Systemic thrombolytic therapy for acute pulmonary embolism: A systematic review and meta-analysis: Supplementary Appendix
List of contents :
-
1. Detailed Pubmed Search strategy
-
Table 1 : Study quality assesment
-
Table 2 : Major Bleeding and Fatal or intracranial haemorrhage, by type of diagnostic procedure
-
Table 3 : Efficacy and safety endpoints, by age limit
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Table 4: Efficacy and safety endpoints, by duration of symptoms
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Table 5: Efficacy and safety endpoints, by length of follow-up
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Table 6: Meta-regression for the association between intervention's effect and publication year
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Figure 1 : PE-related mortality (Forest plot)
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Figure 2 : Death or treatment escalation (Forest plot)
-
Figure 3 : PE recurrence (Forest plot)
-
Figure 4 : Fatal or intracranial haemorrhage (Forest plot)
-
Figure 5: Overall mortality, cumulative meta-analysis
Appendix 1 : Detailed Pubmed search strategy: ("pulmonary embolism"[MeSH Terms] OR ("pulmonary"[All Fields] AND "embolism"[All Fields]) OR
"pulmonary embolism"[All Fields]) AND (thrombolysis[All Fields] OR ("thrombolytic therapy"[MeSH Terms] OR ("thrombolytic"[All Fields] AND "therapy"[All
Fields]) OR "thrombolytic therapy"[All Fields]) OR ("streptokinase"[MeSH Terms] OR "streptokinase"[All Fields]) OR ("urokinase-type plasminogen
activator"[MeSH Terms] OR ("urokinase-type"[All Fields] AND "plasminogen"[All Fields] AND "activator"[All Fields]) OR "urokinase-type plasminogen
activator"[All Fields] OR "urokinase"[All Fields]) OR ("tenecteplase"[Supplementary Concept] OR "tenecteplase"[All Fields]) OR ("salivary plasminogen
activator alpha 1, Desmodus rotundus"[Supplementary Concept] OR "salivary plasminogen activator alpha 1, Desmodus rotundus"[All Fields] OR
"desmoteplase"[All Fields]) OR ("tissue plasminogen activator"[MeSH Terms] OR ("tissue"[All Fields] AND "plasminogen"[All Fields] AND "activator"[All
Fields]) OR "tissue plasminogen activator"[All Fields]) OR ("reteplase"[Supplementary Concept] OR "reteplase"
Appendix Table 1: Quality of included studies according to Jadad criteria21
1stAuthor
Year
Randomisation
Blinding
Attrition
Total
Becattini
2010
2
2
1
5
Dalla Volta
1992
1
1
1
3
Dotter
1979
1
0
1
2
Fasullo
2011
2
2
1
5
Goldhaber
1993
2
1
1
4
Jerjes-Sanchez
1995
1
0
1
2
Kline
2013
2
2
1
5
Konstantinides
2002
2
2
1
5
Levine
1990
1
2
1
4
Ly
1978
2
1
1
4
Marini
1988
1
0
1
2
Meyer (PEITHO)
2014
2
2
1
5
Sharifi
2013
2
1
1
4
Stein (PIOPED)
1990
1
2
1
4
UPET
1970
2
2
1
5
(MAPPET)
Appendix Table 2: Major Bleeding and Fatal or intracranial haemorrhage, by type of diagnostic procedure
All studies
No invasive procedure
Invasive procedure (>60%)
Group difference
I2 (%)
OR (95% CI)
OR (95% CI)
p-value
2.91 (1.95 to 4.36) <0.001
25
4.00 (2.51 to 6.39)
2.00 (1.04 to 3.83)
0.14
3.18 (1.25 to 8.11)
0
7.32 (1.64 to 32.63)
2.92 (0.31 to 27.87)
0.51
pOR (95% CI)
Major bleeding
value
Fatal or intracranial
haemorrhage
0.02
Appendix Table 3: Efficacy and safety endpoints, by age limit
All studies
No age limitation
Age limitation
Group difference
OR (95% CI)
p-value
I2 (%)
OR (95% CI)
OR (95% CI)
p-value
Mortality
0.59 (0.36 to 0.96)
0.034
0
0.58 (0.32 to 1.06)
0.59 (0.24 to 1.44)
0.99
PE Recurrence
0.50 (0.27 to 0.94)
0.031
0
0.40 (0.18 to 0.91)
0.71 (0.26 to 1.95)
0.39
PE Mortality
0.29 (0.14 to 0.60)
0.0009
0
0.29 (0.11 to 0.74)
0.28 (0.09 to 0.93)
0.98
Death or Escalation
0.34 (0.22 to 0.52) <0.0001
0
0.36 (0.20 to 0.65)
0.31 (0.17 to 0.58)
0.72
Major bleeding
2.91 (1.95 to 4.36)
<0.001
25
3.71 (2.32 to 5.92)
1.13 (0.47 to 2.71)
0.02
3.18 (1.25 to 8.11)
0.02
0
4.11 (1.25 to 13.50)
