapeutic effect during 6 months of treatment. Regarding clinical treatment, it remains to be determined when EPAG should be initiated after basic IST therapy for optimal results. The phase 2 NIH trial[ 6 ] suggested that the best outcomes were achieved when eltrombopag was introduced on day 0. To prevent possible cumulative toxicity from concurrent ATG administration, eltrombopag was initiated on day 14 in de Latour et al.’s trial[ 12 ], which found no detrimental effect on early hematologic response. Our subgroup analysis based on EPAG initiation time showed that concurrent therapy (adding EPAG within 7 days of IST treatment) significantly improved overall and complete responses at 3 months; however, no statistical significance was found for responses at 6 months. Given that survival and long-term outcomes for AA patients correlate with the quality of HI at 3 months and the presence of early recovery after ATG administration[ 21 ], our analysis suggests that concurrent therapy is associated with a more favorable long-term prognosis for AA patients. We also conducted a subgroup analysis based on age to assess whether age affected the efficacy of EPAG. Results indicated that EPAG + IST was more effective than IST alone in adults; however, in pediatric subgroup, the addition of EPAG did not demonstrate significant efficacy overall. Age is known to be a prognostic factor in AA patients treated with IST, particularly with antithymocyte globulin combined with cyclosporine being effective in children[ 21 ]–[ 24 ]. We speculate that this discrepancy may be due to pediatric patients responding better to IST treatment than adults, resulting in a less significant effect of EPAG in the younger subgroup. Additionally, adult patients with AA may have a higher absolute neutrophil count (ANC) than pediatric patients, and some studies suggest that EPAG is more effective in AA patients with higher ANC[ 25 ],[ 26 ]. Although current guidelines do not include EPAG combined with standard IST therapy as a first-line treatment option for pediatric SAA, it has been demonstrated that EPAG not only increases ANC and CR rates in pediatric patients, but also that the early addition of EPAG can help rapidly identify nonresponders who in urgent need of HSCT.The varying efficacy of EPAG among different age groups should inform future therapeutic regimen selection. Subgroup analysis by region revealed that in the Asian subgroup, the addition of EPAG to IST significantly improved ORR and CRR at 3 and 6 months. In contrast, the North America (NA) subgroup showed no effect on overall response, except for complete response at 6 months. This discrepancy may stem from different indications for EPAG in various regions and patient age demographics. Currently, eltrombopag is approved only in specific countries to treat AA, with most patients in the NA subgroup having severe AA (SAA) or very severe AA (VSAA)[ 25 ],[ 27 ],[ 28 ]. Additionally, two NA subgroup articles[ 14 ],[ 28 ] included pediatric patients, and the limited number of studies may have influenced the results of this analysis. Beyond liver function abnormalities, the risk of clonal evolution from EPAG treatment cannot be overlooked. Current studies suggest that alterations in the immune bone marrow environment may contribute to the clonal evolution of AA patients[ 29 ], though the addition of EPAG has not significantly increased the risk of high-risk clonal evolution events[ 6 ],[ 30 ]. Groarke et al.[ 30 ] evaluated predictors of clonal evolution in AA patients post-IST treatment, finding that pretreatment age > 48 years and ANC > 0.87 × 10 9 /L were strong predictors of high-risk evolution. Moreover, RUNX1, splicing factor, and ASXL1 somatic mutations detected 6 months after IST treatment could predict high-risk evolution. In future IST or EPAG treatments, it is crucial to consider the characteristics of clonal evolution in AA patients and extend follow-up for targeted monitoring. Our meta-analysis has some limitations. First, among the 21 studies included, there were 17 cohort studies and 4 RCTs; therefore, the mixed results from different study types may affect the conclusions. Second, certain baseline characteristics of patients, such as disease severity in included studies, could not be determined, potentially leading to bias. Third, definitions of complete response and partial response varied by region due to ethnic heterogeneity, which may also introduce potential bias. For example, the definition of complete response in Zhao et al.’s Asian study was an ANC ≥ 1.5×10 9 /L, while in De Latour et al.’s European study, it was an ANC ≥ 1×10 9 /L. Conclusion Our results indicated that the combination of EPAG and IST achieves a better HI in patients with AA compared to those treated with IST alone. The concurrent therapy of EPAG and IST and maintaining EPAG therapy for 3 to 6 months yields could achieve significant HIs. In the adult group, The HIs of concurrent therapy and prolonged maintenance (≥ 3 months) were evident, while it emerged later (EPAG response time ≥ 6 months) in the pediatric group. When EPAG was maintained for more than 12 months, there was no significant difference in outcomes between the two age groups. The main adverse event associated with EPAG was liver dysfunction, highlighting the need for monitoring indicators such as transaminase and bilirubin levels. Declarations Funding The study was supported by grants from the National Natural Science Foundation of China (NSFC) (project no 82300161); Beijing High Innovation Program·Spring Bud Project; Scholar Support Program of HuiZhi Talent Project of Xuanwu Hospital, Capital Medical University (project no HZ2025ZCYX003); Beijing High-level Overseas Returnee Talent Funding Project (project no 2-2-008-0243), Capital Medical University Science and Innovation Elite Plan Project (project no 2024KCJY0405), the “National Natural Science Foundation of Youth Cultivation Project” of “Xuanwu Hospital, Capital Medical University, Beijing, China” (project no QNPY2022014), the “Person of Outstanding Ability Training Program” of “Xuanwu Hospital, Capital Medical University, Beijing, China” (project no YC20220127), the Natural Science Foundation of Beijing Municipality (project no Z200022), and the Natural Science Foundation of Beijing Municipality (project no 7242072). Author contributions S.Tan, MY. 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Effectiveness and safety of tacrolimus with or without eltrombopag, as a part of immunosuppressive treatment of aplastic anemia in adults: a retrospective case series. Ann Hematol. 2021;100(4):933–9. Patel BA, Groarke EM, Lotter J, Shalhoub R, Gutierrez-Rodrigues F, Rios O, et al. Long-term outcomes in patients with severe aplastic anemia treated with immunosuppression and eltrombopag: a phase 2 study. Blood. 2022 Jan 6;139(1):34–43. Zhang Y, Liu M, Zhan X. The efficacy of immunosuppression combined with Eltrombopag in the treatment of severe aplastic anemia in children [Internet]. [cited 2024 Apr 28]. Available from: http://qikan.cqvip.com/Qikan/Article/Detail?id=7106916895&from=Qikan_Search_Index Zhao Y, Yang W, Zhao X, Hu X, Hu J, Liu X, et al. Efficacy of eltrombopag with immunosuppressive therapy for children with acquired aplastic anemia. Front Pediatr. 2023 Jan 10;10:1095143. Tables Table 1. Characteristics of included studies in the meta-analysis. EPAG: eltrombopag, IST: immunosuppressive therapy, RCT: randomized controlled trial, NA: no report, hATG: horse antityhymocyte globulin, rATG: rabbit antityhymocyte globulin, pATG: pig antityhymocyte globulin, CsA: cyclosporin A. Author Year Total no. Study design Age types of patients/years old EPAG+IST IST Patients(n) Gender (female/male) ,n EPAG Initiation time Intervention Patients(n) Gender (female/male) ,n Intervention Assi[9] 2018 38 Prospective study ≥ 18 21 10/11 0-7d EPAG+hATG+CsA 17 8/9 hATG+CsA Cai[31] 2021 86 Retrospective study Unlimited 42 22/20 0-7d EPAG+CsA 44 23/21 CsA Chai[32] 2021 35 Retrospective study ≥ 18 24 9/15 0-7d EPAG+rATG+CsA 11 6/5 rATG+CsA De Latour[8] 2022 197 RCT Unlimited 96 49/52 >7d EPAG+hATG+CsA 101 49/52 hATG+CsA Fang[12] 2021 57 Retrospective study 7d EPAG+pATG+CsA 39 18/21 pATG+CsA Fang[13] 2023 90 Retrospective study Unlimited 45 22/23 0-7d EPAG+rATG+CsA 45 22/23 rATG+CsA Goronkova[19] 2023 98 RCT <18 49 14/35 0-7d EPAG+hATG+CsA 49 19/30 hATG+CsA Groarke[14] 2021 127 Prospective study 7d EPAG+r/pATG+CsA 74 40/34 r/pATG+CsA Jie[16] 2021 42 Retrospective study <18 14 NA Unlimited EPAG+rATG+CsA 28 NA rATG+CsA Jin[10] 2022 121 Retrospective study ≥ 18 54 26/28 0-7d EPAG+rATG+CSA 67 30/37 rATG+CSA Lesmana[20] 2021 25 Retrospective study <18 9 2/7 0-7d EPAG+hATG+CsA 16 12/4 hATG+CsA Liang[33] 2023 89 Retrospective study ≥ 18 42 23/19 0-7d EPAG+CsA 47 24/23 CsA Lin[17] 2023 76 Retrospective study ≥ 18 45 24/21 0-7d EPAG+CsA 31 16/15 CsA Martynova[34] 2021 21 Retrospective study ≥ 18 12 8/4 0-7d EPAG+hATG+Tacrolimus 9 6/3 hATG+Tacrolimus Patel[35] 2022 280 Prospective study Unlimited 178 NA Unlimited EPAG+hATG+CsA 102 NA hATG+CsA Shinn[27] 2023 82 Retrospective study ≥ 18 48 23/25 0-7d EPAG+hATG+CsA 34 16/18 hATG+CsA Yang[18] 2021 125 RCT ≥ 18 63 25/38 0-7d EPAG+CsA 62 27/35 CsA Zaimoku[25] 2021 416 Retrospective study ≥ 18 176 89/87 Unlimited EPAG+hATG+CsA 240 99/141 hATG+CsA Zhang[36] 2022 63 Retrospective study <18 31 15/16 0-7d EPAG+rATG+CsA 32 16/16 rATG+CsA Zhao[37] 2023 60 Retrospective study <18 15 5/10 0-7d EPAG+r/pATG+CsA 45 19/26 r/pATG+CsA Table 2. Quality assessment of non-RCTs included in this meta-analysis. The Newcastle-Ottawa Scale (NOS) was used to evaluate the quality of the non-RCTs. Scores ranged from 0 to 9: scores of 1 or less were considered low quality (high risk of bias), scores of 2–5 were medium quality (unclear), and scores of 6–9 were high-quality literature (low risk of bias). Selection Comparability Outcome/Exposure Scores Representativ-eness of the exposed cohort Selection of the non-exposed cohort Determination of exposure Ascertainment of no outcome before the study Matching the most important factors Control of confounding factors Evaluation of outcome Adequacy of follow up Adequacy of follow up Zhao 2023 1 1 1 1 1 1 1 1 1 9 Patel 2022 1 1 1 1 1 0 1 1 1 8 Jin 2022 1 1 1 1 0 1 1 1 1 8 Martynova 2021 1 1 1 1 0 0 1 1 1 7 Fang 2023 1 1 1 1 1 1 1 1 1 9 Lesmana 2021 1 0 1 0 0 1 1 1 1 6 Lin 2023 1 1 1 1 1 1 1 1 1 9 Zhang 2022 1 1 1 1 1 1 1 1 1 9 Zaimoku 2021 1 0 1 0 0 1 1 1 1 6 Jie 2021 1 1 0 1 0 0 1 1 1 6 Groarke 2021 1 0 1 0 1 1 1 1 1 7 Fang 2021 1 1 1 1 1 1 1 1 1 9 Assi 2018 1 1 1 1 0 1 1 1 1 8 Hu 2022 1 0 1 1 1 1 1 1 1 8 Chai 2021 1 1 1 1 0 0 1 1 1 7 Liang 2023 1 1 1 1 0 1 1 1 1 8 Cai 2021 1 0 1 1 1 1 1 0 1 7 Shinn 2023 1 1 1 1 1 1 1 1 1 9 Additional Declarations No competing interests reported. 