Efficacy and safety of fingolimod in stroke: A systemic review and meta-analysis

Table 1 Agreement of studies included by Zhao K and Guo Y

Zhao K	Guo Y		Total
	+	-
+	4	3	7
-	2	176	179
Total	6	179	185

Kappa = 0.601, P < 0.001.

Table 2 Characteristics of studies used to perform the meta-analysis

Ref.	Publication	Fingolimod group	Types of stroke	Age (mean ± SD)	Sex (male %)	Dose of fingolimod	Conclusion
Fu et al[15]	2014	11	AIS	62.3 ± 8.0	73	0.5 mg/d orally, 3 consecutive days after hospitalization	It could safely limit secondary tissue injury, decrease microvascular permeability, attenuate neurological deficits, and promote recovery.
Fu et al[16]	2014	11	ICH	60.7 ± 12.3	36	0.5 mg/d orally, 3 consecutive days after hospitalization	It could safely reduce PHE, attenuate neurologic deficits, and promote recovery.
Zhu et al[17]	2015	22	AIS	60.0 ± 2.5	59	0.5 mg/d orally, 3 consecutive days after hospitalization	In this pilot study, combination therapy of fingolimod and alteplase was well tolerated, which attenuated reperfusion injury and improved clinical outcomes in AIS patients.
Tian et al[18]	2018	23	AIS	67 ± 6.7	39	0.5 mg/d orally, 3 consecutive days after hospitalization	Fingolimod may enhance the efficacy of alteplase administration in the 4.5- to 6-h time window in patients with a proximal cerebral arterial occlusion and salvageable penumbral tissue by promoting both anterograde reperfusion and retrograde collateral flow.

SD: Standard deviation.

Table 3 Agreement of data extraction between Zhao K and Guo Y

Zhao K	Guo Y		Total
	+	-
+	16	5	21
-	3	20	23
Total	19	25	44

Kappa = 0.634, P < 0.001.

Table 4 Changes of T-lymphocytes with cluster of differentiation 8 expression/infarction or hematoma volume/modified Barthel index scores in the fingolimod and control groups

Ref.	Size of fingolimod group	Fingolimod group	Size of control group	Control group
CD8+ T cell count (mean ± SD, × 106/mL)1
Fu et al[15]	11	-0.16 ± 0.04	11	0.08 ± 0.08
Tian et al[18]	23	-0.09 ± 0.02	23	-0.02 ± 0.02
Lesion Volume (mean ± SD, mL)2
Fu et al[15]	11	9.91 ± 79.62	11	25.45 ± 75.45
Fu et al[16]	11	-1.97 ± 6.25	12	-1.35 ± 1.77
mBI score (mean ± SD)3
Fu et al[15]	11	72.7 ± 7.5	11	45.3 ± 10.9
Fu et al[16]	11	75.2 ± 4.7	12	65.4 ± 4.8

¹The outcome equaled CD8⁺ T cell count at 1 d after taking fingolimod orally minus CD8⁺ T cell count at baseline.

²Lesion volume consisted of infarct volume of AIS and hematoma volume of ICH. The outcome is lesion volume at 7 d after taking fingolimod orally minus lesion volume at baseline.

³The outcome is mBI score at 90 days after fingolimod taken orally minus mBI score at baseline.

CD8⁺ T cell: T-lymphocytes with cluster of differentiation 8 expression. Lesion volume: Infarction or hematoma volume; mBI score: Modified Barthel index score.

Table 5 Complications and adverse events in the fingolimod and control groups

Ref.	Size of fingolimod group	Events of fingolimod group	Size of control group	Events of control group	Risk ratio (95%CI)
Fever
Fu et al[15]	11	3	11	3	1 (0.16, 6.08)
Fu et al[16]	11	3	12	5	0.64 (0.12, 3.34)
Zhu et al[17]	22	5	25	5	1.15 (0.29, 4.51)
Suspected lung infection
Fu et al[15]	11	3	11	3	1 (0.16, 6.08)
Fu et al[16]	11	3	12	5	0.64 (0.12, 3.34)
Zhu et al[17]	22	3	25	3	1.17 (0.21, 6.39)
Adverse events occurring at least once
Fu et al[15]	11	3	11	3	1 (0.16, 6.08)
Fu et al[16]	11	4	12	6	0.72 (0.12, 4.38)
Zhu et al[17]	22	6	25	8	0.84 (0.25, 2.81)
Tian et al[18]	23	3	23	4	0.76 (0.15, 3.81)
Other serious events
Hemorrhage of digestive tract
Zhu et al[17]	22	1	25	3	0.42 (0.04, 4.30)
Cerebral hernia
Tian et al[18]	23	2	23	6	0.35 (0.06, 1.90)
Bradycardia
Fu et al[16]	11	1	12	0	N/A
Atrial flutter
Tian et al[18]	23	2	23	0	N/A
Thrombocytopenia
Tian et al[18]	23	2	23	0	N/A

Table 6 Overall standard mean difference or pooled risk ratio via random-effects model and pooled risk ratio of remaining studies after the study with the highest quality is omitted

Method	Overall SMD or RR (95%CI)	Test of heterogeneity
		I2 (%)	P
Random-effects model
CD8+ T cells	-3.59 (-4.37, -2.80)	0.0	0.737
Lesion volume	-0.17 (-0.75, 0.42)	0.0	0.917
mBI score	2.43 (1.59, 3.26)	10.6	0.290
RR of fever	0.93 (0.37, 2.32)	0.0	0.864
RR of suspected lung infection	0.90 (0.33, 2.43)	0.0	0.876
RR of adverse events occurring at least once	0.82 (0.36, 1.87)	0.0	0.995
Article deleted
Zhu et al[17] (RR of fever)	0.78 (0.23, 2.68)	0.0	0.723
Zhu et al[17] (RR of suspected lung infection)	0.78 (0.23, 2.68)	0.0	0.723
Tian et al[18] (RR of adverse events occurring at least once)	0.84 (0.33, 2.18)	0.0	0.969

SMD: Standard mean difference; RR: Risk ratio; CD8⁺ T cell: T-lymphocytes with cluster of differentiation 8 expression; Lesion volume: Infarction or hematoma volume; mBI score: Modified Barthel index score.