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Study flow diagram.
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Figure 1

Study flow diagram.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
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Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

"Risk of bias summary: review authors' judgements about each risk of bias item for each included study.'+' = low risk of bias;'‐' = high risk of bias;'?' = unclear risk of bias.
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Figure 3

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

'+' = low risk of bias;

'‐' = high risk of bias;

'?' = unclear risk of bias.

Trial Sequential Analysis of 10 randomised clinical trials (474 participants) evaluating terlipressin versus other vasoactive drugs for people with hepatorenal syndrome on mortality. The analysis was made with power 90%, alpha 3%, a relative risk reduction (RRR) of 20%, a control group risk (CGR) of mortality of 52%, and a model variance ‐ based heterogeneity correction of 30%. The risk ratio was 0.96 (97% confidence interval 0.79 to 1.18). The cumulative Z‐curve (blue line) did not cross the diversity‐adjusted trial monitoring boundary for benefit.
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Figure 4

Trial Sequential Analysis of 10 randomised clinical trials (474 participants) evaluating terlipressin versus other vasoactive drugs for people with hepatorenal syndrome on mortality. The analysis was made with power 90%, alpha 3%, a relative risk reduction (RRR) of 20%, a control group risk (CGR) of mortality of 52%, and a model variance ‐ based heterogeneity correction of 30%. The risk ratio was 0.96 (97% confidence interval 0.79 to 1.18). The cumulative Z‐curve (blue line) did not cross the diversity‐adjusted trial monitoring boundary for benefit.

Trial Sequential Analysis of nine randomised clinical trials (394 participants) evaluating terlipressin versus other vasoactive drugs for people with hepatorenal syndrome on lack of reversal of hepatorenal syndrome. The analysis was made with power 90%, alpha 3%, a relative risk reduction (RRR) of 25%, a control group risk (CGR) of lack of reversal of hepatorenal syndrome of 63%, and a heterogeneity correction of 50%. The risk ratio was 0.79 (97% confidence interval 0.48 to 1.31). The cumulative Z‐curve (blue line) does not cross the diversity‐adjusted trial monitoring boundary for benefit.
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Figure 5

Trial Sequential Analysis of nine randomised clinical trials (394 participants) evaluating terlipressin versus other vasoactive drugs for people with hepatorenal syndrome on lack of reversal of hepatorenal syndrome. The analysis was made with power 90%, alpha 3%, a relative risk reduction (RRR) of 25%, a control group risk (CGR) of lack of reversal of hepatorenal syndrome of 63%, and a heterogeneity correction of 50%. The risk ratio was 0.79 (97% confidence interval 0.48 to 1.31). The cumulative Z‐curve (blue line) does not cross the diversity‐adjusted trial monitoring boundary for benefit.

Trial Sequential Analysis of two randomised clinical trials (88 participants) evaluating terlipressin versus other vasoactive drugs for people with hepatorenal syndrome on cardiovascular adverse events. The analysis was made with power 90%, alpha 3%, a relative risk reduction (RRR) of 25%, a control group risk (CGR) of cardiovascular adverse events of 15%, and a heterogeneity correction of 20%. The diversity‐adjusted trial monitoring boundary for harm was not included in the figure due to insufficient information. The estimated required information size was 4831 participants. Accordingly, with an accrued number of participants of 88, the required number of participants was not achieved.
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Figure 6

Trial Sequential Analysis of two randomised clinical trials (88 participants) evaluating terlipressin versus other vasoactive drugs for people with hepatorenal syndrome on cardiovascular adverse events. The analysis was made with power 90%, alpha 3%, a relative risk reduction (RRR) of 25%, a control group risk (CGR) of cardiovascular adverse events of 15%, and a heterogeneity correction of 20%. The diversity‐adjusted trial monitoring boundary for harm was not included in the figure due to insufficient information. The estimated required information size was 4831 participants. Accordingly, with an accrued number of participants of 88, the required number of participants was not achieved.

Comparison 1 Terlipressin versus other vasoactive drugs, Outcome 1 Mortality: bias control.
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Analysis 1.1

Comparison 1 Terlipressin versus other vasoactive drugs, Outcome 1 Mortality: bias control.

Comparison 1 Terlipressin versus other vasoactive drugs, Outcome 2 Mortality: type of vasoactive drug.
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Analysis 1.2

Comparison 1 Terlipressin versus other vasoactive drugs, Outcome 2 Mortality: type of vasoactive drug.

Comparison 1 Terlipressin versus other vasoactive drugs, Outcome 3 Mortality: type of hepatorenal syndrome.
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Analysis 1.3

Comparison 1 Terlipressin versus other vasoactive drugs, Outcome 3 Mortality: type of hepatorenal syndrome.

Comparison 1 Terlipressin versus other vasoactive drugs, Outcome 4 Mortality: publication status.
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Analysis 1.4

Comparison 1 Terlipressin versus other vasoactive drugs, Outcome 4 Mortality: publication status.

