The efficacy and safety of cyclosporine A plus androgen versus androgen alone for adult patients with non-severe aplastic anemia in China: a meta-analysis of randomized controlled trials

Figures & data

Figure 1. The details of the literature search and study selection process.

Table 1. The baseline characteristics of included studies.

Study	Sample size	Age (years)	Percentage male (%)	CsA	Androgen	Duration of treatment	Study quality
Yu 2001 [14]	57 (31/26)	33.1	56.1	CsA 5–8 mg/kg/day, bid/tid	Stanozolol 2 mg, tid	6.0 months	2
Xu 2004 [15]	76 (42/34)	32.6	67.1	CsA 0.5–5 mg/kg/day, bid	Stanozolol 6 mg/day or TU 500 mg, twice/month	6.0 months	1
Dong 2006 [16]	80 (44/36)	32.6	65.0	CsA 0.5–5 mg/kg/day, bid	Stanozolol 6–8 mg/day or TU 250–500 mg/15 days	6.0 months	2
Zhao 2007 [17]	48 (28/20)	36.8	56.3	CsA 3–5 mg/kg/day	TU 120 mg/day, tid	NA	2
Tang 2007 [18]	31 (15/16)	32.0	54.8	CsA 3–5 mg/kg/day	Stanozolol 6–8 mg/day	6.0 months	2
Yang 2008 [19]	65 (35/30)	37.0	55.4	CsA 3–5 mg/kg/day, bid	Stanozolol 2 mg, tid	6.0 months	2
Shu 2008 [20]	34 (18/16)	30.0	52.9	CsA 3–6 mg/kg/day, bid/tid	Stanozolol 2 mg, tid	3.0–9.0 months	2
Zhu 2009 [21]	60 (30/30)	36.2	58.3	CsA 3–5 mg/kg/day, bid	TP 50 mg, 3 times/week	NA	2
Wang 2009 [22]	50 (26/24)	32.0	56.0	CsA 3–6 mg/kg/day, bid/tid	Stanozolol 2 mg, tid	3.0–9.0 months	1
Xia 2009 [23]	52 (29/23)	36.5	57.7	CsA 3–5 mg/kg/day, bid	Stanozolol 2 mg, tid	6.0 months	2
Zhou 2009 [24]	38 (24/14)	36.0	60.5	CsA 3–5 mg/kg/day, bid	TU 40 mg/day, tid	6.0 months	1
Li 2010 [25]	42 (22/20)	37.0	64.3	CsA 3–5 mg/kg/day, bid	TU 40 mg/day, tid	6.0 months	2
Dai 2010 [26]	56 (28/28)	33.0	53.6	CsA 3–6 mg/kg/day, bid/tid	Stanozolol 2 mg, tid	3.0–9.0 months	1
Zeng 2010 [27]	68 (34/34)	34.5	55.9	CsA 3–5 mg/kg/day, bid	Stanozolol 6–12 mg, tid	6.0 months	2
Zhao 2010 [28]	30 (16/14)	32.0	60.0	CsA 3–5 mg/kg/day, bid	Stanozolol 2 mg, tid	3.0–10.0 months	1
Yang 2011 [29]	62 (31/31)	34.1	56.5	CsA 3–5 mg/kg/day, bid	Stanozolol 2 mg, tid	6.0 months	2
Feng 2011 [30]	104 (52/52)	14.0-65.0	62.5	CsA 3–5 mg/kg/day, bid	Stanozolol 2 mg, tid	6.0 months	1
Yu 2011 [31]	52 (26/26)	34.8	55.8	CsA 3–6 mg/kg/day, bid/tid	Stanozolol 2 mg, tid	3.0–9.0 months	2
Liang 2012 [32]	42 (24/18)	31.2	61.9	CsA 4 mg/kg/day, bid	Stanozolol 6 mg/day	6.0 months	1
