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Terlipresina versus otros fármacos vasoactivos para el síndrome hepatorrenal

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References

References to studies included in this review

Alessandria 2007 {published data only}

Alessandria C, Marzano A, Ottobrelli A, Debernardi‐Venon W, Todros L, Torrni M, et al. Noradrenaline vs terlipressin in hepatorenal syndrome: a prospective, randomized study. Journal of Hepatology 2006;44:S83. CENTRAL
Alessandria C, Ottobrelli A, Debernardi‐Venon W, Todros L, Cerenzia MT, Martini S, et al. Noradrenalin vs terlipressin in patients with hepatorenal syndrome: a prospective, randomized, unblinded, pilot study. Journal of Hepatology 2007;47:499‐505. [DOI: 10.1016/j.jhep.2007.04.010]CENTRAL

Badawy 2013 {published data only}

Badawy S, Meckawy N, Ahmed A. Norepinephrine versus terlipressin in patients with type 1 hepatorenal syndrome refractory to treatment with octreotide, midodrine, and albumin: a prospective randomized comparative study. Egyptian Journal of Cardiothoracic Anesthesia 2013;7:13‐8. [DOI: 10.7123/01.EJCA.0000431078.82595.1f]CENTRAL

Cavallin 2016 {published data only}

Cavallin M, Kamath PS, Merli M, Fasolato S, Toniutto P, Salerno F, et al. Terlipressin plus albumin versus midodrine and octreotide plus albumin in the treatment of hepatorenal syndrome: a randomized trial. Hepatology (Baltimore, Md.) 2016;63:983‐92. [DOI: 10.1002/hep.27709]CENTRAL

Copaci 2013 {published data only}

Copaci I, Chiriac G, Micu L, Mindrut E. Alternative treatments for hepato‐renal syndrome in patients with cirrhosis. Falk Symposium 191. Abstract book: Liver Diseases in 2013: Advances in Pathogenesis and Treatment2013:87. CENTRAL
Copaci I, Micu L, Chiriac G. Reversal of type 1 hepato‐renal syndrome with terlipressin and octreotide. Journal of Hepatology 2016;64:S660. CENTRAL

Ghosh 2013 {published data only}

Ghosh S, Choudhary NS, Sharma AK, Singh B, Kumar P, Agarwal R, et al. Noradrenaline vs terlipressin in the treatment of type 2 hepatorenal syndrome: a randomized pilot study. Liver International 2013;33:1187‐93. [DOI: 10.1111/liv.12179]CENTRAL

Goyal 2016 {published data only}

Goyal I. Terlipressin versus noradrenalin in hepatorenal syndrome: a prospective, randomised, unblinded study. Journal of Gastroenterology and Hepatology 2008;23:A76. CENTRAL
Goyal O, Sidhu S, Sehgal N, Puri S. Noradrenaline is as effective as terlipressin in hepatorenal syndrome type 1: a prospective, randomized trial. Journal of the Association of Physicians of India 2016;64:30‐5. [PUBMED: 27762512]CENTRAL

Indrabi 2013 {published data only}

Indrabi RA, Javid G, Zargar SA, Khan BA, Yattoo GN, Shah SH, et al. Noradrenaline is equally effective as terlipressin in reversal of type 1 hepatorenal syndrome: a randomized prospective study. Journal of Clinical and Experimental Hepatology 2013;3:S97. CENTRAL

Sharma 2008 {published data only}

Sharma P, Kumar A, Shrama BC, Sarin SK. An open label, pilot, randomized controlled trial of noradrenaline versus terlipressin in the treatment of type 1 hepatorenal syndrome and predictors of response. American journal of Gastroenterology 2008;103:1689‐97. [DOI: 10.1111/j.1572‐0241.2008.01828.x]CENTRAL
Sharma P, Kumar A, Shrama BC, Sarin SK. Noradrenaline versus terlipressin in the treatment of type 1 hepatorenal syndrome: a randomized controlled trial. Hepatology (Baltimore, Md.) 2006;44:449A. CENTRAL

Singh 2012 {published data only}

Singh V, Ghosh S, Singh B, Kumar P, Sharma N, Bhalla A, et al. Noradrenaline vs. terlipressin in the treatment of hepatorenal syndrome: a randomized study. Journal of Hepatology 2012;56:1293‐8. [DOI: 10.1016/j.jhep.2012.01.012]CENTRAL