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2","display":"","copyAsset":false,"role":"figure","size":174188,"visible":true,"origin":"","legend":"\u003cp\u003eOverall response at 3, 6, and 12 months. \u003cstrong\u003eA:\u003c/strong\u003eOverall response at 3 months. \u003cstrong\u003eB:\u003c/strong\u003e Overall response at 6 months. \u003cstrong\u003eC:\u003c/strong\u003eOverall response at 12 months. EPAG: eltrombopag, IST: immunosuppressive therapy, CI: confidence interval.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-7631623/v1/71208b0fab32505628b1b48d.png"},{"id":93241651,"identity":"e833def1-4eec-4dbf-ab08-14ddc5ce2d0e","added_by":"auto","created_at":"2025-10-10 14:52:15","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":203843,"visible":true,"origin":"","legend":"\u003cp\u003eComplete response at 3, 6, and 12 months. \u003cstrong\u003eA: \u003c/strong\u003eComplete response at 3 months.\u003cstrong\u003e B:\u003c/strong\u003e Complete response at 6 months. \u003cstrong\u003eC: \u003c/strong\u003eComplete response at 12 months. EPAG: eltrombopag, IST: immunosuppressive therapy, CI: confidence interval.\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-7631623/v1/fb43938f7d5991ee4d502def.png"},{"id":93241654,"identity":"3f34eb31-5f05-4eb8-a3d9-d224ec3bcfaf","added_by":"auto","created_at":"2025-10-10 14:52:15","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":576362,"visible":true,"origin":"","legend":"\u003cp\u003eSubgroup analysis of EPAG initiation time at 3 and 6 months. \u003cstrong\u003eA:\u003c/strong\u003e Overall response at 3 months. \u003cstrong\u003eB:\u003c/strong\u003e Complete response at 3 months. \u003cstrong\u003eC:\u003c/strong\u003e Overall response at 6 months. \u003cstrong\u003eD: \u003c/strong\u003eComplete response at 6 months. EPAG: Eltrombopag, IST: Immunosuppressive therapy, CI: Confidence interval.\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-7631623/v1/d860da5a34fdb3aa86863c26.png"},{"id":93241660,"identity":"f9518a16-b529-43bc-b25b-fc298be52f58","added_by":"auto","created_at":"2025-10-10 14:52:15","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":738668,"visible":true,"origin":"","legend":"\u003cp\u003eSubgroup analysis of different ages at 3, 6, and 12 months. \u003cstrong\u003eA:\u003c/strong\u003e Overall response at 3 months. \u003cstrong\u003eB:\u003c/strong\u003e Complete response at 3 months. \u003cstrong\u003eC: \u003c/strong\u003eOverall response at 6 months. \u003cstrong\u003eD:\u003c/strong\u003eComplete response at 6 months. \u003cstrong\u003eE:\u003c/strong\u003e Overall response at 12 months. \u003cstrong\u003eF: \u003c/strong\u003eComplete response at 12 months. EPAG: Eltrombopag, IST: Immunosuppressive therapy, CI: Confidence interval.\u003c/p\u003e","description":"","filename":"floatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-7631623/v1/d4ae6bb2183730a0579c7636.png"},{"id":93243766,"identity":"d1c79480-435a-444e-b620-0f3de8d15399","added_by":"auto","created_at":"2025-10-10 15:00:15","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":721387,"visible":true,"origin":"","legend":"\u003cp\u003eSubgroup analysis of different regions at 3, 6, and 12 months. \u003cstrong\u003eA:\u003c/strong\u003e Overall response at 3 months. \u003cstrong\u003eB:\u003c/strong\u003e Complete response at 3 months. \u003cstrong\u003eC:\u003c/strong\u003e Overall response at 6 months. \u003cstrong\u003eD: \u003c/strong\u003eComplete response at 6 months. \u003cstrong\u003eE:\u003c/strong\u003e Overall response at 12 months. \u003cstrong\u003eF: \u003c/strong\u003eComplete response at 12 months. EPAG: Eltrombopag, IST: Immunosuppressive therapy, CI: Confidence interval, NA: North America.\u003c/p\u003e","description":"","filename":"floatimage6.png","url":"https://assets-eu.researchsquare.com/files/rs-7631623/v1/4736a3c33c000385e3cda37f.png"},{"id":107480617,"identity":"34f3f823-03a9-4d4d-a6fb-d735fb2ebd1d","added_by":"auto","created_at":"2026-04-22 02:12:31","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2864053,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7631623/v1/a1e37454-cfe5-4b9c-a086-c342fab3514c.pdf"},{"id":93243765,"identity":"ba1eca7e-ef3e-44b1-882b-8ab8d7fe6b32","added_by":"auto","created_at":"2025-10-10 15:00:15","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":219524,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementalmaterials.docx","url":"https://assets-eu.researchsquare.com/files/rs-7631623/v1/f8aa1cdef6df6d46347ca974.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"This Meta-Analysis Evaluates the Optimal Timing for Initiating and Discontinuing Eltrombopag for Aplastic Anemia","fulltext":[{"header":"Highlights","content":"\u003cp\u003eOur study indicates that Eltrombopag should be used as early as possible, as it shows better hematological improvements (HIs) compared with simply IST\u0026nbsp;treatment\u0026nbsp;within 3-6 months,\u0026nbsp;with no significant difference in risk.\u003c/p\u003e\n\u003cul start=\"50\"\u003e\n \u003cli\u003eFor adults, it is recommended the concurrent therapy of EPAG and IST (EPAG was added within 7 days of the start of IST treatment), and continue for a period of 3 months to achieve significant HI. If EPAG was added after 7 days, patients will achieve HI for about 6 months.\u003c/li\u003e\n \u003cli\u003eFor\u0026nbsp;children, regardless of the concurrent or nonconcurrent therapy, there was no significant difference compared with IST alone in 3 months. It is recommended to continue for about 6 months to achieve better HI.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eFor all AA patients, the HIs of additional Eltrombopag for more than 12 months were not significantly different from those of simply IST.\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"Introduction","content":"\u003cp\u003eAplastic anemia (AA), a bone marrow failure (BMF) syndrome, is characterized by marrow hypoplasia and peripheral blood cytopenia[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The pathophysiology of BMF can arise from chemical or physical damage, a compromised immune system (primarily due to T cells), or constitutional genetic defects affecting immune regulation[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The incidence of AA ranges from 0.6 to 7 cases per million people per year, with a higher rate observed in adolescents and older adults[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Frontline treatment of AA depends on disease severity, donor availability, and patient age, primarily involving immunosuppressive therapy (IST) and hematopoietic stem cell transplantation (HSCT). Standard IST, including anti-thymocyte globulin (ATG) and cyclosporine A (CSA), yields a hematologic response rate and transfusion independence of 60 to 70%[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e],[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Nonetheless, about one-third of patients relapse, and 10 to 15% may develop cytogenetic abnormalities in the long term[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eEltrombopag (EPAG), an oral thrombopoietin-receptor agonist, is effective in patients with aplastic anemia refractory to immunosuppression[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e],[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Recent studies indicate that adding EPAG to IST is associated with significantly higher rates of hematologic response in patients with severe aplastic anemia compared to standard IST[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e],[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. However, response rates with EPAG combined with IST vary between adults and children[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e],[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], and also depend on different EPAG maintenance durations[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. In clinical practice, there are no conclusive guidelines regarding the optimal timing for initiating and discontinuing eltrombopag for different populations. Therefore, we conducted this systematic review and meta-analysis to compare the efficacy of EPAG\u0026thinsp;+\u0026thinsp;IST with that of standard IST in patients with AA and to assess the optimal initiation and maintenance timing of EPAG in both adults and children.