Study characteristics
We identified 1019 potentially relevant studies, with 994 excluded after screening for title and abstract. The remaining 25 studies were full-text retrieved for detailed evaluation. Based on the search criteria, a total of 18 studies reporting the efficacy and safety of thrombolysis for acute IS with AF were included in this study (Figure 1). Baseline characteristics of patients included in these studies were shown in Table 1 and Table 2. Eleven studies [6,8,10,12-14,16-19,24] compared IVT-treated AF to non-AF patients, two studies [20-21] compared IVT-treated to non-IVT in AF patients, and five studies [5,7,9,11,15] included two kinds of comparative data mentioned above.
Table 1 Characteristics of studies comparing AF IVT with non-AF IVT
Study
|
Study design
|
Comparison
|
No. of patients
|
Mean age, y
|
Men (%)
|
Treatment
|
Hypertension (%)
|
Diabetes mellitus (%)
|
Dyslipidemia (%)
|
Baseline
NIHSS
|
Onset to needle (min)
|
Mortality, %
|
SICH, %
|
Bluhmki 20095
|
RCT
|
AF/non-AF
|
53/365
|
NR
|
NR
|
rtPA
3-4.5h
|
NR
|
NR
|
NR
|
NR
|
NR
|
22.6/5.5,
90d
|
17.0/6.6
|
Kimura
20096
|
prospective
|
AF/non-AF
|
44/41
|
77.2/69.4
|
61.4/70.7
|
rtPA
<3h
|
63.6/51.2
|
18.2/22.0
|
13.6/31.7
|
17.3/12.3
|
148.3/147.6
|
18.2/7.3,
90d
|
NR
|
Awadh
201024
|
retrospective
|
AF/non-AF
|
74/154
|
76/66.4
|
40/59
|
rtPA
<4.5h
|
70/64
|
16.2/7.8
|
19/22
|
14/ 14.5
|
162.7/173.3
|
NR
|
4.0/4.5
|
Sanak
201016
|
retrospective
|
AF/non-AF
|
66/91
|
68.1/66.5
|
57.6/65.9
|
rtPA
<3h
|
NR
|
NR
|
NR
|
13.0/10.0
|
146.3/145.5
|
18.2/3.3,
7d
|
4.5/0
|
Zhang
20107
|
prospective
|
AF/non-AF
|
22/31
|
68.3/60.7
|
40.9/74.2
|
rtPA
<4.5h
|
72.7/38.5
|
13.6/6.5
|
NR
|
12.0/9.1
|
203.7/196.7
|
18.2/9.7,
90d
|
18.2/6.5
|
Seet
20118
|
retrospective
|
AF/non-AF
|
76/138
|
78.9 /71.5
|
42.1/53.6
|
rtPA
<3h
|
78.9/75.4
|
10.5/14.5
|
50.0/51.4
|
13 /12
|
138.3/143.5
|
22.4/15.2,
90d
|
13.2/5.1
|
Frank
20129
|
retrospective
|
AF/non-AF
|
639/2388
|
74.2 /65.7
|
47.3/58.2
|
rtPA
<3h
|
71.1/61.6
|
NR
|
NR
|
15 /13
|
NR
|
21.8/13.6,
90d
|
2.7/1.7
|
Padjen
201310
|
prospective
|
AF/non-AF
|
155/579
|
76 /64
|
41.9/55.6
|
rtPA
|
80.0/62.3
|
20.0/15.7
|
45.2/45.9
|
14/10
|
148/153
|
21.9/9.0,
90d
|
5.8/5.5
|
Saposnik
201311
|
prospective
|
AF/non-AF
|
316/1373
|
NR
|
NR
|
rtPA
|
NR
|
NR
|
NR
|
NR
|
NR
|
26.3/14.2, 30d
|
9.2/6.4
|
Sung
201314
|
retrospective
|
AF/non-AF
|
72/71
|
68.3/64.6
|
58.3/64.8
|
rtPA
<3h
|
79.2/77.5
|
27.8/39.4
|
51.4/64.8
|
17.7/14.4
|
113/119
|
6.9/12.7, 90d
|
8.3/9.8
|
Al-Khaled 201417
|
prospective
|
AF/non-AF
|
387/620
|
NR
|
NR
|
rtPA