Huang 2012 [33]	60 (30/30)	13.0-60.0	41.7	CsA 5–12 mg/kg/day	Stanozolol 2 mg, tid	6.0 months	2
Tang 2012 [34]	50 (25/25)	47.5	54.0	CsA 12 mg/kg/day	Stanozolol 2 mg, tid	6.0 months	1
Liu 2013 [35]	37 (20/17)	33.0	54.1	CsA 4–6 mg/kg/day, bid	Stanozolol 2 mg, tid	NA	1
Yin 2013 [36]	40 (20/20)	NA	57.5	CsA 5–12 mg/kg/day	TU 40 mg/day, tid	6.0 months	1
Wei 2013 [37]	60 (30/30)	35.2	56.7	CsA 4 mg/kg/day, bid	Stanozolol 2 mg, tid	6.0 months	2
Yinlidaer 2013 [38]	48 (24/24)	37.5	58.3	CsA 3–4 mg/kg/day, bid	Androgen 40 mg, tid	NA	1
Hu 2013 [39]	88 (44/44)	45.3	61.4	CsA 4 mg/kg/day, bid	Stanozolol 6 mg/day	NA	1
Sun 2014 [40]	73 (39/34)	34.3	53.4	CsA 3 mg/kg/day, bid	Stanozolol 2 mg, tid	6.0 months	1
Liu 2014 [41]	52 (26/26)	35.3	53.8	CsA 3–5 mg/kg/day, bid	Stanozolol 6–12 mg/day, tid	NA	2
Zhuang 2015 [42]	90 (45/45)	44.7	NA	CsA 6 mg/kg/day, bid	Stanozolol 6 mg/day	NA	2
Du 2015 [43]	98 (49/49)	31.0	56.1	CsA 3–5 mg/kg/day, bid	Stanozolol 2 mg, tid	NA	2
Xiong 2015 [44]	70 (35/35)	34.0	51.4	CsA 3–5 mg/kg/day, bid	Stanozolol 2 mg, tid	6.0 months	1
Liang 2016 [45]	120 (60/60)	33.7	60.0	CsA 3–5 mg/kg/day, bid	TU 2–4 mg, tid	6.0 months	2
Pang 2016 [46]	50 (25/25)	31.4	56.0	CsA 3–5 mg/kg/day, bid	Stanozolol 2 mg, tid	6.0 months	2
Zhou 2016 [47]	38 (19/19)	NA	50.0	CsA 4 mg/kg/day, bid	Stanozolol 2 mg, tid	6.0 months	2
Tian 2017 [48]	76 (38/38)	43.4	53.9	CsA 3–5 mg/kg/day, bid	Stanozolol 2 mg, tid	6.0 months	1
Chen 2017 [49]	62 (31/31)	44.0	74.2	CsA 3–5 mg/kg/day, bid	Stanozolol 6–12 mg/day, tid	NA	1
Yang 2017 [50]	44 (22/22)	40.5	59.1	CsA 3–5 mg/kg/day, bid	Stanozolol 2 mg, tid	6.0 months	2
Ru 2018 [51]	68 (34/34)	32.4	70.6	CsA 3–5 mg/kg/day, bid	Stanozolol 2 mg, tid	6.0 months	2
Yang 2018 [52]	80 (40/40)	34.3	61.3	CsA 4 mg/kg/day, bid	Stanozolol 2 mg, tid	6.0 months	2
Hu 2019 [53]	64 (32/32)	36.2	48.4	CsA 4 mg/kg/day, bid	Stanozolol 2 mg, tid	6.0 months	1
Sun 2019 [54]	50 (25/25)	38.5	65.0	CsA 3–5 mg/kg/day, bid	Stanozolol 2 mg, tid	6.0 months	1
Zhang 2019 [55]	84 (42/42)	39.9	59.5	CsA 4 mg/kg/day, bid	Stanozolol 2 mg, tid	6.0 months	2
Yao 2020 [56]	61 (30/31)	46.8	55.7	CsA 3–5 mg/kg/day, bid	Stanozolol 2 mg, tid	6.0 months	1

Note: CsA: cyclosporine A; TU: Testosterone Undecanoate; TP: testosterone propionate.