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThe recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines[11] were used to formulate the systematic review and meta-analysis eligibility criteria.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSearch strategy\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEligible studies published before July 1, 2025, were retrieved by two independent authors (S. Tan and MY. Shang) from PubMed, EMBASE, Web of Science, the Cochrane Library, LILACS, CNKI, WANFANG, VIP, and the Chinese Biomedical Literature Database (CBM). The search terms used to retrieve relevant studies included \u0026quot;Aplastic Anemia\u0026quot; , \u0026quot;Eltrombopag\u0026quot; and \u0026quot;immunosuppressive therapy\u0026quot;. Additional studies were identified from the bibliographies of screened articles as appropriate.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOutcomes and study selection\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe primary outcomes were overall response (defined as either complete or partial response) and complete response (defined as an absolute neutrophil count [ANC] \u0026ge; 1.0 \u0026times; 10\u003csup\u003e9\u003c/sup\u003e/L, hemoglobin [Hb] levels \u0026ge; 100 g/L, and a platelet count \u0026ge; 100 \u0026times; 10\u003csup\u003e9\u003c/sup\u003e/L) at 3, 6, and 12 months. The secondary outcome was partial response (as defined in each included study) at the same time points. Two authors (YX. Guo and L. Su) independently screened the titles and abstracts of all studies and subsequently examined the full texts of eligible studies. In cases of disagreement during the study selection process, consensus was reached through group discussion with a third author (HY. Wang).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData extraction\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTwo authors (Q. Ma and WH. Hui) independently collated the baseline characteristics of each included study using a standardized Excel table. The baseline characteristics were as follows: (1) study data, including the first author, publication year, and study design; (2) patient data, encompassing the number of patients, age categories, and gender distribution; (3) grouping information, detailing the initiation time of EPAG and immunosuppressive therapy programs; and (4) primary and secondary outcomes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eQuality assessment and bias risk assessment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTwo authors (J. Ni and ZH. Cai) independently evaluated the quality of non-randomized controlled trials (non-RCTs) using the Newcastle-Ottawa Scale (NOS). This assessment utilized nine items in three main categories: selection (score 3), comparability (score 3), and outcome assessment (score 3). Each study received a total score of 9, with a score of \u0026ge; 6 indicating high quality.\u003c/p\u003e\n\u003cp\u003eFor randomized controlled trials (RCTs), the Cochrane Collaboration tool was employed. Assessments were categorized as \u0026ldquo;low risk of bias,\u0026rdquo; \u0026ldquo;unclear risk of bias,\u0026rdquo; or \u0026ldquo;high risk of bias\u0026rdquo; based on seven criteria: Random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other biases. Any disagreements in this process were resolved through discussion or adjudication by a third author (HZ. He).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll statistical tests were conducted using RevMan 5.4 software. A fixed-effects model was employed to calculate odds ratios (ORs) with 95% confidence intervals (CIs) for both primary and secondary outcomes.\u003cem\u003e\u0026nbsp;I\u0026sup2;\u003c/em\u003e statistics were used to assess the heterogeneity of the included studies. The fixed-effects model was applied when \u003cem\u003ep\u003c/em\u003e \u0026gt; 0.1 and \u003cem\u003eI\u0026sup2;\u003c/em\u003e \u0026lt; 50%, while the random-effects model was used when\u003cem\u003e\u0026nbsp;p\u003c/em\u003e \u0026lt; 0.1 and\u003cem\u003e\u0026nbsp;I\u0026sup2;\u003c/em\u003e \u0026gt; 50%. Subgroup analyses were performed based on the initiation time of EPAG (0\u0026ndash;7 days vs. \u0026gt; 7 days), age (\u0026lt; 18 years vs. \u0026ge; 18 years), and region (Asia vs. North America).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eOutcomes of the search process\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe initial search yielded a total of 2,609 records among all databases, from which 596 duplicates were detected and removed. After reviewing the titles and abstracts of the remaining 2,013 studies according to the exclusion criteria, 1,949 studies were excluded. We then examined the full texts of the remaining 64 articles, resulting in 21 studies that met the inclusion criteria and were ultimately included in our meta-analysis (Figure 1).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy Characteristics and Quality Evaluation\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe characteristics of the included studies are summarized in Table 1. In total, 2,239 patients were included in our meta-analysis, with 1,059 treated with EPAG + IST and 1,180 treated with IST alone. Of the 21 included studies, 7 were prospective (4 were RCTs) and 14 were retrospective. The quality assessments of the 17 cohort studies are shown in Table 2: 6 studies had a NOS score of 9, 5 studies had a score of 8, 4 studies had a score of 7, and 3 studies had a score of 6, all meeting the study criteria. The Cochrane risk of bias assessment for the three RCTs indicated low risk of bias and high quality, as presented in Supplemental Figure 1.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOutcomes of\u0026nbsp;this Meta‑Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eOverall Response\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe overall response after 3 months was evaluated in 14 studies, encompassing 1,159 patients with AA (Fig. 2A). The results indicated that the overall response rate in the EPAG combined with IST group was higher than in the IST group (OR=2.13, 95% CI 1.65\u0026ndash;2.74, \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.00001), with no heterogeneity among these studies (\u003cem\u003ep\u003c/em\u003e = 0.10,\u003cem\u003e\u0026nbsp;I\u0026sup2;\u003c/em\u003e = 34%). At 6 months, 18 studies including 1,990 patients with AA were evaluated (Fig. 2B), showing a similar trend: The overall response rate in the EPAG combined with IST group was higher than in the IST group (OR=2.13, 95% CI 1.73\u0026ndash;2.61, \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.00001), again with no heterogeneity (\u003cem\u003ep\u003c/em\u003e = 0.24, \u003cem\u003eI\u0026sup2;\u003c/em\u003e = 18%). At 12 months, 10 studies with 953 patients were assessed (Fig. 2C), revealing no significant difference between the EPAG + IST and IST alone groups according to the pooled results (OR=1.14, 95% CI 0.86\u0026ndash;1.51, \u003cem\u003ep\u003c/em\u003e = 0.36, \u003cem\u003eI\u0026sup2;\u003c/em\u003e = 35%).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eComplete Response\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe complete response at 3 months was evaluated in 13 studies involving 1,124 patients with AA (Fig. 3A). Our analysis suggested that the complete response rate in the EPAG combined with IST group was higher than in the IST group (OR=2.31, 95% CI 1.63\u0026ndash;3.28, \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.00001), with no heterogeneity (\u003cem\u003ep\u003c/em\u003e = 0.94, \u003cem\u003eI\u0026sup2;\u003c/em\u003e = 0%). At 6 months, 17 studies including 1,955 patients were assessed (Fig. 3B), indicating a higher complete response rate in the EPAG combined with IST group (OR=2.37, 95% CI 1.92\u0026ndash;2.94, \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.00001), with some heterogeneity present (\u003cem\u003ep\u003c/em\u003e = 0.06, \u003cem\u003eI\u0026sup2;\u003c/em\u003e = 37%). At 12 months, 10 studies with 953 patients were analyzed (Fig. 3C), finding no significant difference between the EPAG + IST and IST alone groups (OR=1.32, 95% CI 0.99\u0026ndash;1.75, \u003cem\u003ep\u003c/em\u003e = 0.06, I\u0026sup2; = 16%).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eSubgroup Analysis\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSubgroup analysis based on EPAG initiation time was performed using overall response and complete response after 3 and 6 months as indices (Fig. 4). The start of IST treatment was designated as day 0, with subgroup analyses separating EPAG initiation at day 7 after IST treatment as the cut-off. The results for the 0-7 days EPAG initiation subgroup indicated that IST combined with EPAG improved both overall and complete responses at 3 and 6 months for AA patients. Conversely, the \u0026gt;7 days EPAG initiation subgroup showed improvements in overall and complete responses only at 6 months. Overall, the \u003cem\u003ep\u003c/em\u003e-values for interactions were greater than 0.05, indicating that the overall and complete responses were not significantly influenced by the timing of EPAG initiation in AA patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eSubgroup Analysis of Different Ages\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSubgroup analysis was performed using overall response and complete response at 3, 6, and 12 months as indices, categorized by age (Fig. 5). The results for the subgroup of patients aged \u0026lt;18 years (children)\u0026nbsp;indicated that IST combined with EPAG improved overall \u0026nbsp;and complete response at 6 months. However, there was no effect \u0026nbsp;at 3 and 12 months. For the subgroup of patients aged \u0026ge;18 years (adults), IST combined with EPAG improved overall response and complete response at 3 and 6 months. Additionally, it affected overall response at 12 months but did not influence complete response at that time. Overall, the p-value for the interaction of overall response at 3 months was less than 0.05, indicating that the age of AA patients had a significant effect on this response.