Comparison 1 Terlipressin versus other vasoactive drugs, Outcome 5 Hepatorenal syndrome: type of vasoactive drug.
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Analysis 1.5

Comparison 1 Terlipressin versus other vasoactive drugs, Outcome 5 Hepatorenal syndrome: type of vasoactive drug.

Comparison 1 Terlipressin versus other vasoactive drugs, Outcome 6 Hepatorenal syndrome: type hepatorenal syndrome.
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Analysis 1.6

Comparison 1 Terlipressin versus other vasoactive drugs, Outcome 6 Hepatorenal syndrome: type hepatorenal syndrome.

Comparison 1 Terlipressin versus other vasoactive drugs, Outcome 7 Hepatorenal syndrome: publication status.
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Analysis 1.7

Comparison 1 Terlipressin versus other vasoactive drugs, Outcome 7 Hepatorenal syndrome: publication status.

Comparison 1 Terlipressin versus other vasoactive drugs, Outcome 8 Serious adverse events, type of vasoactive drug.
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Analysis 1.8

Comparison 1 Terlipressin versus other vasoactive drugs, Outcome 8 Serious adverse events, type of vasoactive drug.

Comparison 1 Terlipressin versus other vasoactive drugs, Outcome 9 Serious adverse events, type of event.
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Analysis 1.9

Comparison 1 Terlipressin versus other vasoactive drugs, Outcome 9 Serious adverse events, type of event.

Comparison 1 Terlipressin versus other vasoactive drugs, Outcome 10 Non‐serious adverse events.
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Analysis 1.10

Comparison 1 Terlipressin versus other vasoactive drugs, Outcome 10 Non‐serious adverse events.

Comparison 1 Terlipressin versus other vasoactive drugs, Outcome 11 Non‐serious adverse event: types.
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Analysis 1.11

Comparison 1 Terlipressin versus other vasoactive drugs, Outcome 11 Non‐serious adverse event: types.

Summary of findings for the main comparison. Terlipressin compared to other vasoactive drugs for hepatorenal syndrome

Terlipressin compared to other vasoactive drugs for hepatorenal syndrome

Patient or population: people with cirrhosis and hepatorenal syndrome
Setting: hospital
Intervention: terlipressin
Comparison: other vasoactive drugs

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Risk with other vasoactive drugs

Risk with terlipressin

Mortality (All‐cause)

Study population

RR 0.96
(0.88 to 1.06)

474
(10 randomised clinical trials*)

⊕⊝⊝⊝
Very lowa,b,c

Downgraded because of clinical heterogeneity, 8/10 randomised clinical trials were at high risk of bias and, the results of Trial Sequential Analysis.

601 per 1000

577 per 1000
(529 to 637)

Hepatorenal syndrome

(Number of participants who did not achieve reversal of hepatorenal syndrome)

Study population

RR 0.79
(0.63 to 0.99)

394
(9 randomised clinical trials)

⊕⊝⊝⊝
Very lowb,c,d

Downgraded because of clinical heterogeneity, all trials were judged as high risk of bias, and results of Trial Sequential Analysis.

560 per 1000

442 per 1000
(353 to 554)

Serious adverse events

Study population

RR 0.96
(0.88 to 1.06)

474
(10 randomised clinical trials)

⊕⊝⊝⊝
Very lowb,c,d

Downgraded because of clinical heterogeneity, all trials were judged as high risk of bias, and results of Trial Sequential Analysis.

609 per 1000

585 per 1000
(536 to 646)

Non‐serious adverse events: diarrhoea or abdominal pain, or both

Study population

RR 3.50
(1.19 to 10.27)

221
(5 randomised clinical trials)

⊕⊝⊝⊝
Very lowb,c,d

Downgraded because of clinical heterogeneity, all trials were judged as high risk of bias, and results of the Trial Sequential Analysis.

19 per 1000

65 per 1000
(22 to 190)

*The risk in the intervention group (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: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect.
Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect.

aIn the assessment of mortality, we classified two randomised clinical trials at low risk of bias and eight at high risk of bias.

bThe randomised clinical trials were not designed for equivalence or inferiority analysis. The Trial Sequential Analysis showed that sample size did not reach the required information size for equivalence/inferiority meta‐analysis.

cClinical heterogeneity.

dWe classified all randomised clinical trials at high risk of bias in all non‐mortality outcomes.

