Terlipressin versus other vasoactive drugs for hepatorenal syndrome

Mads Israelsen; Aleksander Krag; Andrew S Allegretti; Manol Jovani; Alison H Goldin; Rachel W Winter; Lise Lotte Gluud

doi:10.1002/14651858.CD011532.pub2

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Appendices

Appendix 1. Search strategies

Database	Time span	Search strategy	No of hits
The Cochrane Hepato‐Biliary Group Controlled Trials Register	November 2016.	(terlipressin* OR glypressin* OR vasoconstric) AND hepatorenal syndrom	31
The Cochrane Central Register of Controlled Trials (CENTRAL)	2016, Issue 11.	#1 MeSH descriptor: [Vasoconstrictor Agents] explode all trees #2 terlipressin* or glypressin* or vasoconstric* #3 #1 or #2 #4 MeSH descriptor: [Hepatorenal Syndrome] explode all trees #5 hepatorenal syndrom* #6 #4 or #5 #7 #3 and #6	35
MEDLINE Ovid	1946 to November 2016.	1. exp Vasoconstrictor Agents/ 2. (terlipressin* or glypressin* or vasoconstric).mp. [mp=title, original title, abstract, name of substance word, subject heading word] 3. 1 or 2 4. exp Hepatorenal Syndrome/ 5. hepatorenal syndrom.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 6. 4 or 5 7. 6 and 3 8. (random* or blind* or placebo* or meta‐analysis).mp. [mp=title, original title, abstract, name of substance word, subject heading word] 9. 8 and 7	59
Embase Ovid	1974 to November 2016.	1. exp Terlipressin/ 2. exp Vasoconstrictor Agent/ 3. (terlipressin* or glypressin* or vasoconstric).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name] 4. 1 or 3 or 2 5. exp Hepatorenal Syndrome/ 6. hepatorenal syndrom.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name] 7. 6 or 5 8. 4 and 7 9. (random* or blind* or placebo* or meta‐analysis).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name] 10. 8 and 9	204
Science Citation Index Expanded (Web of Science)	1900 to November 2016.	#5 #4 AND #3 #4 TS=(random* or blind* or placebo* or meta‐analysis) #3 #1 AND #2 #2 TS=(hepatorenal syndrom) #1 TS=(terlipressin or glypressin* or vasoconstric*)	118

Appendix 2. Diagnostic criteria of hepatorenal syndrome (Arroyo 1996)

Diagnostic criteria described in Arroyo 1996.

Major criteria

Chronic or acute liver disease with advanced hepatic failure and portal hypertension.
Low glomerular filtration rate, as indicated by serum creatinine of greater than 133 mmol/L (1.5 mg/dL) or 24‐hour creatinine clearance less than 40 mL/minute.
Absence of shock, ongoing bacterial infection, and current or recent treatment with nephrotoxic drugs. Absence of gastrointestinal fluid losses (repeated vomiting or intense diarrhoea) or renal fluid losses (weight loss greater than 500 g/day for several days in people with ascites without peripheral oedema or 1000 g/day in people with peripheral oedema).
No sustained improvement in renal function (decrease in serum creatinine to 1.5 mg/dL or less or increase in creatinine clearance to 40 mL/minute or more) following diuretic withdrawal and expansion of plasma volume with 1.5 L of isotonic saline.
Proteinuria less than 500 mg/dL and no ultrasonographic evidence of obstructive uropathy or parenchymal renal disease.

Additional criteria

Urine volume less than 500 mL/day.
Urine sodium less than 10 mEq/L.
Urine osmolality greater than plasma osmolality.
Urine red blood cells less than 50 per high power field.
Serum sodium concentration less than 130 mEq/L.

Appendix 3. Diagnostic criteria of hepatorenal syndrome (Salerno 2007)

Diagnostic criteria described in Salerno 2007.

Cirrhosis with ascites.
Serum creatinine greater than 133 mmol/L (1.5 mg/dL).
No improvement of serum creatinine (decrease to a level of 133 mmol/L or less after at least two days with diuretic withdrawal and volume expansion with albumin. The recommended dose of albumin 1 g/kg of bodyweight per day up to a maximum of 100 g/day.
Absence of shock.
No current or recent treatment with nephrotoxic drugs.
Absence of parenchymal kidney disease as indicated by proteinuria greater than 500 mg/day, microhaematuria (more than 50 red blood cells per high power field) and abnormal renal ultrasonography.