Figure 2. Effect of combined therapy versus androgen therapy on the incidence of effective rate.

Table 2. Subgroup analysis for the effective rate.

Variables	Subgroup	Number of studies	RR and 95%CI	P-value	Heterogeneity (%)	P-value for Q statistic	P-value between subgroups
Publication year	Before 2010	11	1.47 (1.31–1.66)	<0.001	0.0	0.998	0.094
	2010 or after	31	1.33 (1.26–1.40)	<0.001	0.0	0.999
Mean age (years)	≥35.0	19	1.31 (1.23–1.40)	<0.001	0.0	0.890	0.513
	<35.0	19	1.40 (1.29–1.51)	<0.001	0.0	1.000
Percentage male (%)	≥60.0	12	1.35 (1.24–1.47)	<0.001	0.0	0.956	0.155
	<60.0	29	1.37 (1.29–1.46)	<0.001	0.0	1.000
Control	Stanozolol	35	1.34 (1.27–1.40)	<0.001	0.0	1.000	0.266
	Other	7	1.44 (1.26–1.65)	<0.001	0.0	0.941
Study quality	2	23	1.35 (1.27–1.44)	<0.001	0.0	0.997	0.923
	1	19	1.34 (1.25–1.44)	<0.001	0.0	0.980

Figure 3. Effect of combined therapy versus androgen therapy on the level of the WBC.

Figure 4. Effect of combined therapy versus androgen therapy on the level of hemoglobin.

Figure 5. Effect of combined therapy versus androgen therapy on the level of the platelet.

Table 3. The results of adverse events in patients treated with combined therapy.

Study	Sample size	Hirsutism	Handshake	Gingiva hyperplasia	Liver function damage	Renal function damage
Yu 2001	31	11	9	3	5	1
Xu 2004	42	38	24	30	20	–
Dong 2006	44	39	25	30	20	–
Zhao 2007	28	25	–	27	–	8
Tang 2007	15	3	4	2	1	–
Yang 2008	35	16	19	17	14	–
Shu 2008	18	12	2	2	4	–
Wang 2009	26	14	1	3	4	–
Xia 2009	29	–	1	2	–	–
Zhou 2009	24	3	–	2	5	1
Dai 2010	28	8	9	5	10	–
Zeng 2010	34	8	12	5	10	–
Zhao 2010	16	8	1	2	3	–
Yang 2011	31	–	2	2	–	–
Feng 2011	52	12	18	8	15	–
Yu 2011	26	12	13	10	11	–
Liang 2012	24	19	–	8	3	–
Liu 2013	20	10	2	2	4	–
Yin 2013	20	1	–	–	–	–
Wei 2013	30	6	–	–	2	–
Yinlidaer 2013	24	3	–	–	5	–
Xiong 2015	35	6	–	–	3	1
Pang 2016	25	2	1	1	–	–
Yang 2017	22	–	–	1	1	–
Yang 2018	40	2	–	–	3	–
Hu 2019	32	–	2	1	1	–
Sun 2019	25	4	6	2	5	–
Zhang 2019	42	1	–	–	2	–
Yao 2020	30	1	–	1	6	2
Pooled	848	264	151	166	157	13
Incidence and 95%CI	–	0.35 (0.22–0.48)	0.24 (0.15–0.32)	0.22 (0.10–0.35)	0.19 (0.14–0.25)	0.06 (0.01–0.11)

Yu G, Zhang C, Li D. Effect of cyclosporine A combined with kangilong in the treatment of chronic aplastic anemia. Heilongjiang Med Pharm. 2001;24:21.

 Google Scholar

Xu H, Chen T, Zhang X, et al. Effect observation of cyclosporine A combined with androgen in the treatment of chronic aplastic anemia. Chin J Hemorh. 2004;14:477–478.

 Google Scholar

Dong J, Xu H, Fang F, et al. Observing the effect of cyclosporine A combined androgen on chronic aplastic anemia. Hebei Med. 2006;12:1156–1157.