Srivastava 2015 {published data only}

Srivastava S, Shalimar, Vishnubhatla S, Prakash S, Sharma H, Thakur B, et al. Randomized controlled trial comparing the efficacy of terlipressin and albumin with a combination of concurrent dopamine, furosemide, and albumin in hepatorenal syndrome. Journal of Clinical and Experimental Hepatology 2015;5:276‐85. [DOI: 10.1016/j.jceh.2015.08.003; PUBMED: 26900268]CENTRAL

References to studies excluded from this review

Boyer 2016 {published data only}

Boyer TD, Medicis JJ, Pappas SC, Potenziano J, Jamil K. A randomized, placebo‐controlled, double‐blind study to confirm the reversal of hepatorenal syndrome type 1 with terlipressin: the REVERSE trial design. Open Access Journal of Clinical Trials 2012;4:39‐49. CENTRAL
Boyer TD, Sanyal AJ, Wong F, Frederick RT, Lake JR, O'Leary JG, et al. Terlipressin plus albumin is more effective than albumin alone in improving renal function in patients with cirrhosis and hepatorenal syndrome type 1. Gastroenterology 2016;150:1579‐89. [PUBMED: 26896734]CENTRAL

Cavallin 2015 {published data only}

Angeli P, Fasolato S, Cavallin M, Maresio G, Callegaro A, Sticca A, et al. Terlipressin given as continuous intravenous infusion is the more suitable schedule for the treatment of type 1 hepatorenal syndrome (HRS) in patients with cirrhosis: results of a controlled clinical study. Hepatology (Baltimore, Md.) 2008;48:378A. CENTRAL
Cavallin M, Piano S, Romano A, Fasolato S, Frigo AC, Benetti G, et al. Terlipressin given by continuous intravenous infusion versus intravenous boluses in the treatment of hepatorenal syndrome: a randomized controlled study. Hepatology (Baltimore, Md.) 2015;63:983‐92. [PUBMED: 25644760]CENTRAL

Hadengue 1998 {published data only}

Hadengue A, Gadano A, Giostra E, Negro F, Moreau R, Valla D, et al. Terlipressin in the treatment of hepatorenal syndrome (HRS): a double blind cross‐over study. Hepatology (Baltimore, Md.) 1995;22:165A. CENTRAL
Hadengue A, Gadano A, Giostra E, Negro F, Moreau R, Valla D, et al. Terlipressin in the treatment of hepatorenal syndrome (HRS): a double blind cross‐over study. Journal of Hepatology 1998;29:565‐70. [PUBMED: 9824265]CENTRAL

Martín‐Llahí 2008 {published data only}

Martin‐Llahi M, Pepin MN, Guevara M, Torre A, Monescillo A, Soriano G, et al. Randomized, comparative study of terlipressin and albumin vs albumin alone in patients with cirrhosis and hepatorenal syndrome. Journal of Hepatology 2007;46:S36. CENTRAL
Martín‐Llahí M, Pépin MN, Guevara M, Díaz F, Torre A, Monescillo A, et al. Terlipressin and albumin vs albumin in patients with cirrhosis and hepatorenal syndrome: a randomized study. Gastroenterology 2008;134:1352‐9. [PUBMED: 7939047]CENTRAL

Neri 2008 {published data only}

Neri S, Pulvirenti D, Malaguarnera M, Cosimo BM, Bertino G, Ignaccolo L, et al. Terlipressin and albumin in patients with cirrhosis and type I hepatorenal syndrome. Digestive Diseases and Sciences 2008;53:830‐5. [PUBMED: 17939047]CENTRAL

Nguyen‐Tat 2015 {published data only}

Nguyen‐Tat M, Gotz E, Scholz‐Kreisel P, Ahrens J, Sivanathan V, Schattenberg J, et al. Response to Terlipressin and albumin is associated with improved outcome in patients with cirrhosis and hepatorenal syndrome [Leberzirrhose und hepatorenales Syndrom: Das Ansprechen auf Terlipressin und Albumin ist mit besserem Überleben assoziiert]. Deutsche Medizinische Wochenschrift 2015;140:21‐6. [PUBMED: 25612289]CENTRAL

Pulvirenti 2008 {published data only}

Pulvirenti D, Tsami A. Low doses of terlipressin and albumin in the type I hepatorenal syndrome [Terlipressina a basso dosaggio e albumina nella sindrome epatorenale di tipo I]. Italian Journal of Medicine 2008;2:34‐8. CENTRAL