<4.5h
|
NR
|
NR
|
NR
|
NR
|
up to 4.5 hours
|
10.8/6.6, in-hospital
|
7.5/4.7
|
Saarinen
201418
|
retrospective
|
AF/non-AF
|
92/179
|
77 /69
|
46/55
|
NR
<3h
|
74/63
|
32/17
|
NR
|
NR
|
NR
|
20/6,
90d
|
NR
|
Tu
201519
|
prospective
|
AF/non-AF
|
28/111
|
76.5/73
|
61/52
|
rtPA
3-6h
|
64/64
|
21/26
|
29/32
|
16/11
|
NR
|
36/16,
90d
|
7.1/4.5
|
Zhao
201712
|
retrospective
|
AF/non-AF
|
30/93
|
69.8/63.5
|
46.7/67.7
|
rtPA
<4.5h
|
73.3/65.6
|
30.0/18.3
|
30.0/39.8
|
12/8
|
227/174
|
13.3/2.2
|
13.3/5.4
|
Mehrpour 201913
|
prospective
|
AF/non-AF
|
24/94
|
NR
|
NR
|
rtPA
<4.5h
|
NR
|
NR
|
NR
|
NR
|
NR
|
NR
|
NR
|
Yang
201915
|
retrospective
|
AF/non-AF
|
47/56
|
71.2 /60.4
|
34.0/80.4
|
rtPA
3-9h
|
74.5/64.3
|
19.1/23.2
|
NR
|
11.5 /9.3
|
322.9/370.4
|
10.6/7.1,
90d
|
2.1/3.6
|
Table2 Characteristics of studies comparing IVT with non-IVT in AF pattents
Study
|
Study design
|
Comparison
|
No. of patients
|
age, y
|
Men (%)
|
Treatment
|
Hypertension (%)
|
Diabetes mellitus (%)
|
Dyslipidemia (%)
|
Baseline
NIHSS
|
Onset to needle (min)
|
Mortality, %
|
SICH, %
|
Bluhmki
20095
|
RCT
|
IVT/Non-IVT
|
53/55
|
NR
|
NR
|
rtPA
3-4.5h
|
NR
|
NR
|
NR
|
NR
|
NR
|
22.6/14.5,
90d
|
17.0/6.6
|
Zhang
20107
|
prospective
|
IVT/Non-IVT
|
22/44
|
68.3/70.4
|
40.9/43.2
|
rtPA
<4.5h
|
72.7/63.6
|
13.6/20.5
|
NR
|
12.0/12.6
|
203.7/NR
|
18.2/20.5,
90d
|
18.2/6.8
|
Frank
20129
|
retrospective
|
IVT/Non-IVT
|
639/992
|
74.2/73.9
|
47.3/47.6
|
rtPA
<3h
|
71.1/75.5
|
NR
|
NR
|
15 /14
|
NR
|
21.8/23.2,
90d
|
2.7/0.9
|
Saposnik
201311
|
prospective
|
IVT/Non-IVT
|
316/1373
|
NR
|
NR
|
rtPA
|
NR
|
NR
|
NR
|
NR
|
NR
|
26.3/18.1, 30d
|
NR
|
Padjen 201420
|
prospective
|
IVT/Non-IVT
|
34/97
|
68/72
|
58.8/51.5
|
rtPA
<4.5h
|
94.1/87.6
|
20.6/24.7
|
29.4/38.8
|
11/14
|
NR
|
14.7/45.4,90d
|
5.9/4.1
|
Zhao
201621
|
retrospective
|
IVT/Non-IVT
|
151/116
|
71.3/73.5
|
43.7/43.1
|
rtPA
<4.5h
|
73.5/67.2
|
15.9/19.0
|
17.2/12.1
|
15.1/13.9
|
165.7/179.3
|
23.2/25.0,
90d
|
13.9/1.7
|
Yang
201915
|
retrospective
|
IVT/Non-IVT
|
47/31
|
71.2/74.7
|
34.0/58.1
|
rtPA
3-9h
|
74.5/93.4
|
19.1/32.2
|
NR
|
11.5 /13.7
|
322.9 /310.4
|
10.6/14.8,
90d
|
2.1/0
|
mRS 0-1 at 90 days after stroke
Compared with non-AF patients, the proportion of patients with mRS 0-1 was significantly lower in IVT-treated AF patients (24.1% vs. 34.5%; OR 0.57; 95% CI 0.50-0.65; I2=71.0%; P=0.000) (Figure 2A). In contrast, there was no significant difference in the proportion of AF patients with a mRS of 0-1 between IVT and non-IVT therapy (24.0% vs. 21.4%; OR 1.0; 95% CI 0.84-1.18; I2=87.1%; P=0.955) (Figure 2B).