 Google Scholar

Zhao Y, Zhu X, Yu T, et al. Cyclosporine A combined with testosterone undecanoate in the treatment of chronic aplastic anemia. Chin Hydro Med. 2007;5:270–271.

 Google Scholar

Tang X, Zeng Y, He W, et al. Oserving the effect of cyclosporine A combined stanozolol on chronic aplastic anaemia. West China Med J. 2007;22:528.

 Google Scholar

Yang G. Clinical observation of 35 cases of chronic aplastic anemia treated by cyclosporine A combined with kanglilong. Shandong Med J. 2008;48:92–93.

 Google Scholar

Shu H, Fang T, Ge S. Effect of cyclosporine soft capsule combined with kanglilong in the treatment of chronic aplastic anemia. Chin J Misdiag. 2008;8:3577–3578.

 Google Scholar

Zhu W, Li L. Therapeutic effect of cyclosporin A combined with testosterone propionate on chronic aplastic anemia. Prac Prev Med. 2009;16:1557–1558.

 Google Scholar

Wang P, He Y, Fu H. Effect of cyclosporine A combined with kangilong in the treatment of chronic aplastic anemia. Chin Prac Med. 2009;4:161–162.

 Google Scholar

Xia Z. Effect observation of cyclosporine A combined with kangilong in the treatment of 29 cases of chronic aplastic anemia. Huazhong Med J. 2009;33:345–346.

 Google Scholar

Zhou Z, Wang Z, Zhao X. Clinical observation of cyclosporine A combined therapy for chronic aplastic anemia. J Qiqihar Med Coll. 2009;30:2763–2764.

 Google Scholar

Li Y, Pan H. Effect of cyclosporine A combined with testosterone undecatrate in the treatment of chronic aplastic anemia. Youjiang Med. 2010;38:427–428.

 Google Scholar

Dai Q, Xu X, Meng W, et al. Effect of cyclosporine A combined with kanglilong in the treatment of chronic aplastic anemia. J Clin Med Prac. 2010;14:52–53.

 Google Scholar

Zeng X. Observation on the curative effect of cyclosporine A combined with kangilong in the treatment of chronic aplastic anemia. Hebei Med J. 2010;32:37–38.

 Google Scholar

Zhao J. Observation on the curative effect of cyclosporine A combined with kangilong in the treatment of chronic aplastic anemia. Chin Commun Phys. 2010;15:16.

 Google Scholar

Yang J. Effect of cyclosporine A combined with kanglilong in the treatment of 31 cases of chronic aplastic anemia. Guide Chin Med. 2011;9:72–73.

 Google Scholar

Feng G. The effect of cyclosporine A combined with kangilong in the treatment of 52 cases of chronic aplastic anemia. Chin Prac Med. 2011;6:135–136.

 Google Scholar

Yu H, Zhang Z, Wu T. The clinical observation of cyclosporine A combined with stanozolol used in chronic aplastic anemia. Chin Mod Doct. 2011;49:52–53.

 Google Scholar

Liang Y, Lu L, Cui X, et al. Clinical observation of cyclosporine A combined with stazolium in the treatment of chronic aplastic anemia. Chin J Chin Ration Drug Use. 2012;5:65–66.

 Google Scholar

Huang W. Evaluation of efficacy on stanozolol tablets joint ciclosporine capsules in the treatment of 30 patients with chronic aplastic anemia. Chin Med Pharm. 2012;2:84–85.

 Google Scholar

Tang W, Chen J. Evaluation of efficacy on stanozolol tablets joint cyclosporine capsules in the treatment of 50 patients with chronic aplastic anemia. Chin Foreign Med. 2012;32:73–74.

 Google Scholar

Liu X. Effect of cyclosporine A combined with kanglilong in the treatment of chronic aplastic anemia. J Med Theor Prac. 2013;26:2185–2186.

 Google Scholar

Yin Y. Cyclosporin A joint stanozolol tablets in treatment of chronic aplastic anemia clinical curative effect. Chin J Trau Disab Med. 2013;21:19–21.