Sanyal 2008 {published data only}

Sanyal A, Boyer T, Garcia‐Tsao G, Regenstein F, Rossaro L, Teuber P. A prospective, randomized, double blind, placebo‐controlled trial of terlipressin for type 1 hepatorenal syndrome (HRS). Hepatology (Baltimore, Md.) 2006;44:694A. CENTRAL
Sanyal AJ, Boyer T, Garcia‐Tsao G, Regenstein F, Rossaro L, Appenrodt B, et al. A randomized, prospective, double‐blind, placebo‐controlled trial of terlipressin for type 1 hepatorenal syndrome. Gastroenterology 2008;134:1360‐8. [MEDLINE: 18471513; clinicaltrials.gov NCT00089570]CENTRAL
Sanyal AJ, Boyer TD, Garcia‐Tsao G, Blei AT, Teuber P, Terlipressin Study Group. Effect of terlipressin on mean arterial pressure (MAP) and its relation to serum creatinine concentration in type 1 hepatorenal syndrome (HRS): analysis of data from the pivotal phase 3 trial. Hepatology (Baltimore, Md.) 2008;48:1071A. CENTRAL
Sanyal AJ, Boyer TD, Teuber P. Prognostic factors for hepatorenal syndrome (HRS) in patients with type 1 HRS enrolled in a randomized double‐blind, placebo‐controlled trial. Hepatology (Baltimore, Md.) 2007;46:565A. CENTRAL

Silawat 2011 {published data only}

Silawat FN, Shaikh MK, Lohana RK, Devrajani BR, Shah SZA, Ansari A. Efficacy of terlipressin and albumin in the treatment of hepatorenal syndrome. World Applied Sciences Journal 2011;12:1946‐50. CENTRAL

Solanki 2003 {published data only}

Solanki P, Chawla A, Garg R, Gupta R, Jain M, Sarin SK. Beneficial effects of terlipressin in hepatorenal syndrome: a prospective, randomized placebo‐controlled clinical trial. Journal of Gastroenterology and Hepatology 2003;18:152‐6. CENTRAL

Tavakkoli 2012 {published data only}

Tavakkoli H, Yazdanpanah K, Mansourian M. Noradrenalin versus the combination of midodrine and octreotide in patients with hepatorenal syndrome: randomized clinical trial. International Journal of Preventive Medicine 2012;3:764‐69. CENTRAL

Wan 2014 {published data only}

Wan S, Wan X, Zhu Q, Peng J. A comparative study of high‐or low‐dose terlipressin therapy in patients with cirrhosis and type 1 hepatorenal syndrome. Chinese Journal of Hepatology 2014;22:349‐53. [PUBMED: 25180869]CENTRAL

Yang 2001 {published data only}

Yang YZ, Dan ZL, Liu NZ, Liu M. Efficacy of terlipressin in treatment of liver cirrhosis with hepatorenal syndrome. Journal of Internal Intensive Medicine 2001;7:123‐5. CENTRAL

Allegretti 2017

Allegretti AS, Israelsen M, Krag A, Jovani M, Goldin AH, Schulman AR, et al. Terlipressin versus placebo or no intervention for people with cirrhosis and hepatorenal syndrome. Cochrane Database of Systematic Reviews 2017, Issue 6. [DOI: 10.1002/14651858.CD005162.pub4]

Angeli 1999

Angeli P. Reversal of type 1 hepatorenal syndrome with the administration of midodrine and octreotide. Hepatology (Baltimore, Md.) 1999;29:1690‐7.

Angeli 2015

Angeli P, Gines P, Wong F, Bernardi M, Boyer TD, Gerbes A, et al. Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites. Gut 2015;64:531‐7.

Arroyo 1996

Arroyo V, Gines P, Gerbes AL, Dudley FJ, Gentilini P, Laffi G, et al. Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. International Ascites Club. Hepatology (Baltimore, Md.) 1996;23:164‐76.

Cardenas 2003

Cardenas A, Arroyo V. Hepatorenal syndrome. Annals of Hepatology 2003;2:23‐9.

Duvoux 2002

Duvoux C, Zanditenas D, Hezode C, Chauvat A, Monin JL, Roudot‐Thoraval F, et al. Effects of noradrenalin and albumin in patients with type I hepatorenal syndrome: a pilot study. Hepatology (Baltimore, Md.) 2002;36:374‐80.

EASL 2010

European Association for the Study of the Liver. EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis. Journal of Hepatology 2010;53:397‐417.

