Tranexamic acid for upper gastrointestinal bleeding

Cathy Bennett; Sarah Louise Klingenberg; Ebbe Langholz; Lise Lotte Gluud

doi:10.1002/14651858.CD006640.pub3

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Figure 1

Study flow diagram.

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Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Figure 3

Trial sequential analysis of eight trials on tranexamic acid versus placebo or no intervention. Outcome measure is mortality. Analysis was performed with alpha 5% and power 80%. Model‐based heterogeneity correction was 0%, relative risk reduction 30% and control group incidence 10%. Graph shows the Z‐curve, which is the cumulative result of analysis with trials added according to year of publication. Horizontal line represents 'traditional' 5% level of significance, and inward sloping red line shows trial sequential monitoring boundary. Vertical line represents required information size. Analysis shows that the Z‐curve crosses the trial sequential monitoring boundary, suggesting that the result of the meta‐analysis is confirmed when analysis is adjusted for cumulative testing. Total number of included participants (N = 1701) is only 62% of required information size (N=2714). The meta‐analysis therefore remains inconclusive.

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Figure 4

Trial sequential analysis of seven trials on tranexamic acid versus placebo or no intervention. Outcome measure is bleeding. Analysis was performed with alpha 5% and power 80%. Model‐based heterogeneity correction was 53%, relative risk reduction 30% and control group incidence 10%. Graph shows the Z‐curve, which is the cumulative result of analysis with trials added according to year of publication. Horizontal line represents 'traditional' 5% level of significance, and inward sloping red line shows trial sequential monitoring boundary. Vertical line represents required information size. Analysis shows that the Z‐curve does not cross the trial sequential monitoring boundary, and the total number of participants (N = 1651) is 95% of required information size (N = 1734). The meta‐analysis therefore remains inconclusive.

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Analysis 1.1

Comparison 1 Tranexamic acid vs placebo, Outcome 1 Mortality.

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Analysis 1.2

Comparison 1 Tranexamic acid vs placebo, Outcome 2 Mortality scenario analysis, treatment failure if participant missing.

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Analysis 1.3

Comparison 1 Tranexamic acid vs placebo, Outcome 3 Mortality in trials with low risk of bias.

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Analysis 1.4

Comparison 1 Tranexamic acid vs placebo, Outcome 4 Mortality in relation to endoscopic therapy.

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Analysis 1.5

Comparison 1 Tranexamic acid vs placebo, Outcome 5 Mortality in relation to language of publication.

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Analysis 1.6

Comparison 1 Tranexamic acid vs placebo, Outcome 6 Rebleeding.

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Analysis 1.7

Comparison 1 Tranexamic acid vs placebo, Outcome 7 Rebleeding scenario analysis, treatment failure if participant missing.

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Analysis 1.8

Comparison 1 Tranexamic acid vs placebo, Outcome 8 Rebleeding in trials with low risk of bias.

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Analysis 1.9

Comparison 1 Tranexamic acid vs placebo, Outcome 9 Rebleeding in relation to endoscopic therapy.

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Analysis 1.10

Comparison 1 Tranexamic acid vs placebo, Outcome 10 Rebleeding in relation to language of publication.

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Analysis 1.11

Comparison 1 Tranexamic acid vs placebo, Outcome 11 Myocardial infarction, pulmonary embolism and cerebral infarction.

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Analysis 1.12

Comparison 1 Tranexamic acid vs placebo, Outcome 12 Deep venous thrombosis.

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Analysis 1.13

Comparison 1 Tranexamic acid vs placebo, Outcome 13 Any thromboembolic event.

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Analysis 1.14

Comparison 1 Tranexamic acid vs placebo, Outcome 14 Surgery.

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Analysis 1.15

Comparison 1 Tranexamic acid vs placebo, Outcome 15 Transfusion required.

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Analysis 2.1

Comparison 2 Tranexamic acid vs cimetidine or lansoprazole, Outcome 1 Mortality.