mRS 0-2 at 90 days after stroke
Compared with non-AF patients, a significantly lower proportion of IVT treated AF patients with mRS 0-2 (33.6% vs. 47.8%; OR 0.50; 95 % CI 0.44-0.57; I2= 55.2 %; P=0.000) (Figure 3A). The proportion of IVT treated AF patients with mRS 0-2 was lower than which of without thrombolytic therapy, but the difference did not reach statistical significance (31.0% vs. 32.5%; OR 0.86; 95% CI 0.74-1.00; I2=90.5%; P=0.05) (Figure 3B).
Mortality
A significantly higher proportion of IVT treated AF patients with mortality compared to non-AF patients (19.4% vs. 11.5%; OR 2.05; 95% CI 1.79-2.36; I2 = 44.1%; P=0.000) (Figure 4A). Mortality was no difference in AF patients between IVT and non-IVT (22.4% vs. 20.7%; OR 1.07; 95% CI 0.90-1.26; I2=71.7%; P=0.446) (Figure 4B).
sICH
The proportion of patients with sICH was significantly higher in IVT treated AF patients than non-AF patients (6.4% vs. 4.1%; OR 1.60; 95 % CI 1.27-2.01; I2= 0.0%; P=0.000) (Figure 5A). A significantly higher of sICH proportion in IVT treated AF patients compared to non-IVT therapy (5.7% vs. 1.6%; OR 3.44; 95% CI 2.04-5.82; I2=0.0%; P=0.000) (Figure 5B).
Subgroup analysis
Subgroup analysis was performed according to study design (Table 3). In both prospective and retrospective AF IVT versus non-AF IVT studies, the functional outcomes of IVT patients with AF was worse than that of patients without AF (P<0.001), mortality (P<0.001) and sICH incidence (P<0.05) were also higher. On the other hand, in AF IVT and AF non-IVT prospective studies, the results suggested a poorer functional prognosis and higher mortality in AF patients treated thrombolytic therapy compared with non-thrombolysis (P<0.05), while in the retrospective studies, there were no statistically significant differences in these clinical outcomes. Both prospective and retrospective studies showed that risk of sICH was higher in AF IVT patients than AF non-IVT patients (P<0.05).
Table 3 Subgroup analyses of efficacy and safety of thrombolysis for acute IS with AF based on study design
Study design
|
mRS 0-1
|
Test of association
|
Heterogeneity
|
AF
|
Non-AF
|
OR (95 % CI)
|
p
|
I2 (%)
|
p
|
Retrospective(n=5)
|
242/864
|
974/2746
|
0.68(0.58-0.81)
|
<0.001
|
75.0
|
0.003
|
Prospective(n=5)
|
109/590
|
798/2389
|
0.41(0.32-0.52)
|
<0.001
|
0.0
|
0.47
|
|
IVT
|
Non-IVT
|
OR (95 % CI)
|
p
|
I2 (%)
|
p
|
Retrospective(n=3)
|
230/837
|
266/1139
|
1.20(0.98-1.48)
|
0.082
|
76.9
|
0.013
|
Prospective(n=4)
|
73/425
|
415/2048
|
0.71(0.53-0.95)
|
0.02
|
90.7
|
<0.001
|
|
mRS 0-2
|
Test of association
|
Heterogeneity
|
AF
|
Non-AF
|
OR (95 % CI)
|
p
|
I2 (%)
|