Fabrizi 2009

Fabrizi F, Dixit V, Messa P, Martin P. Terlipressin for hepatorenal syndrome: a meta‐analysis of randomized trials. International Journal of Artificial Organs 2009;32:133‐40.

Facciorusso 2017

Facciorusso A, Chandar A, Murad M, Prokop L, Muscatiello N, Kamath P, et al. Comparative efficacy of pharmacological strategies for management of type 1 hepatorenal syndrome: a systematic review and network meta‐analysis. Lancet Gastroenterology and Hepatology 2017;2(2):94‐102.

Fede 2012

Fede G, D'Amico G, Arvaniti V, Tsochatzis E, Germani G, Georgiadis D, et al. Renal failure and cirrhosis: a systematic review of mortality and prognosis. Journal of Hepatology 2012;56:810‐8.

Gilford 2017

Gifford F, Morling J, Fallowfield J. Systematic review with meta‐analysis: vasoactive drugs for the treatment of hepatorenal syndrome type 1. Alimentary Pharmacology & Therapeutics 2017;45(5):593‐603.

Gines 1993

Gines A, Escorsell A, Gines P, Salo J, Jimenez W, Inglada L, et al. Incidence, predictive factors, and prognosis of hepatorenal syndrome in cirrhosis. Gastroenterology 1993;105:229‐36.

Gines 2003

Gines P, Guevara M, Arroyo V, Rodes J. Hepatorenal syndrome. Lancet 2003;362:1819‐27.

Gluud 2017

Gluud C, Nikolova D, Klingenberg SL. Cochrane Hepato‐Biliary Group. About The Cochrane Collaboration (Cochrane Review Groups (CRGs)) 2017, Issue 6. Art. No.: LIVER.

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Brozek J, Oxman A, Schünemann H. GRADEpro. Version 3.2 for Windows. Grade Working Group, 2008.

Harbord 2006

Harbord RM, Egger M, Sterne JA. A modified test for small‐study effects in meta‐analyses of controlled trials with binary endpoints. Statistics in Medicine 2006;25:3443‐57.

Higgins 2008

Higgins JPT, White IR, Wood AM. Imputation methods for missing outcome data in meta‐analysis of clinical trials. Clinical Trials 2008;5:225‐39.

Higgins 2011

Higgins JP, Green S, editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from handbook.cochrane.org.

ICH‐GCP 1997

International Conference on Harmonisation Expert Working Group. International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use. ICH harmonised tripartite guideline. Guideline for good clinical practice CFR & ICH Guidelines. Vol. 1, Philadelphia (PA): Barnett International/PAREXEL, 1997.

Israelsen 2015

Israelsen ME, Gluud LL, Krag A. Acute kidney injury and hepatorenal syndrome in cirrhosis. Journal of Gastroenterology and Hepatology 2015;30:236‐43. [DOI: 10.1111/jgh.12709]

Krag 2008

Krag A, Borup T, Moller S, Bendtsen F. Efficacy and safety of terlipressin in cirrhotic patients with variceal bleeding or hepatorenal syndrome. Advances in Therapy 2008;25:1105‐40.

Mattos 2016

Mattos ÂZ, Mattos AA, Ribeiro RA. Terlipressin versus noradrenaline in the treatment of hepatorenal syndrome: systematic review with meta‐analysis and full economic evaluation. European Journal of Gastroenterology & Hepatology March 2016;28(3):345‐51.

Mehta 2007

Mehta RL, Kellum JA, Shah SV, Molitoris BA, Ronco C, Warnock DG, et al. Acute Kidney Injury Network. Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Critical Care 2007;11:21.

Moller 2004

Moller S, Henriksen JH. Review article: pathogenesis and pathophysiology of hepatorenal syndrome ‐ is there scope for prevention?. Alimentary Pharmacology & Therapeutics 2004;20:31‐41.

Nassar 2014

Nassar AP, Farias AQ, D'Albuquerque LA, Carrilho FJ, Malbouisson LM. Terlipressin versus norepinephrine in the treatment of hepatorenal syndrome: a systematic review and meta‐analysis. PloS One 2014;9:e107466.

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Pasqualetti P, Festuccia V, Collacciani A, Acitelli P, Casale R. Circadian rhythm of arginine vasopressin in hepatorenal syndrome. Nephron 1998;78:33‐7.

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Runyon 2013

Runyon BA, AASLD. Introduction to the revised American Association for the Study of Liver Diseases Practice Guideline management of adult patients with ascites due to cirrhosis 2012. Hepatology (Baltimore, Md.) 2013;57(4):1651‐3.