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Analysis 2.2

Comparison 2 Tranexamic acid vs cimetidine or lansoprazole, Outcome 2 Bleeding.

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Analysis 2.3

Comparison 2 Tranexamic acid vs cimetidine or lansoprazole, Outcome 3 Surgery.

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Analysis 2.4

Comparison 2 Tranexamic acid vs cimetidine or lansoprazole, Outcome 4 Transfusion.

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Summary of findings for the main comparison. Tranexamic acid vs placebo for upper gastrointestinal bleeding

Tranexamic acid vs placebo for upper gastrointestinal bleeding
Patient or population: patients with upper gastrointestinal bleeding Settings: Intervention: tranexamic acid vs placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	Number of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	Tranexamic acid vs placebo
Mortality Clinical Follow‐up: median 5 days	Study population		RR 0.6 (0.42‐0.87)	1701 (8 studies)	⊕⊕⊕⊝ moderate^a,b
	84 per 1000	50 per 1000 (34‐72)
	Moderate
	83 per 1000	50 per 1000 (34‐71)
Rebleeding Clinical and endoscopic assessment Follow‐up: median 5 days	Study population		RR 0.72 (0.50‐1.03)	1651 (7 studies)	⊕⊕⊝⊝ low^a,b,c
	177 per 1000	142 per 1000 (113‐177)
	Moderate
	196 per 1000	157 per 1000 (125‐196)
Any thromboembolic event Clinical and radiological assessment Follow‐up: median 5 days	Study population		RR 1.86 (0.66‐5.24)	1095 (4 studies)	⊕⊕⊕⊝ moderate^a,b
	11 per 1000	20 per 1000 (7‐57)
	Moderate
	10 per 1000	19 per 1000 (7‐52)
Surgery Number of participants who underwent surgery Follow‐up: median 5 days	Study population		RR 0.61 (0.35‐1.04)	1551 (7 studies)	⊕⊕⊕⊝ moderate^a
	142 per 1000	103 per 1000 (79‐135)
	Moderate
	154 per 1000	112 per 1000 (86‐146)
Transfusion Number needing blood transfusion Follow‐up: median 3 weeks	Study population		RR 1.02 (0.94‐1.1)	931 (5 studies)	⊕⊝⊝⊝ very low^a,d
	564 per 1000	558 per 1000 (507‐620)
	Moderate
	583 per 1000	577 per 1000 (525‐641)
The basis for the assumed risk* (e.g. median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio.
GRADE Working Group grades of evidence. High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
^aMost trials had high risk of attrition bias. ^bNot possible to evaluate because number of trials was limited. ^cStatistical between‐trial heterogeneity approached 50%. ^dThe number of participants who needed transfusion is an indirect measure of bleeding and varies among clinical sites.

Summary of findings for the main comparison. Tranexamic acid vs placebo for upper gastrointestinal bleeding

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Summary of findings 2. Tranexamic acid vs cimetidine or lansoprazole for upper gastrointestinal bleeding

Tranexamic acid vs cimetidine or lansoprazole for upper gastrointestinal bleeding
Patient or population: patients with upper gastrointestinal bleeding Settings: Intervention: tranexamic acid vs cimetidine or lansoprazole
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	Number of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	Tranexamic acid vs cimetidine or lansoprazole
Mortality Number of participants who died Follow‐up: median 5 days	Study population		RR 0.91 (0.50‐1.64)	720 (2 studies)	⊕⊕⊕⊝ moderate
	61 per 1000	56 per 1000 (31‐101)
	Moderate
	48 per 1000	44 per 1000 (24‐79)
Rebleeding Clinical and endoscopic assessment Follow‐up: median 5 days	Study population		RR 0.87 (0.64‐1.2)	720 (2 studies)	⊕⊕⊕⊝ moderate^a,b
	188 per 1000	166 per 1000 (121‐226)
	Moderate
	161 per 1000	142 per 1000 (103‐193)
Surgery Number of participants who underwent surgery Follow‐up: median 5 days	Study population		RR 0.83 (0.54‐1.26)	720 (2 studies)	⊕⊕⊕⊝ moderate^a,b
	139 per 1000	115 per 1000 (79‐168)
	Moderate
	105 per 1000	87 per 1000 (60‐127)
Transfusion Number of participants who required at least 1 blood transfusion Follow‐up: median 5 days	Study population		RR 0.97 (0.78‐1.22)	720 (2 studies)	⊕⊕⊝⊝ low^a,b,c
	573 per 1000	579 per 1000 (510‐654)
	Moderate
	599 per 1000	605 per 1000 (533‐683)
The basis for the assumed risk* (e.g. median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio.
GRADE Working Group grades of evidence. High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
^aHigh risk of bias based on assessment of attrition. ^bNot possible to evaluate because number of trials was limited. ^cThis outcome measure is a surrogate estimate for bleeding.