Figures and Tables -
Summary of findings for the main comparison. Terlipressin compared to other vasoactive drugs for hepatorenal syndrome
Comparison 1. Terlipressin versus other vasoactive drugs

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Mortality: bias control Show forest plot

10

474

Risk Ratio (M‐H, Random, 95% CI)

0.96 [0.88, 1.06]

1.1 Low risk of bias

2

94

Risk Ratio (M‐H, Random, 95% CI)

0.92 [0.63, 1.36]

1.2 High risk of bias

8

380

Risk Ratio (M‐H, Random, 95% CI)

0.97 [0.88, 1.07]

2 Mortality: type of vasoactive drug Show forest plot

10

474

Risk Ratio (M‐H, Random, 95% CI)

0.96 [0.88, 1.06]

2.1 Noradrenaline

7

306

Risk Ratio (M‐H, Random, 95% CI)

0.98 [0.88, 1.08]

2.2 Midodrine/octreotide

1

48

Risk Ratio (M‐H, Random, 95% CI)

0.71 [0.40, 1.28]

2.3 Octreotide

1

40

Risk Ratio (M‐H, Random, 95% CI)

0.75 [0.32, 1.77]

2.4 Dopamine/furosemide

1

80

Risk Ratio (M‐H, Random, 95% CI)

0.97 [0.77, 1.22]

3 Mortality: type of hepatorenal syndrome Show forest plot

10

474

Risk Ratio (M‐H, Random, 95% CI)

0.96 [0.88, 1.06]

3.1 Type 1 hepatorenal syndrome

9

375

Risk Ratio (M‐H, Random, 95% CI)

0.96 [0.87, 1.06]

3.2 Type 2 hepatorenal syndrome

3

99

Risk Ratio (M‐H, Random, 95% CI)

0.95 [0.68, 1.33]

4 Mortality: publication status Show forest plot

10

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

4.1 Full paper

8

374

Risk Ratio (M‐H, Random, 95% CI)

0.97 [0.83, 1.14]

4.2 Abstract

2

100

Risk Ratio (M‐H, Random, 95% CI)

0.96 [0.86, 1.08]

5 Hepatorenal syndrome: type of vasoactive drug Show forest plot

9

394

Risk Ratio (M‐H, Random, 95% CI)

0.79 [0.63, 0.99]

5.1 Noradrenaline

7

306

Risk Ratio (M‐H, Random, 95% CI)

0.96 [0.76, 1.21]

5.2 Midodrine/octreotide

1

48

Risk Ratio (M‐H, Random, 95% CI)

0.47 [0.30, 0.72]

5.3 Octreotide

1

40

Risk Ratio (M‐H, Random, 95% CI)

0.56 [0.33, 0.96]

6 Hepatorenal syndrome: type hepatorenal syndrome Show forest plot

9

394

Risk Ratio (M‐H, Random, 95% CI)

0.79 [0.63, 0.98]

6.1 Type 1 hepatorenal syndrome

8

335

Risk Ratio (M‐H, Random, 95% CI)

0.79 [0.62, 1.01]

6.2 Type 2 hepatorenal syndrome

2

59

Risk Ratio (M‐H, Random, 95% CI)

0.86 [0.36, 2.10]

7 Hepatorenal syndrome: publication status Show forest plot

9

394

Risk Ratio (M‐H, Random, 95% CI)

0.79 [0.63, 0.98]

7.1 Full paper articles

7

294

Risk Ratio (M‐H, Random, 95% CI)

0.82 [0.63, 1.06]

7.2 Abstracts

2

100

Risk Ratio (M‐H, Random, 95% CI)

0.72 [0.44, 1.17]

8 Serious adverse events, type of vasoactive drug Show forest plot

10

474

Risk Ratio (M‐H, Random, 95% CI)

0.96 [0.88, 1.06]

8.1 Noradrenaline

7

306

Risk Ratio (M‐H, Random, 95% CI)

0.98 [0.88, 1.08]

8.2 Midodrine/octreotide

1

48

Risk Ratio (M‐H, Random, 95% CI)

0.72 [0.42, 1.23]

8.3 Octreotide

1

40

Risk Ratio (M‐H, Random, 95% CI)

0.75 [0.32, 1.77]

8.4 Dopamine/furosemide

1

80

Risk Ratio (M‐H, Random, 95% CI)

0.97 [0.77, 1.22]

9 Serious adverse events, type of event Show forest plot

10

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

9.1 Death

10

474

Risk Ratio (M‐H, Random, 95% CI)

0.96 [0.88, 1.06]

9.2 Major cardiovascular events

7

323

Risk Ratio (M‐H, Random, 95% CI)

0.88 [0.13, 5.98]

10 Non‐serious adverse events Show forest plot

6

301

Risk Ratio (M‐H, Random, 95% CI)

1.82 [1.00, 3.31]

11 Non‐serious adverse event: types Show forest plot

6

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

11.1 Diarrhoea or abdominal pain, or both

5

221

Risk Ratio (M‐H, Random, 95% CI)

3.50 [1.19, 10.27]

11.2 Peripheral cyanosis

2

92

Risk Ratio (M‐H, Random, 95% CI)

3.0 [0.32, 27.83]

11.3 Minor cardiovascular events

6

301

Risk Ratio (M‐H, Random, 95% CI)

0.84 [0.37, 1.93]

Figures and Tables -
Comparison 1. Terlipressin versus other vasoactive drugs