1.82 (0.37 to 8.93)
0.42
Fatal or intracranial
haemorrhage
Appendix Table 4: Efficacy and safety endpoints, by duration of symptoms
All studies
Symptoms ≤ 7 days
Symptoms> 7 days
Group difference
OR (95% CI)
p-value
I2 (%)
OR (95% CI)
OR (95% CI)
p-value
Mortality
0.59 (0.36 to 0.96)
0.034
0
0.66 (0.32 to 1.38)
0.51 (0.25 to 1.05)
0.62
PE Recurrence
0.50 (0.27 to 0.94)
0.031
0
0.85 (0.37 to 1.97)
0.24 (0.08 to 0.74)
0.08
PE Mortality
0.29 (0.14 to 0.60)
0.0009
0
0.29 (0.08 to 1.03)
0.26 (0.09 to 0.71)
0.89
Death or Escalation
0.34 (0.22 to 0.52) <0.0001
0
0.32 (0.17 to 0.60)
0.35 (0.19 to 0.64)
0.84
Major bleeding
2.91 (1.95 to 4.36)
<0.001
25
1.66 (0.89 to 3.10)
4.19 (2.43 to 7.25)
0.03
3.18 (1.25 to 8.11)
0.02
0
0.74 (0.09 to 6.32))
4.61 (1.41 to 15.01)
0.14
Fatal or intracranial
haemorrhage
Appendix Table 5: Efficacy and safety endpoints, by length of follow-up
All studies
Follow-up 5-14 days
Follow-up 30 days
Group difference
OR (95% CI)
p-value
I2 (%)
OR (95% CI)
OR (95% CI)
p-value
Mortality
0.59 (0.36 to 0.96)
0.034
0
0.55 (0.31 to 0.98)
0.70 (0.26 to 1.90)
0.69
PE Recurrence
0.50 (0.27 to 0.94)
0.031
0
0.36 (0.16 to 0.79)
1.09 (0.34 to 3.44)
0.12
PE Mortality
0.29 (0.14 to 0.60)
0.0009
0
0.27 (0.11 to 0.64)
0.35 (0.09 to 1.32)
0.75
Death or Escalation
0.34 (0.22 to 0.52) <0.0001
0
0.35 (0.20 to 0.61)
0.32 (0.17 to 0.62)
0.87
Major bleeding
2.91 (1.95 to 4.36)
<0.001
25
3.60 (2.30 to 5.64)
0.73 (0.24 to 2.22)
0.009
3.18 (1.25 to 8.11)
0.02
0
4.11 (1.25 to 153.50)
1.82 (0.37 to 8.93)
0.42
Fatal or intracranial
haemorrhage
Appendix Table 6: Meta-regression for the association between intervention's effect and
publication year
Outcome
Regression slope (se)
p-value
Mortality
-0.012 (0.031)
0.70
PE Recurrence
-0.027 (0.020)
0.20
PE mortality
-0.006 (0.016)
0.71
Death or Escalation
0.015 (0.024)
0.52
Major Hemorrage
0.014 (0.019)
0.46
Fatal/intracranial
0.057 (0.042)
0.18
Se: Standard error
Appendix Figure 1: PE related Mortality.
Appendix Figure 2: Death or treatment escalation.
Appendix Figure 3: PE Recurrence
Appendix Figure 4: Fatal or intracranial haemorrhage.
Study
1 - Others thrombolytics
Dotter 1979
Marini 1988
Levine 1990
Stein 1990
Dalla -Volta 1992
Goldhaber 1993
Konstantinides 2002
Fasullo 2011
Sharifi 2013
Fixed effect model
M-H. Odds Ratio
Thrombolysis
Control
Events Total Events Total
0
0
0
1
2
0
0
0
0
3
15
20
33
9
20
46
118
37
61
359
0
0
0
0
0
1
1
0
0
2
16
10
25
4
16
55
138
35
60
359
1
1
11
13
28
40
506
574
0
0
1
1
30
43
499
572
16
933
3
931
OR
[95% CI]
Weights
1.59
4.46
0.39
0.39
[0.05; 47.52]
[0.20; 99.79]
[0.02; 9.82]
[0.02; 9.58]
1.09
[0.27; 4.40]
0.0%
0.0%
0.0%
10.0%
8.6%
23.8%
24.2%
0.0%
0.0%
66.5%
3.33 [0.13; 85.11]
3.30 [0.13; 83.47]
11.07 [1.42; 86.04]
7.32 [1.64; 32.63]
8.0%
8.2%
17.3%
33.5%
Heterogeneity: I-squared=0%
2 - Tenecteplase
Becattini 2010
Kline 2013
Meyer 2014
Fixed effect model
Heterogeneity: I-squared=0%
Fixed effect model
3.18
Heterogeneity: I-squared=0%
0.01
0.1
0.5 1 2
Favours Thrombolysis
10
65
Favours Control
[1.24; 8.11]
100%
Appendix Figure 5: Overall mortality, cumulative meta-analysis
Odds Ratio
Study
OR
95% -CI
Adding UPET 1970 (k=1)
Adding Ly 1978 (k=2)
Adding Dotter 1979 (k=3)
Adding Marini 1988 (k=4)
Adding Levine 1990 (k=5)
Adding Stein 1990 (k=6)
Adding Dalla -Volta 1992 (k=7)
Adding Goldhaber 1993 (k=8)
Adding Jerjes-Sanchez 1995 (k=9)
Adding Konstantinides 2002 (k=10)
Adding Becattini 2010 (k=11)
Adding Fasullo 2011 (k=12)
Adding Kline 2013 (k=13)
Adding Sharifi 2013 (k=14)
Adding Meyer 2014 (k=15)
0.80
0.69
0.66
0.66
0.74
0.78
0.85
0.76
0.60
0.72
0.70
0.58
0.59
0.57
0.59
[0.26; 2.50]
[0.25; 1.94]
[0.25; 1.71]
[0.25; 1.71]
[0.30; 1.82]
[0.33; 1.86]
[0.38; 1.92]
[0.35; 1.64]
[0.29; 1.23]
[0.38; 1.37]
[0.37; 1.31]
[0.32; 1.05]
[0.33; 1.06]
[0.32; 1.00]
[0.36; 0.96]
Fixed effect model
0.59 [0.36; 0.96]
0.5
1
2