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eSubgroup Analysis of Different Regions\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eUsing overall response and complete response at 3, 6, and 12 months as indices, subgroup analysis was performed by region (Fig. 6). The analysis for the Asian region revealed that IST combined with EPAG improved overall response and complete response at 3 and 6 months, but had no effect at 12 months. In contrast, the North America (NA) region analysis indicated that IST combined with EPAG had no effect except on complete response after 6 months.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003ePublication Bias\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStata 15 was used to evaluate publication bias in overall response and complete response at the 3, 6, and 12 months intervals. Begg\u0026rsquo;s and Egger\u0026rsquo;s tests were conducted, revealing no significant publication bias in this study (3 months ORR: Begg\u0026rsquo;s test \u003cem\u003ep\u003c/em\u003e = 0.511, Egger\u0026rsquo;s test \u003cem\u003ep\u003c/em\u003e = 0.669; 3 months CRR: Begg\u0026rsquo;s test \u003cem\u003ep\u003c/em\u003e = 0.502, Egger\u0026rsquo;s test \u003cem\u003ep\u003c/em\u003e = 0.697; 6 months ORR: Begg\u0026rsquo;s test \u003cem\u003ep\u003c/em\u003e = 0.596, Egger\u0026rsquo;s test \u003cem\u003ep\u003c/em\u003e = 0.479; 6 months CRR: Begg\u0026rsquo;s test \u003cem\u003ep\u003c/em\u003e = 0.837, Egger\u0026rsquo;s test \u003cem\u003ep\u003c/em\u003e = 0.879; 12 months ORR: Begg\u0026rsquo;s test \u003cem\u003ep\u003c/em\u003e = 0.592, Egger\u0026rsquo;s test \u003cem\u003ep\u003c/em\u003e = 0.797; 12 months CRR: Begg\u0026rsquo;s test \u003cem\u003ep\u003c/em\u003e = 1.000, Egger\u0026rsquo;s test \u003cem\u003ep\u003c/em\u003e = 0.854).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAdverse Events\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe most common adverse event related to EPAG is liver dysfunction, primarily characterized by increased bilirubin, aspartate aminotransferase, and alanine transaminase levels[8],[10],[12]\u0026ndash;[18]. Liver dysfunction led to treatment interruptions[7],[19] or dose reductions[20] in some study patients. Generally, liver function abnormalities in most AA patients were temporary and reversible; however, 10 out of 49 (20%) pediatric patients in Goronkova et al.\u0026rsquo;s study[19] experienced grade 3 to 4 liver function abnormalities that persisted for more than 21 days after drug discontinuation. In Lesmana et al.\u0026rsquo;s study, renal insufficiency was more prevalent among patients receiving EPAG. Additionally, gastrointestinal adverse reactions, primarily abdominal distension and mild diarrhea, were noted in Lin et al.\u0026rsquo;s study[17]. None of these adverse events resulted in dose reduction or discontinuation of EPAG. Other reported adverse events included febrile neutropenia, infection, hypertension, skin hyperpigmentation, rash, myalgia, joint pain, and cardiac disorders.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eMany studies have confirmed the efficacy of EPAG\u0026thinsp;+\u0026thinsp;IST versus IST alone for treating AA; however, a unanimous conclusion is still lacking. De Latour et al.\u0026rsquo;s multicenter trial[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] showed that complete response at 3 months was 10% in the IST combined with EPAG group and 22% in the IST group (odds ratio, 3.2; 95% confidence interval [CI], 1.3 to 7.8; P\u0026thinsp;=\u0026thinsp;0.01). There was no significant difference in overall response or complete response at 6 months. Conversely, Jin et al.\u0026rsquo;s study[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] demonstrated that the overall response rates (ORR) at 3, 6, and 12 months were higher in the IST combined with EPAG group (p\u0026thinsp;=\u0026thinsp;0.002, 0.028, 0.006, 0.031), while the complete response rates (CRR) were similar between the two groups. Our meta-analysis indicated that overall response and complete response at 3 and 6 months improved in the IST combined with EPAG group compared to the IST group, with no significant differences at 12 months. This suggests that adding EPAG can increase the rate, rapidity, and strength of hematologic responses in AA patients, maintaining a desirable therapeutic effect during 6 months of treatment.\u003c/p\u003e\u003cp\u003eRegarding clinical treatment, it remains to be determined when EPAG should be initiated after basic IST therapy for optimal results. The phase 2 NIH trial[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] suggested that the best outcomes were achieved when eltrombopag was introduced on day 0. To prevent possible cumulative toxicity from concurrent ATG administration, eltrombopag was initiated on day 14 in de Latour et al.\u0026rsquo;s trial[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], which found no detrimental effect on early hematologic response. Our subgroup analysis based on EPAG initiation time showed that concurrent therapy (adding EPAG within 7 days of IST treatment) significantly improved overall and complete responses at 3 months; however, no statistical significance was found for responses at 6 months. Given that survival and long-term outcomes for AA patients correlate with the quality of HI at 3 months and the presence of early recovery after ATG administration[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e], our analysis suggests that concurrent therapy is associated with a more favorable long-term prognosis for AA patients.\u003c/p\u003e\u003cp\u003eWe also conducted a subgroup analysis based on age to assess whether age affected the efficacy of EPAG. Results indicated that EPAG\u0026thinsp;+\u0026thinsp;IST was more effective than IST alone in adults; however, in pediatric subgroup, the addition of EPAG did not demonstrate significant efficacy overall. Age is known to be a prognostic factor in AA patients treated with IST, particularly with antithymocyte globulin combined with cyclosporine being effective in children[\u003cspan additionalcitationids=\"CR22 CR23\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u0026ndash;[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. We speculate that this discrepancy may be due to pediatric patients responding better to IST treatment than adults, resulting in a less significant effect of EPAG in the younger subgroup. Additionally, adult patients with AA may have a higher absolute neutrophil count (ANC) than pediatric patients, and some studies suggest that EPAG is more effective in AA patients with higher ANC[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e],[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Although current guidelines do not include EPAG combined with standard IST therapy as a first-line treatment option for pediatric SAA, it has been demonstrated that EPAG not only increases ANC and CR rates in pediatric patients, but also that the early addition of EPAG can help rapidly identify nonresponders who in urgent need of HSCT.The varying efficacy of EPAG among different age groups should inform future therapeutic regimen selection.\u003c/p\u003e\u003cp\u003eSubgroup analysis by region revealed that in the Asian subgroup, the addition of EPAG to IST significantly improved ORR and CRR at 3 and 6 months. In contrast, the North America (NA) subgroup showed no effect on overall response, except for complete response at 6 months. This discrepancy may stem from different indications for EPAG in various regions and patient age demographics. Currently, eltrombopag is approved only in specific countries to treat AA, with most patients in the NA subgroup having severe AA (SAA) or very severe AA (VSAA)[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e],[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e],[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Additionally, two NA subgroup articles[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e],[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e] included pediatric patients, and the limited number of studies may have influenced the results of this analysis.\u003c/p\u003e\u003cp\u003eBeyond liver function abnormalities, the risk of clonal evolution from EPAG treatment cannot be overlooked. Current studies suggest that alterations in the immune bone marrow environment may contribute to the clonal evolution of AA patients[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e], though the addition of EPAG has not significantly increased the risk of high-risk clonal evolution events[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e],[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Groarke et al.