| Objective:To systematically review the efficacy and safety of cyclosporin A(CsA),androgen and CsA combined with androgen in the treatment of non-severe aplastic anemia.Methods:The Cochrane Library,EMbase,PubMed,CBM,CNKI,VIP and Wanfang Date databases were searched from inception to December 31,2019 to collect randomized controlled trials of CsA and/or androgen in the treatment of non-severe aplastic anemia.Two reviewers screened studies,extracted date,and evaluated risk of bias of included studies according to the inclusion and exclusion criteria independently,and conducted statistical analysis on the data.The Rev Man 5.3 software was used to make the meta-analysis forest map.The State software was used for sensitivity analysis,and the funnel plot was drawn to detect publication bias.Results:50 randomized controlled trials with a total of 3427 patients were involved in this research.8 studies were included in the comparison between CsA and androgen,37 studies were included in the comparison between CsA combined with androgen and androgen,5 studies were included in the comparison between CsA combined with androgen and CsA.The results of the Meta-analysis are as follows:① The comparison between CsA and androgen in the treatment of non-severe aplastic anemia.In terms of therapeutic efficiency,the total effective rate and complete remission rate in the CsA group were higher than those in the androgen group[RR=1.16,95%Cl(1.04,1.28),P=0.005;RR=1.57,95%Cl(1.23,2.02),P=0.0003].In terms of the changes of hematological indicators,the increase of leukocytes and hemoglobin in the CsA group were higher than those in the androgen group[MD=0.74,95%Cl(0.33,1.16),P=0.0004;MD=11.45,95%Cl(1.15,21.76),P=0.03],but there was no significant difference in the increase of platelet between two groups[MD=15.71,95%Cl(-1.44,32.86),P=0.07].In terms of the expression of growth factor,the increase of VEGF expression in the CsA group was higher than that in the androgen group[MD=22.12,95%Cl(20.20,24.04),P<0.00001].In terms of the incidence of adverse reactions,there were no significant differences in the incidence of liver injury,gingival hyperplasia,tremor,polytrichia and edema of lower limbs between two groups(P>0.05).②The comparison between CsA combined with androgen and androgen in the treatment of non-severe aplastic anemia.In terms of therapeutic efficiency,the total effective rate and complete response rate in the CsA combined with androgen group were higher than those in the androgen group[RR=1.39,95%Cl(1.32,1.47),P<0.00001;RR=1.91,95%Cl(1.55,2.34),P<0.00001],and the onset time in the CsA combined with androgen group was faster than that in the androgen group[MD=-24.50,95%Cl(-28.38,-20.62),P<0.00001];In terms of the changes of hematological indicators,the increase of leukocytes,hemoglobin and platelets in the CsA combined with androgen group were higher than those in the androgen group[MD=1.08,95%Cl(0.69,1.47),P<0.00001;MD=16.33,95%Cl(14.22,18.45),P<0.00001;MD=11.30,95%Cl(8.77,13.82),P<0.00001];In terms of the expression of growth factor and receptor,the increase of VEGF,bFGF and bFGFR expression in the CsA combined with androgen group were higher than those in the androgen group[MD=16.83,95%Cl(10.95,22.71),P<0.00001;MD=0.61,95%Cl(0.53,0.69),P<0.00001;MD=0.70,95%Cl(0.66,0.74),P<0.00001].In terms of the incidence of adverse reactions,there were no significant differences in the incidence of liver injury,kidney injury,gastrointestinal reactions,skin paresthesia,hyperglycemia,rash and pigmentation between two groups(P>0.05),but the incidence of gingival hyperplasia,tremor,polytrichia and hypertension in the CsA combined with androgen group were higher than those in the androgen group[RR=8.39,95%Cl(4.85,14.51),P<0.00001;RR=9.94,95%Cl(5.53,17.85),P<0.00001;RR=6.98,95%Cl(3.13,15.18),P<0.00001;RR=3.24,95%Cl(1.32,7.94),P=0.01].③The comparison between CsA combined with androgen and CsA in the treatment of non-severe aplastic anemia.In terms of therapeutic efficiency,the total effective rate and complete response rate in the CsA combined with androgen group were higher than those in the CsA group[RR=1.58,95%Cl(1.28,1.96),P<0.0001;RR=1.82,95%Cl(1.10,3.01),P=0.02];In terms of the changes of hematological indicators,the increase of leukocytes,hemoglobin and platelets in the CsA combined with androgen group were higher than those in the CsA group[MD=1.32,95%Cl(1.01,1.63),P<0.00001;MD=5.60,95%Cl(1.49,9.71),P=0.008;MD=5.60,95%Cl(3.68,7.51),P<0.00001];In terms of the expression of growth factor,the increase of VEGF expression in the CsA combined with androgen group were higher than those in the CsA group[MD=19.46,95%Cl(17.34,21.58),P<0.00001].In terms of the incidence of adverse reactions,there were no significant differences in the incidence of liver injury,tremor,polytrichia,elevation of blood pressure,edema of lower limbs between two groups(P>0.05),but the incidence of gingival hyperplasia in the CsA combined with androgen group were higher than those in the CsA group[RR=24.11,95%Cl(1.53,380.12),P=0.02].Conclusions:1.Compared with CsA or androgen,CsA combined with androgen is more effective.Therefore,CsA combined with androgen is preferred for the treatment of non-severe aplastic anemia,but we should pay attention to the incidence of adverse reactions such as gingival hyperplasia,tremor,polytrichia and hypertension,monotherapy may be considered when the adverse reactions cannot be tolerated.2.Compared with androgen,CsA is more effective,and the safety of the two treatments is comparable.Therefore,CsA is preferred for the treatment of non-severe aplastic anemia based monotherapy.Due to the limited methodological quality of the included studies,the conclusions of this study need to be further validated by large-scale,multi-center and high-quality randomized controlled trials. |
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