p
|
Retrospective(n=6)
|
349/930
|
1451/2837
|
0.55(0.47-0.64)
|
<0.001
|
67.0
|
0.01
|
Prospective(n=5)
|
152/561
|
920/2118
|
0.42(0.34-0.53)
|
<0.001
|
3.6
|
0.386
|
|
IVT
|
Non-IVT
|
OR (95 % CI)
|
p
|
I2 (%)
|
p
|
Retrospective(n=3)
|
293/837
|
372/1139
|
1.08(0.89-1.30)
|
0.45
|
52.2
|
0.123
|
Prospective(n=3)
|
82/372
|
646/1993
|
0.58(0.44-0.75)
|
<0.001
|
94.5
|
<0.001
|
|
Mortality
|
Test of association
|
Heterogeneity
|
AF
|
Non-AF
|
OR (95 % CI)
|
p
|
I2 (%)
|
p
|
Retrospective(n=7)
|
200/1022
|
375/3016
|
1.86(1.53-2.25)
|
<0.001
|
56.8
|
0.031
|
Prospective(n=7)
|
393/2027
|
707/6136
|
2.29(1.88-2.81)
|
<0.001
|
11.1
|
0.345
|
|
IVT
|
Non-IVT
|
OR (95 % CI)
|
p
|
I2 (%)
|
p
|
Retrospective(n=3)
|
179/837
|
263/1139
|
0.92(0.74-1.14)
|
0.427
|
0.0
|
0.982
|
Prospective(n=4)
|
104/425
|
396/2048
|
1.32(1.02-1.69)
|
0.031
|
80.1
|
0.002
|
|
sICH
|
Test of association
|
Heterogeneity
|
AF
|
Non-AF
|
OR (95 % CI)
|
p
|
I2 (%)
|
p
|
Retrospective(n=7)
|
44/1004
|
69/2991
|
1.62(1.09-2.40)
|
0.017
|
0
|
0.437
|
Prospective(n=6)
|
82/961
|
249/6070
|
1.59(1.20-2.10)
|
0.001
|
0
|
0.566
|
|
IVT
|
Non-IVT
|
OR (95 % CI)
|
p
|
I2 (%)
|
p
|
Retrospective(n=3)
|
39/837
|
11/1139
|
4.22(2.13-8.33)
|
<0.001
|
0.0
|
0.374
|
Prospective(n=3)
|
15/109
|
11/196
|
2.38(1.02-5.54)
|
0.044
|
0.0
|
0.812
|
Assessment of quality and publication bias
Most studies were of high quality, ranging from NOS 6 to 9 (Table 4). The mean NOS of all the included studies were 7. The funnel plot and Egger's test were performed to evaluate the publication bias of this meta-analysis. The Egger's test with the P=0.783, provided statistical evidence that there was no publication bias. Meanwhile, no signficant publication bias was detected by Begg's funnel plot (Figure 6).
Table 4 Quality assessments of the included studies with the NOS
Study
|
Selection
|
Comparability
|
Outcome
|
Total score
|
Mehrpour et al 201913
|
****
|
*
|
**
|
7
|
Yang et al 201915
|
****
|
*
|
***
|
8
|
Zhao et al 201712
|
***
|
**
|
**
|
7
|
Zhao et al 201621
|
****
|
**
|
**
|
8
|
Tu et al 201519
|
***
|
**
|
**
|
7
|
Al-khaled et al 201417
|
***
|
*
|
*
|
5
|
Saarinen et al 201418
|
***
|
**
|
***
|
8
|
Padjen et al 201420
|
***
|
**
|
**
|
7
|
Padjen et la 201310
|
****
|
*
|
***
|
8
|
Saposnik et al 201311
|
****
|
*
|
*
|
6
|
Sung et al 201314
|
***
|
**
|
**
|
7
|
Frank et al 20129
|
***
|
*
|
**
|
6
|
Seet et al 20118
|
***
|
**
|
**
|
7
|
Awadh et al 201025
|
****
|
*
|
**
|
7
|
Sanak et al 201016
|
****
|
**
|
*
|
7
|
Zhang et al 20107
|
***
|
**
|
**
|
7
|
Bluhmki et al 20095
|
****
|
**
|
***
|
9
|
Kimura et al 20096
|
***
|
*
|
**
|
6
|