[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e] evaluated predictors of clonal evolution in AA patients post-IST treatment, finding that pretreatment age\u0026thinsp;\u0026gt;\u0026thinsp;48 years and ANC\u0026thinsp;\u0026gt;\u0026thinsp;0.87 \u0026times; 10\u003csup\u003e9\u003c/sup\u003e/L were strong predictors of high-risk evolution. Moreover, RUNX1, splicing factor, and ASXL1 somatic mutations detected 6 months after IST treatment could predict high-risk evolution. In future IST or EPAG treatments, it is crucial to consider the characteristics of clonal evolution in AA patients and extend follow-up for targeted monitoring.\u003c/p\u003e\u003cp\u003eOur meta-analysis has some limitations. First, among the 21 studies included, there were 17 cohort studies and 4 RCTs; therefore, the mixed results from different study types may affect the conclusions. Second, certain baseline characteristics of patients, such as disease severity in included studies, could not be determined, potentially leading to bias. Third, definitions of complete response and partial response varied by region due to ethnic heterogeneity, which may also introduce potential bias. For example, the definition of complete response in Zhao et al.\u0026rsquo;s Asian study was an ANC\u0026thinsp;\u0026ge;\u0026thinsp;1.5\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L, while in De Latour et al.\u0026rsquo;s European study, it was an ANC\u0026thinsp;\u0026ge;\u0026thinsp;1\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eOur results indicated that the combination of EPAG and IST achieves a better HI in patients with AA compared to those treated with IST alone. The concurrent therapy of EPAG and IST and maintaining EPAG therapy for 3 to 6 months yields could achieve significant HIs. In the adult group, The HIs of concurrent therapy and prolonged maintenance (\u0026ge;\u0026thinsp;3 months) were evident, while it emerged later (EPAG response time\u0026thinsp;\u0026ge;\u0026thinsp;6 months) in the pediatric group. When EPAG was maintained for more than 12 months, there was no significant difference in outcomes between the two age groups. The main adverse event associated with EPAG was liver dysfunction, highlighting the need for monitoring indicators such as transaminase and bilirubin levels.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was supported by grants from the National Natural Science Foundation of China (NSFC) (project no 82300161); Beijing High Innovation Program\u0026middot;Spring Bud Project; Scholar Support Program of HuiZhi Talent Project of Xuanwu Hospital, Capital Medical University (project no HZ2025ZCYX003); Beijing High-level Overseas Returnee Talent Funding Project (project no 2-2-008-0243), Capital Medical University Science and Innovation Elite Plan Project (project no 2024KCJY0405), the \u0026ldquo;National Natural Science Foundation of Youth Cultivation Project\u0026rdquo; of \u0026ldquo;Xuanwu Hospital, Capital Medical University, Beijing, China\u0026rdquo; (project no QNPY2022014), the \u0026ldquo;Person of Outstanding Ability Training Program\u0026rdquo; of \u0026ldquo;Xuanwu Hospital, Capital Medical University, Beijing, China\u0026rdquo; (project no YC20220127), the Natural Science Foundation of Beijing Municipality (project no Z200022), and the Natural Science Foundation of Beijing Municipality (project no 7242072).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eS.Tan, MY. Shang, and YX. Guo performed the study, literature review, interpreted the data, and wrote the manuscript; S. Tan, MY. Shang, YX. Guo, L. Su, HY. Wang, Q. Ma, WH. Hui, J. Ni, ZH. Cai, HZ. He, YF. Cao, YX. Li, YM. Li, YC. Chen, and J. Sun interpreted the data, wrote the manuscript, and revised the manuscript; S. Tan and WL. Sun designed the study, interpreted the data, and organized the research.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors state that they have no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData sharing is not applicable to this article as no data were created or analyzed in this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHuman Ethics and Consent to Participate declarations: not applicable.\u003c/strong\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eYoung NS. Current concepts in the pathophysiology and treatment of aplastic anemia. Hematology. 2013 Dec 6;2013(1):76\u0026ndash;81. \u003c/li\u003e\n\u003cli\u003eYoung NS. APLASTIC ANEMIA. N Engl J Med. 2018 Oct 25;379(17):1643\u0026ndash;56. \u003c/li\u003e\n\u003cli\u003eVaht K, G\u0026ouml;ransson M, Carlson K, Isaksson C, Lenhoff S, Sandstedt A, et al. Incidence and outcome of acquired aplastic anemia: real-world data from patients diagnosed in Sweden from 2000-2011. Haematologica. 2017 Oct;102(10):1683\u0026ndash;90. \u003c/li\u003e\n\u003cli\u003eScheinberg P, Nunez O, Weinstein B, Scheinberg P, Biancotto A, Wu CO, et al. Horse versus rabbit antithymocyte globulin in acquired aplastic anemia. N Engl J Med. 2011 Aug 4;365(5):430\u0026ndash;8. \u003c/li\u003e\n\u003cli\u003eScheinberg P. Novel therapeutic choices in immune aplastic anemia. F1000Research. 2020;9:F1000 Faculty Rev-1118. \u003c/li\u003e\n\u003cli\u003eTownsley DM, Scheinberg P, Winkler T, Desmond R, Dumitriu B, Rios O, et al. Eltrombopag Added to Standard Immunosuppression for Aplastic Anemia. N Engl J Med. 2017 Apr 20;376(16):1540\u0026ndash;50. \u003c/li\u003e\n\u003cli\u003eDesmond R, Townsley DM, Dumitriu B, Olnes MJ, Scheinberg P, Bevans M, et al. Eltrombopag restores trilineage hematopoiesis in refractory severe aplastic anemia that can be sustained on discontinuation of drug. Blood. 2014 Mar 20;123(12):1818\u0026ndash;25. \u003c/li\u003e\n\u003cli\u003ePeffault de Latour R, Kulasekararaj A, Iacobelli S, Terwel SR, Cook R, Griffin M, et al. Eltrombopag Added to Immunosuppression in Severe Aplastic Anemia. N Engl J Med. 2022 Jan 6;386(1):11\u0026ndash;23. \u003c/li\u003e\n\u003cli\u003eAssi R, Garcia-Manero G, Ravandi F, Borthakur G, Daver NG, Jabbour E, et al. Addition of eltrombopag to immunosuppressive therapy in patients with newly diagnosed aplastic anemia. Cancer. 2018 Nov 1;124(21):4192\u0026ndash;201. \u003c/li\u003e\n\u003cli\u003eJin Y, Li R, Lin S, Jia J, Yang Y, Zhang D, et al. A real-word experience of eltrombopag plus rabbit antithymocyte immunoglobulin-based IST in Chinese patients with severe aplastic anemia. Ann Hematol. 2022 Nov;101(11):2413\u0026ndash;9. \u003c/li\u003e\n\u003cli\u003ePage MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021 Mar 29;372:n71. \u003c/li\u003e\n\u003cli\u003eFang M, Song H, Zhang J, Li S, Shen D, Tang Y. Efficacy and safety of immunosuppressive therapy with or without eltrombopag in pediatric patients with acquired aplastic anemia: A Chinese retrospective study. Pediatr Hematol Oncol. 2021 Oct;38(7):633\u0026ndash;46. \u003c/li\u003e\n\u003cli\u003eFang M. Effects of Eltrombopag combined with intensive immunosuppression in treatment of patients with aplastic anemia. Med J Chin Peoples Health. 2023;35(3):28-30+34. \u003c/li\u003e\n\u003cli\u003eGroarke EM, Patel BA, Gutierrez-Rodrigues F, Rios O, Lotter J, Baldoni D, et al. Eltrombopag added to immunosuppression for children with treatment-na\u0026iuml;ve severe aplastic anaemia. Br J Haematol. 2021 Feb;192(3):605\u0026ndash;14. \u003c/li\u003e\n\u003cli\u003eHu X. Efficacy and prognosis assessment of V/SAA patients based on the standard immunosuppressive regimen. Peking Union Medical College; 2023 [cited 2024 Aug 25]. Available from: https://kns.cnki.net/kcms2/article/abstract?v=GygzKunDVUfPBihPTTlxGlkxfLr1WceEtZQ-tLn0GiJ5vjv0LhD4CITL0vrKBrVf8ISSru3idR5hTjvNCX4jtfTRgtivWMvdRkpTmboVrHkcs5mywElw8mh6iu91JSzgWfXws0nNHxrSxHTGk9fQYvwk0tvdX62kjs7FTErxDkeY0zM5s6HH5zPIF3mX7gmU-TlKMJDKh4a3E5ejEA3vJpjCnJRonfaw\u0026amp;uniplatform=NZKPT\u0026amp;language=CHS\u003c/li\u003e\n\u003cli\u003eJie M, Fu L, Li S, He Y, Yao J, Cheng X, et al. Efficacy and safety of eltrombopag in the first-line therapy of severe aplastic anemia in children. Pediatr Hematol Oncol. 2021 Oct 3;38(7):647\u0026ndash;57. \u003c/li\u003e\n\u003cli\u003eLin Y, Zhang R, Lin Z, Chen Q, Chen R. Effect of Eltrombopag on Response to Immunosuppressive Therapy in Patients with Transfusion-Dependent Non-Severe Aplastic Anemia. J Exp Hematol. 2023;31(3):823\u0026ndash;9. \u003c/li\u003e\n\u003cli\u003eYang X, Yang X, Xu C, Yan B. Effects of itropopa combined with cyclosporine A on serum thrombopoietin, granulocyte colony stimulating factor and granulocyte macrophage colony stimulating factor in patients with aplastic anemia. World Clin Drug. 2021;42(12):1108\u0026ndash;12. \u003c/li\u003e\n\u003cli\u003eGoronkova O, Novichkova G, Salimova T, Kalinina I, Baidildina D, Petrova U, et al. Efficacy of combined immunosuppression with or without eltrombopag in children with newly diagnosed aplastic anemia. Blood Adv. 2023 Mar 28;7(6):953\u0026ndash;62. \u003c/li\u003e\n\u003cli\u003eLesmana H, Jacobs T, Boals M, Gray N, Lewis S, Ding J, et al. Eltrombopag in children with severe aplastic anemia. Pediatr Blood Cancer. 2021 Aug;68(8):e29066. \u003c/li\u003e\n\u003cli\u003eRosenfeld S, Follmann D, Nunez O, Young NS. Antithymocyte globulin and cyclosporine for severe aplastic anemia: association between hematologic response and long-term outcome. JAMA. 2003 Mar 5;289(9):1130\u0026ndash;5. \u003c/li\u003e\n\u003cli\u003eKojima S, Hibi S, Kosaka Y, Yamamoto M, Tsuchida M, Mugishima H, et al. Immunosuppressive therapy using antithymocyte globulin, cyclosporine, and danazol with or without human granulocyte colony-stimulating factor in children with acquired aplastic anemia. Blood. 2000 Sep 15;96(6):2049\u0026ndash;54. \u003c/li\u003e\n\u003cli\u003eScheinberg P, Wu CO, Nunez O, Young NS. Predicting response to immunosuppressive therapy and survival in severe aplastic anaemia. Br J Haematol. 