Russell 2008

Russell JA, Walley KR, Singer J, Gordon AC, Hebert PC, Cooper DJ, et al. Vasopressin versus norepinephrine infusion in patients with septic shock. New England Journal of Medicine 2008;358:877‐87. [PUBMED: 18305265]

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Salerno F, Gerbes A, Ginès P, Wong F, Arroyo V. Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis. Gut 2007;56:1310‐8.

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Salerno F, Navickis R, Wilkes M. Albumin treatment regimen for type 1 hepatorenal syndrome: a dose‐response meta‐analysis. BMC Gastroenterology 2015;15(67):1‐11.

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Sort P, Navasa M, Arroyo V, Aldeguer X, Planas R, Ruiz‐del‐Arbol L, et al. Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis. New England Journal of Medicine 1999;341(6):403‐9.

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References to other published versions of this review

Gluud 2010

Gluud LL, Christensen K, Christensen E, Krag A. Systematic review of randomized trials on vasoconstrictor drugs for hepatorenal syndrome. Hepatology (Baltimore, Md.) 2010;51:576‐84. [PUBMED: 19885875]

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Gluud LL, Christensen K, Christensen E, Krag A. Terlipressin for hepatorenal syndrome. Cochrane Database of Systematic Reviews 2012, Issue 9. [DOI: 10.1002/14651858.CD005162.pub3]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Jump to:

Alessandria 2007

Methods

Open‐label, single‐centre randomised clinical trial.

Participants

Criteria used to define hepatorenal syndrome:Arroyo 1996 (Appendix 2).

Type 1 hepatorenal syndrome = 9 participants included.

Type 2 hepatorenal syndrome = 13 participants included.

Demographics:

Terlipressin group: mean age 55 years, 75% men, alcoholic cirrhosis 33%.

Other vasoactive drug group: mean age 56 years, 70% men, alcohol‐related cirrhosis 20%.

Interventions

Terlipressin:

Administration form: intravenous bolus injection.

Dose: dose titration regimen.

Initial dose 1 mg/4 hours. With no response, dose increased to 2 mg/4 hours. Response defined as reduction in serum creatinine ≥ 25% from baseline after 3 days of treatment.

Other vasoactive drug:noradrenaline.

Administration form: continuous intravenous infusion.

Dose: dose titration regimen.

Initial dose 0.1 μg/kg/minute. Dose increased in steps of 0.05 μg/kg/minute every 4 hours until the mean arterial pressure was increased to at least 10 mmHg compared to baseline. Maximum dose 0.7 μg/kg/minute.

Cointervention:

Both arms treated with albumin to maintain a central venous pressure between 10 cmH2O and 15 cmH2O. Mean dose of albumin in terlipressin group. 46 g/day (range 35 to 65). Mean dose of albumin in noradrenaline group 56 g/day (range 40 to 75).

During follow‐up, participants with ascites were treated with diuretics and large volume paracentesis followed by albumin infusions as needed.

Outcomes

No predefined outcome (pilot study). Survival and reversal of hepatorenal syndrome reported.

Treatment duration

Treatment duration: until reversal of hepatorenal syndrome, death, or a maximum 2 weeks.

Follow‐up: 90 days.

Country of origin

Italy.

Inclusion period

Data not available.

Notes

Full paper. All survivors underwent liver transplantation at end of follow‐up.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

No description.

Allocation concealment (selection bias)

Low risk

Serially numbered sealed opaque envelopes.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

No blinding of participants or personnel.

Blinding of outcome assessment (detection bias)
All outcomes

High risk

No blinding of outcome assessment.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No missing outcome data. All participants included in analyses.

Selective reporting (reporting bias)

Low risk

Clinically relevant outcomes defined and reported. No differences between trial registration/protocol and published paper identified.

For‐profit bias

Low risk

No funding or other support from for‐profit organisations.

Overall risk of bias (non‐mortality outcomes)

High risk

Overall risk of bias (mortality)

High risk

Badawy 2013

Methods

Open‐label multicentre randomised clinical trial.

Participants

Criteria used to define hepatorenal syndrome:Arroyo 1996 (Appendix 2).

Type 1 hepatorenal syndrome = 51 participants included.

Demographics:

Terlipressin group: mean age 43 years, 67% men, aetiology mostly viral hepatitis.

Other vasoactive drug group: mean age 46 years, 71% men, aetiology mostly viral hepatitis.