Appendix 4. Diagnostic criteria of hepatorenal syndrome type of acute kidney injury in people with cirrhosis

Diagnostic criteria described in Angeli 2015.

Diagnosis of cirrhosis and ascites.
Diagnosis of acute kidney injury according to the International Ascites Club‐Acute Kidney Injury criteria (see below).
No response after two consecutive days of diuretic withdrawal and plasma volume expansion with albumin 1 g/kg of bodyweight.
Absence of shock.
No current or recent use of nephrotoxic drugs (non‐steroidal anti‐inflammatory drugs, aminoglycosides, iodinated contrast media, etc.).
No macroscopic signs of structural kidney injury, defined as: absence of proteinuria (greater than 500 mg/day), absence of microhaematuria (more than 50 red blood cells per high power field), normal findings on renal ultrasonography.

Definition of acute kidney injury according to the International Ascites Club‐Acute Kidney Injury criteria

Increase in serum creatinine of 0.3 mg/dL or greater (26.5 μmol/L or greater) within 48 hours; or a percentage increase serum creatinine of 50% or greater from baseline which is known, or presumed, to have occurred within the prior seven days.

Staging of acute kidney injury	Stage 1	Stage 2	Stage 3
‐	Increase in serum creatinine ≥ 0.3 mg/dL (≥ 26.5 μmol/L) or an increase in serum creatinine ≥ 1.5‐fold to 2‐fold from baseline.	Increase in serum creatinine > 2‐fold to 3‐fold from baseline.	Increase of serum creatinine > 3‐fold from baseline or serum creatinine ≥ 4.0 mg/dL (≥ 353.6 μmol/L) with an acute increase ≥ 0.3 mg/dL (≥ 26.5 μmol/L) or initiation of renal replacement therapy.
Progression of acute kidney injury	Progression	‐	Regression
‐	Progression of acute kidney injury to a higher stage or need for renal replacement therapy, or both.	‐	Regression of acute kidney injury to a lower stage.
Response to treatment	No response	Partial response	Full response
‐	No regression of acute kidney injury.	Regression of acute kidney injury stage with a reduction of serum creatinine to ≥ 0.3 mg/dL (≥ 26.5 μmol/L) above baseline value.	Return of serum creatinine to within 0.3 mg/dL (26.5 μmol/L) of baseline value.

Baseline serum creatinine: a value of serum creatinine obtained in the previous three months, when available, can be used as baseline serum creatinine. In people with more than one value within the previous three months, the value closest to the admission time to the hospital should be used In people without a previous serum creatinine value, the serum creatinine on admission should be used as baseline.

Figure 1

Study flow diagram.

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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.

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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.

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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.

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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.

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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.

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Analysis 1.1

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

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Analysis 1.2

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

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Analysis 1.3

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

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Analysis 1.4

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

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Analysis 1.5

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

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Analysis 1.6

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

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Analysis 1.7

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

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Analysis 1.8

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

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Analysis 1.9

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

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Analysis 1.10

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

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Analysis 1.11

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

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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 low^a,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 low^b,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 low^b,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 low^b,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.

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

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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]

Comparison 1. Terlipressin versus other vasoactive drugs

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مقایسه ترلیپرسین در برابر سایر داروهای وازواکتیو برای سندرم هپاتورنال

Appendices

Appendix 1. Search strategies

Appendix 2. Diagnostic criteria of hepatorenal syndrome (Arroyo 1996)

Appendix 3. Diagnostic criteria of hepatorenal syndrome (Salerno 2007)

Appendix 4. Diagnostic criteria of hepatorenal syndrome type of acute kidney injury in people with cirrhosis

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Appendices

Appendix 1. Search strategies

Appendix 2. Diagnostic criteria of hepatorenal syndrome (Arroyo 1996)

Appendix 3. Diagnostic criteria of hepatorenal syndrome (Salerno 2007)

Appendix 4. Diagnostic criteria of hepatorenal syndrome type of acute kidney injury in people with cirrhosis

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