2009 Jan;144(2):206\u0026ndash;16. \u003c/li\u003e\n\u003cli\u003eCabannes-Hamy A, Boissel N, Peffault De Latour R, Lenglin\u0026eacute; E, Leblanc T, de Fontbrune FS, et al. The effect of age in patients with acquired aplastic anaemia treated with immunosuppressive therapy: comparison of Adolescents and Young Adults with children and older adults. Br J Haematol. 2018 Dec;183(5):766\u0026ndash;74. \u003c/li\u003e\n\u003cli\u003eZaimoku Y, Patel BA, Shalhoub R, Groarke EM, Feng X, Wu CO, et al. Predicting response of severe aplastic anemia to immunosuppression combined with eltrombopag. Haematologica. 2021 Apr 29;107(1):126\u0026ndash;33. \u003c/li\u003e\n\u003cli\u003eChang MH, Kim KH, Kim HS, Jun HJ, Kim DH, Jang JH, et al. Predictors of response to immunosuppressive therapy with antithymocyte globulin and cyclosporine and prognostic factors for survival in patients with severe aplastic anemia. Eur J Haematol. 2010 Feb 1;84(2):154\u0026ndash;9. \u003c/li\u003e\n\u003cli\u003eShinn LT, Benitez LL, Perissinotti AJ, Reid JH, Buhlinger KM, van Deventer H, et al. Multicenter evaluation of the addition of eltrombopag to immunosuppressive therapy for adults with severe aplastic anemia. Int J Hematol. 2023 Dec;118(6):682\u0026ndash;9. \u003c/li\u003e\n\u003cli\u003ePatel BA, Groarke EM, Lotter J, Shalhoub R, Gutierrez-Rodrigues F, Rios O, et al. Long-term outcomes in patients with severe aplastic anemia treated with immunosuppression and eltrombopag: a phase 2 study. Blood. 2022 Jan 6;139(1):34\u0026ndash;43. \u003c/li\u003e\n\u003cli\u003eDurrani J, Groarke EM. Clonality in immune aplastic anemia: Mechanisms of immune escape or malignant transformation. Semin Hematol. 2022 Jul;59(3):137\u0026ndash;42. \u003c/li\u003e\n\u003cli\u003eGroarke EM, Patel BA, Shalhoub R, Gutierrez-Rodrigues F, Desai P, Leuva H, et al. Predictors of clonal evolution and myeloid neoplasia following immunosuppressive therapy in severe aplastic anemia. Leukemia. 2022 Sep;36(9):2328\u0026ndash;37. \u003c/li\u003e\n\u003cli\u003eCai J. Efficacy analysis of eltrombopag combined with cyclosporine in the treatment of aplastic anaemia. J North Pharm. 2021;18(7):66\u0026ndash;7. \u003c/li\u003e\n\u003cli\u003eChai X, Li R, Du X, He Y, Liu X, Cheng L, et al. Eltrombopag combing with intensive immunosuppressive therapy for elderly severe aplastic anemia：clinical analysis of 35 cases. Chin J Pract Intern Med. 2021;41(4):301\u0026ndash;5. \u003c/li\u003e\n\u003cli\u003eLiang L, Li B, Cheng M. Effect of eltrombopag on clinical efficacy and safety in patients with chronic aplastic anaemia. Shenzhen J Integr Tradit Chin West Med. 2023;33(6):81\u0026ndash;3. \u003c/li\u003e\n\u003cli\u003eMartynova A, Chiu V, Mert M, Hermel D, Weitz IC. Effectiveness and safety of tacrolimus with or without eltrombopag, as a part of immunosuppressive treatment of aplastic anemia in adults: a retrospective case series. Ann Hematol. 2021;100(4):933\u0026ndash;9. \u003c/li\u003e\n\u003cli\u003ePatel BA, Groarke EM, Lotter J, Shalhoub R, Gutierrez-Rodrigues F, Rios O, et al. Long-term outcomes in patients with severe aplastic anemia treated with immunosuppression and eltrombopag: a phase 2 study. Blood. 2022 Jan 6;139(1):34\u0026ndash;43. \u003c/li\u003e\n\u003cli\u003eZhang Y, Liu M, Zhan X. The efficacy of immunosuppression combined with Eltrombopag in the treatment of severe aplastic anemia in children [Internet]. [cited 2024 Apr 28]. Available from: http://qikan.cqvip.com/Qikan/Article/Detail?id=7106916895\u0026amp;from=Qikan_Search_Index\u003c/li\u003e\n\u003cli\u003eZhao Y, Yang W, Zhao X, Hu X, Hu J, Liu X, et al. Efficacy of eltrombopag with immunosuppressive therapy for children with acquired aplastic anemia. Front Pediatr. 2023 Jan 10;10:1095143. \u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1. Characteristics of included studies in the meta-analysis.\u0026nbsp;\u003c/strong\u003eEPAG: eltrombopag, IST: immunosuppressive therapy, RCT: randomized controlled trial, NA: no report, \u0026nbsp;hATG: horse antityhymocyte globulin, rATG: rabbit antityhymocyte globulin, pATG: pig antityhymocyte globulin, CsA: cyclosporin A.\u003c/p\u003e\n\u003cdiv align=\"\"\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 7px;\"\u003e\n \u003cp\u003eAuthor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 4px;\"\u003e\n \u003cp\u003eYear\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 4px;\"\u003e\n \u003cp\u003eTotal no.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 8px;\"\u003e\n \u003cp\u003eStudy design\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 8px;\"\u003e\n \u003cp\u003eAge types of patients/years old\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" style=\"width: 38px;\"\u003e\n \u003cp\u003eEPAG+IST\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 1px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 27px;\"\u003e\n \u003cp\u003eIST\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003ePatients(n)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003eGender (female/male) ,n\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eEPAG Initiation time\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003eIntervention\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 1px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003ePatients(n)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003eGender (female/male) ,n\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eIntervention\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eAssi[9]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 4px;\"\u003e\n \u003cp\u003e2018\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 4px;\"\u003e\n \u003cp\u003e38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eProspective study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u0026ge; 18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e10/11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0-7d\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003eEPAG+hATG+CsA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 1px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003e8/9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003ehATG+CsA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eCai[31]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 4px;\"\u003e\n \u003cp\u003e2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 4px;\"\u003e\n \u003cp\u003e86\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eRetrospective study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eUnlimited\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e22/20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0-7d\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003eEPAG+CsA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 1px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003e23/21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eCsA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eChai[32]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 4px;\"\u003e\n \u003cp\u003e2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 4px;\"\u003e\n \u003cp\u003e35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eRetrospective study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u0026ge; 18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e9/15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0-7d\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003eEPAG+rATG+CsA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 1px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003e6/5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003erATG+CsA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eDe Latour[8]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 4px;\"\u003e\n \u003cp\u003e2022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 4px;\"\u003e\n \u003cp\u003e197\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eRCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eUnlimited\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e96\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e49/52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u0026gt;7d\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003eEPAG+hATG+CsA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 1px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e101\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003e49/52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003ehATG+CsA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eFang[12]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 4px;\"\u003e\n \u003cp\u003e2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 4px;\"\u003e\n \u003cp\u003e57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eRetrospective study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u0026lt;18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e8/10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u0026gt;7d\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003eEPAG+pATG+CsA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 1px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003e18/21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003epATG+CsA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eFang[13]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 4px;\"\u003e\n \u003cp\u003e2023\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 4px;\"\u003e\n \u003cp\u003e90\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eRetrospective