 Google Scholar

Wei T, Gong Z. Clinical effects of ciclopirin A combined with stanozolol in treatment of chronic aplastic anemia. Chin J Coal Indus Med. 2013;16:1802–1804.

 Google Scholar

Yilidaer A, Dilinazi A, Hao J, et al. Clinical treatment of chronic aplastic anemia. Med Infor. 2013;26:223.

 Google Scholar

Hu H. Clinical analysis of stanzole combined with cyclosporine A in the treatment of chronic aplastic anemia. Chin Prac Med. 2013;8:112–113.

 Google Scholar

Sun T, Yang L, Zhang Y. Clinical efficacy of cyclosporine A combined with kangilong in the treatment of chronic aplastic anemia. J Aerospace Med. 2014;25:1705–1706.

 Google Scholar

Liu W, Wu R, Li L. Effect analysis of cyclosporine A combined with kangilong in the treatment of chronic aplastic anemia. Chin J Prev Contr Chron Dis. 2014;22:106–107.

 Google Scholar

Zhuang W. Clinical analysis of 90 cases of chronic aplastic anemia. Med Infor. 2015;28:228.

 Google Scholar

Du Z, Dai C. Effects of cyclosporine A combined with kangilong on bone marrow stromal cell-related cytokines in patients with chronic aplastic anemia. Chin J Gerontol. 2015;35:955–957.

 Google Scholar

Xiong H. Clinical observation of cyclosporine A combined with statazole in the treatment of non-severe aplastic anemia. Chin Prac Med. 2015;10:134–135.

 Google Scholar

Liang Y, Zhang Y, Qin Y, et al. The treatment effect and adverse reaction of cyclosporin A combined testosterone undecanoate on chronic aplastic anemia. J Clin Exper Med. 2016;15:1604–1606.

 Google Scholar

Pang H. Clinical effect of cyclosporine A in the treatment of chronic aplastic anemia (CAA). Chin Health Stand Manag. 2016;7:95–96.

 Google Scholar

Zhou S. The clinical value of stazoll and cyclosporine A in the treatment of chronic aplastic anemia. Chin J Trau Disab Med. 2016;24:25–26.

 Google Scholar

Tian J. Analysis of treatment and outcome of non-severe aplastic anemia. World Clin Med. 2017;11:39–40.

 Google Scholar

Chen Q. Clinical observation of cyclosporine A combined with kanglilong in the treatment of patients with chronic aplastic anemia. Med Front. 2017;7:87–88.

 Google Scholar

Yang X. Observation on the effect of cyclosporine A combined with kanglilong in the treatment of patients with chronic aplastic anemia. Med Front. 2017;7:226–227.

 Google Scholar

Ru W. Study on the clinical effect of kangilong combined with cyclosporine A in the treatment of chronic aplastic anemia. Clin Res. 2018;26:100–101.

 Google Scholar

Yang Q. Treatment of chronic aplastic anemia with stanzole and cyclosporine A. Shenzhen J Integrat Tradit Chin West Med. 2018;28:162–163.

 Google Scholar

Hu X. Effect observation and effect analysis of effectiveness of kangilong combined with cyclosporine A in the treatment of chronic aplastic anemia. J Clin Med. 2019;6:29–30.

 Google Scholar

Sun D, Zhang Z. Effect of cyclosporine A combined with kanglilong in the treatment of chronic aplastic anemia. Guide Chin Med. 2019;17:42–43.

 Google Scholar

Zhang Z, Li Z, Yang X, et al. Efficacy of cyclosporine A combined with stazolium in the treatment of patients with chronic aplastic anemia. Prac Clin J Integrat Tradit Chin West Med. 2019;19:24–26.

 Google Scholar

Yao C. Clinical observation of cyclosporine A combined with stazolium in the treatment of chronic aplastic anemia. Public Med Forum Magaz. 2020;24:79–80.

 Google Scholar

Data availability statement

The data sets used and/or analyzed during the present study are available from the corresponding author on reasonable request.