Summary of findings 2. Tranexamic acid vs cimetidine or lansoprazole for upper gastrointestinal bleeding

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Table 1. Adverse events

Trial	Serious adverse events			Non‐serious adverse events	Non‐serious adverse events
Trial	Tranexamic acid	Control group	Intervention group not specified	Tranexamic acid	Control group
Barer 1983	Fatal stroke (n = 1)	Confusion (n = 1)	Pulmonary embolism (n = 5). Myocardial infarction (n = 8)	None described	Confusion (n = 1)
Biggs 1976	None described	None described	None described	Thrombophlebitis at injection site (n = 3). Nausea or headache (n = 4)	Thrombophlebitis at injection site (n = 2). Nausea or headache (n = 5). Fever (n = 2)
Engquist 1979	Pulmonary embolism (n = 2). Myocardial infarction (n = 2)	Cerebral infarction (n = 2)	None described	None described	None described
Hawkey 2001	None described	None described	Several participants experienced thromboembolic complications. The numbers were described as not significantly different in treatment and control groups, but no specific data are provided	None described	None described
Holstein 1987	None described	Cerebral infarction (n = 2)	Five additional participants were excluded as the result of thromboembolic disease, but whether these participants were randomly assigned to tranexamic acid or placebo is not reported	Nausea and vomiting, tachycardia (n = 3). Hypotension (n = 3). Thrombophlebitis at injection site (n = 2). Deep venous thrombosis (n = 1)	None described

Table 1. Adverse events

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Comparison 1. Tranexamic acid vs placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality Show forest plot	8	1701	Risk Ratio (M‐H, Random, 95% CI)	0.60 [0.42, 0.87]

2 Mortality scenario analysis, treatment failure if participant missing Show forest plot	8	1701	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.43, 1.81]

3 Mortality in trials with low risk of bias Show forest plot	8		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

3.1 Allocation sequence generation	1	516	Risk Ratio (M‐H, Random, 95% CI)	0.46 [0.26, 0.82]
3.2 Allocation concealment	7	1654	Risk Ratio (M‐H, Random, 95% CI)	0.61 [0.42, 0.89]
3.3 Blinding	7	1654	Risk Ratio (M‐H, Random, 95% CI)	0.61 [0.42, 0.89]
3.4 Incomplete outcome data	1	206	Risk Ratio (M‐H, Random, 95% CI)	0.8 [0.22, 2.89]
3.5 Selective reporting	7	1651	Risk Ratio (M‐H, Random, 95% CI)	0.60 [0.41, 0.89]
4 Mortality in relation to endoscopic therapy Show forest plot	8	1701	Risk Ratio (M‐H, Random, 95% CI)	0.60 [0.42, 0.87]

4.1 Endoscopic therapy not used	6	1448	Risk Ratio (M‐H, Random, 95% CI)	0.60 [0.40, 0.88]
4.2 Endoscopic therapy used to control bleeding	2	253	Risk Ratio (M‐H, Random, 95% CI)	0.66 [0.22, 2.00]
5 Mortality in relation to language of publication Show forest plot	8	1701	Risk Ratio (M‐H, Random, 95% CI)	0.60 [0.42, 0.87]