study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eUnlimited\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e22/23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0-7d\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003eEPAG+rATG+CsA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 1px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003e22/23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003erATG+CsA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eGoronkova[19]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 4px;\"\u003e\n \u003cp\u003e2023\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 4px;\"\u003e\n \u003cp\u003e98\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eRCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u0026lt;18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e14/35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0-7d\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003eEPAG+hATG+CsA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 1px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003e19/30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003ehATG+CsA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eGroarke[14]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 4px;\"\u003e\n \u003cp\u003e2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 4px;\"\u003e\n \u003cp\u003e127\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eProspective study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u0026lt;18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e17/23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0-7d\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003eEPAG+hATG+CsA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 1px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e87\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003e36/51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003ehATG+CsA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eHu[15]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 4px;\"\u003e\n \u003cp\u003e2022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 4px;\"\u003e\n \u003cp\u003e111\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eRetrospective study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eUnlimited\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e13/24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u0026gt;7d\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003eEPAG+r/pATG+CsA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 1px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e74\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003e40/34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003er/pATG+CsA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eJie[16]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 4px;\"\u003e\n \u003cp\u003e2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 4px;\"\u003e\n \u003cp\u003e42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eRetrospective study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u0026lt;18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eUnlimited\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003eEPAG+rATG+CsA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 1px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003erATG+CsA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eJin[10]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 4px;\"\u003e\n \u003cp\u003e2022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 4px;\"\u003e\n \u003cp\u003e121\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eRetrospective study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u0026ge; 18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e26/28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0-7d\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003eEPAG+rATG+CSA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 1px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003e30/37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003erATG+CSA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eLesmana[20]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 4px;\"\u003e\n \u003cp\u003e2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 4px;\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eRetrospective study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u0026lt;18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e2/7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0-7d\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003eEPAG+hATG+CsA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 1px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003e12/4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003ehATG+CsA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eLiang[33]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 4px;\"\u003e\n \u003cp\u003e2023\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 4px;\"\u003e\n \u003cp\u003e89\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eRetrospective study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u0026ge; 18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e23/19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0-7d\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003eEPAG+CsA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 1px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003e24/23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eCsA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eLin[17]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 4px;\"\u003e\n \u003cp\u003e2023\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 4px;\"\u003e\n \u003cp\u003e76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eRetrospective study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u0026ge; 18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e24/21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0-7d\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003eEPAG+CsA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 1px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003e16/15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eCsA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eMartynova[34]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 4px;\"\u003e\n \u003cp\u003e2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 4px;\"\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eRetrospective study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u0026ge; 18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e8/4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0-7d\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003eEPAG+hATG+Tacrolimus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 1px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003e6/3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003ehATG+Tacrolimus\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003ePatel[35]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 4px;\"\u003e\n \u003cp\u003e2022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 4px;\"\u003e\n \u003cp\u003e280\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eProspective study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eUnlimited\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e178\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eUnlimited\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003eEPAG+hATG+CsA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 1px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e102\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003ehATG+CsA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eShinn[27]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 4px;\"\u003e\n \u003cp\u003e2023\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 4px;\"\u003e\n \u003cp\u003e82\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eRetrospective study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u0026ge; 18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e23/25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0-7d\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003eEPAG+hATG+CsA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 1px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003e16/18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003ehATG+CsA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eYang[18]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 4px;\"\u003e\n \u003cp\u003e2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 4px;\"\u003e\n \u003cp\u003e125\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eRCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u0026ge; 18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e25/38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0-7d\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003eEPAG+CsA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 1px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003e27/35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eCsA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eZaimoku[25]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 4px;\"\u003e\n \u003cp\u003e2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 4px;\"\u003e\n \u003cp\u003e416\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eRetrospective study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u0026ge; 18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e176\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e89/87\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eUnlimited\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003eEPAG+hATG+CsA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 1px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e240\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003e99/141\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003ehATG+CsA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eZhang[36]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 4px;\"\u003e\n \u003cp\u003e2022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 4px;\"\u003e\n \u003cp\u003e63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eRetrospective study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u0026lt;18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e15/16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0-7d\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003eEPAG+rATG+CsA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 1px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003e16/16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003erATG+CsA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eZhao[37]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 4px;\"\u003e\n \u003cp\u003e2023\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 4px;\"\u003e\n \u003cp\u003e60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eRetrospective study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u0026lt;18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e5/10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0-7d\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003eEPAG+r/pATG+CsA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 1px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003e19/26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003er/pATG+CsA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2. Quality assessment of non-RCTs included in this meta-analysis.\u0026nbsp;\u003c/strong\u003eThe Newcastle-Ottawa Scale (NOS) was used to evaluate the quality of the non-RCTs. Scores ranged from 0 to 9: scores of 1 or less were considered low quality (high risk of bias), scores of 2\u0026ndash;5 were medium quality (unclear), and scores of 6\u0026ndash;9 were high-quality literature (low risk of bias).\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" align=\"\" width=\"728\" class=\"fr-table-selection-hover\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 77px;\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"5\" style=\"width: 296px;\"\u003e\n \u003cp\u003eSelection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 128px;\"\u003e\n \u003cp\u003eComparability\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 182px;\"\u003e\n \u003cp\u003eOutcome/Exposure\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 46px;\"\u003e\n \u003cp\u003eScores\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003eRepresentativ-eness of the exposed cohort\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003eSelection of the non-exposed cohort\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003eDetermination of exposure\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003eAscertainment of no outcome before the study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 67px;\"\u003e\n \u003cp\u003eMatching the most important factors\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003eControl of confounding factors\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 67px;\"\u003e\n \u003cp\u003eEvaluation of outcome\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003eAdequacy of follow up\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68px;\"\u003e\n \u003cp\u003eAdequacy of follow up\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003eZhao 2023\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 46px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003ePatel 2022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 46px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003eJin 2022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 67px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 46px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003eMartynova 2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 67px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 46px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003eFang 2023\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 46px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003eLesmana 2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 67px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 46px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003eLin 2023\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 46px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003eZhang 2022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 46px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003eZaimoku 2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 67px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 46px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003eJie 2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 67px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 46px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003eGroarke 2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 46px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003eFang 2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 46px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003eAssi 2018\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 67px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 46px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003eHu 2022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 46px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003eChai 2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 67px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 46px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003eLiang 2023\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 67px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 46px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003eCai 2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 46px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003eShinn 2023\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 46px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Aplastic anemia (AA), Bone marrow failure (BMF), Eltrombopag(EPAG), Immunosuppressive therapy (IST), Thrombopoietin receptor agonists (TPO-RA)","lastPublishedDoi":"10.21203/rs.3.rs-7631623/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7631623/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eAplastic anemia (AA) is a bone marrow failure syndrome. How to achieve better efficacy of Eltrombopag (EPAG) and IST in the treatment of AA is still unclear. This meta-analysis compares the efficacy of EPAG+IST verses IST alone, and assesses the optimal timing and duration for starting EPAG in different ages of AA patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e The literature was retrieved from Chinese and English databases up to July 1, 2025. The analysis was conducted using RevMan 5.4 software, employing a fixed effects model to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the outcomes. The I² statistic was used to assess heterogeneity among included studies.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003e21 studies involving 2,239 patients were included. The overall response rate in the EPAG+IST group was higher at 3 months (OR = 2.13, 95% CI 1.65–2.74, p \u0026lt; 0.00001) and 6 months (OR = 2.13, 95% CI 1.73–2.61, p \u0026lt; 0.00001). There was no significant difference between two groups at 12 months (OR = 1.14, 95% CI 0.86–1.51, p = 0.36, I² = 35%). For adults, it is recommended the concurrent therapy of EPAG and IST, and continue for a period of 3 months to achieve significant hematological improvement (HI). If EPAG was added after 7 days, patients will achieve HI for about 6 months. For children, regardless of the concurrent or nonconcurrent therapy, it is recommended to continue for about 6 months to achieve better HI.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eEltrombopag should be used as early as possible, as it shows a better HI compared with simply IST treatment within 3-6 months, with no significant difference in risk. Concurrent therapy of EPAG should be performed and extending EPAG treatment beyond 12 months may not yield significantly enhanced benefits.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSystematic Review Registration:\u003c/strong\u003e https://www.crd.york.ac.uk/prospero/, identifier CRD42024604778\u003c/p\u003e","manuscriptTitle":"This Meta-Analysis Evaluates the Optimal Timing for Initiating and Discontinuing Eltrombopag for Aplastic Anemia","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-10 14:52:10","doi":"10.21203/rs.3.rs-7631623/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"7a12f796-0292-4d24-a79d-0cf9e7ec47af","owner":[],"postedDate":"October 10th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-04-16T04:40:06+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-10 14:52:10","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7631623","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7631623","identity":"rs-7631623","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}