5.1 Trials published in English	7	1654	Risk Ratio (M‐H, Random, 95% CI)	0.61 [0.42, 0.89]
5.2 Trials translated from Russian	1	47	Risk Ratio (M‐H, Random, 95% CI)	0.38 [0.04, 3.38]
6 Rebleeding Show forest plot	7	1651	Risk Ratio (M‐H, Random, 95% CI)	0.72 [0.50, 1.03]

7 Rebleeding scenario analysis, treatment failure if participant missing Show forest plot	7	1651	Risk Ratio (M‐H, Random, 95% CI)	0.80 [0.51, 1.27]

8 Rebleeding in trials with low risk of bias Show forest plot	7	5581	Risk Ratio (M‐H, Random, 95% CI)	0.78 [0.65, 0.93]

8.1 Allocation sequence generation	1	516	Risk Ratio (M‐H, Random, 95% CI)	1.16 [0.83, 1.61]
8.2 Allocation concealment	6	1604	Risk Ratio (M‐H, Random, 95% CI)	0.73 [0.50, 1.07]
8.3 Blinding	6	1604	Risk Ratio (M‐H, Random, 95% CI)	0.73 [0.50, 1.07]
8.4 Incomplete outcome data	1	206	Risk Ratio (M‐H, Random, 95% CI)	0.9 [0.38, 2.12]
8.5 Selective reporting	7	1651	Risk Ratio (M‐H, Random, 95% CI)	0.72 [0.50, 1.03]
9 Rebleeding in relation to endoscopic therapy Show forest plot	7	1651	Risk Ratio (M‐H, Random, 95% CI)	0.72 [0.50, 1.03]

9.1 Endoscopic therapy not used	5	1398	Risk Ratio (M‐H, Random, 95% CI)	0.70 [0.45, 1.08]
9.2 Endoscopic therapy used to control bleeding	2	253	Risk Ratio (M‐H, Random, 95% CI)	0.77 [0.36, 1.62]
10 Rebleeding in relation to language of publication Show forest plot	7	1651	Risk Ratio (M‐H, Random, 95% CI)	0.72 [0.50, 1.03]

10.1 Trials published in English	6	1604	Risk Ratio (M‐H, Random, 95% CI)	0.73 [0.50, 1.07]
10.2 Trials translated from Russian	1	47	Risk Ratio (M‐H, Random, 95% CI)	0.45 [0.10, 2.11]
11 Myocardial infarction, pulmonary embolism and cerebral infarction Show forest plot	3	1048	Risk Ratio (M‐H, Random, 95% CI)	1.37 [0.36, 5.28]

12 Deep venous thrombosis Show forest plot	3	1048	Risk Ratio (M‐H, Random, 95% CI)	2.32 [0.60, 8.89]

13 Any thromboembolic event Show forest plot	4	1095	Risk Ratio (M‐H, Random, 95% CI)	1.86 [0.66, 5.24]

14 Surgery Show forest plot	7	1551	Risk Ratio (M‐H, Random, 95% CI)	0.61 [0.35, 1.04]

15 Transfusion required Show forest plot	5	931	Risk Ratio (M‐H, Random, 95% CI)	1.02 [0.94, 1.11]

Comparison 1. Tranexamic acid vs placebo

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Comparison 2. Tranexamic acid vs cimetidine or lansoprazole

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality Show forest plot	2	720	Risk Ratio (M‐H, Random, 95% CI)	0.91 [0.50, 1.64]

2 Bleeding Show forest plot	2	720	Risk Ratio (M‐H, Random, 95% CI)	0.87 [0.64, 1.20]

3 Surgery Show forest plot	2	720	Risk Ratio (M‐H, Random, 95% CI)	0.83 [0.54, 1.26]

4 Transfusion Show forest plot	2	720	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.78, 1.22]

Comparison 2. Tranexamic acid vs cimetidine or lansoprazole

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