Interventions

Terlipressin:

Administration form: continuous intravenous infusion.

Dose: dose titration regimen.

Initial dose 3 mg/24 hours. With no response, dose primarily increased to 6 mg/24 hours and secondarily to 12 mg/24 hours. Response defined as a reduction of serum creatinine ≥ 25% compared to baseline after every 48 hours of treatment.

Other vasoactive drug:noradrenaline.

Administration form: continuous intravenous infusion

Dose: dose titration regimen.

Initial dose 0.5 mg/hour. Dose increased in steps of 0.5 mg/hour every 4 hours guided by a mean arterial pressure around 85 mmHg to 90 mmHg. Maximum dose 3 mg/hour.

Cointervention:

Both arms treated with albumin to maintain a central venous pressure between 10 cmH2O and 15 cmH2O. Dose not reported.

Outcomes

Primary outcome: reversal of hepatorenal syndrome.

Secondary outcomes: 30 days survival and treatment costs.

Treatment duration

Treatment duration: until reversal of hepatorenal syndrome, death, or a maximum of 15 days.

Follow‐up: 30 days.

Country of origin

Egypt.

Inclusion period

January 2009 to April 2012.

Notes

Full paper.

Participants who died within 72 hours after randomisation excluded from study. We contacted the authors, but were unable gather any further information.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

No description.

Allocation concealment (selection bias)

Unclear risk

Sealed opaque envelopes (text did not explain if envelopes were serially numbered).

Blinding of participants and personnel (performance bias)
All outcomes

High risk

No blinding of participants or personnel.

Blinding of outcome assessment (detection bias)
All outcomes

High risk

No blinding of outcome assessment.

Incomplete outcome data (attrition bias)
All outcomes

High risk

No missing outcome data described. Participants who died within 72 hours excluded from analyses, but number allocated to 2 intervention groups not given.

Selective reporting (reporting bias)

Low risk

Clinically relevant outcome reported. No differences between trial registration/protocol and published paper identified.

For‐profit bias

Unclear risk

No description.

Overall risk of bias (non‐mortality outcomes)

High risk

Overall risk of bias (mortality)

High risk

Cavallin 2016

Methods

Open label, multicentre randomised clinical trial.

Participants

Criteria used to define hepatorenal syndrome:Salerno 2007 (Appendix 2).

Type 1 hepatorenal syndrome = 44 participants included.

Type 2 hepatorenal syndrome = 4 participants included.

Demographics:

Terlipressin group: mean age 60 years, men 78%, viral aetiology 37%.

Other vasoactive drug group: mean age 65 years, men 52%, viral aetiology 38%.

Interventions

Terlipressin:

Administration form: continuous intravenous infusion.

Dose: dose titration regimen.

Initial dose 3 mg/24 hours. With no response, dose primarily increased to 6 mg/24 hours and then to 12 mg/24 hours. Response defined as a reduction of serum creatinine of ≥ 25% compared to baseline after every 48 hours of treatment.

Other vasoactive drugs:midodrine and octreotide

Midodrine

Administration form: oral tablet.

Dose: dose titration regimen.

Initial dose 7.5 mg/8 hours. With no response, dose increased to 12.5 mg/8 hours. Response defined as a reduction in serum creatinine of ≥ 25% from baseline after 3 days of treatment.

Octreotide

Administration form: subcutaneous bolus injection.

Dose: dose titration regimen.

Initial dose 100 mg/8 hours. With no response, dose increased to 200 mg/8 hours. Response defined as a reduction in serum creatinine of ≥ 25% from baseline after 3 days of treatment.

Cointervention: both arms treated with albumin; 1 g/kg bodyweight at day 1, followed by 20 g/day to 40 g/day.

Outcomes

Primary: reversal of hepatorenal syndrome.

Secondary: 3 months survival.

Treatment duration

Treatment duration: until reversal of hepatorenal syndrome, death, or a maximum of 14 days.

Follow‐up: 3 months.

Country of origin

Italy.

Inclusion period

2008 to 2012.

Notes

Full paper.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated allocation sequence.

Allocation concealment (selection bias)

Low risk

Serially numbered opaque sealed envelopes.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

No blinding of participants or personnel.

Blinding of outcome assessment (detection bias)
All outcomes

High risk

No blinding of outcome assessment.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No missing outcome data and all participants were accounted for.

Selective reporting (reporting bias)

Low risk

Clinically relevant outcomes reported. No differences between trial registration/protocol and published paper identified.

For‐profit bias

Low risk

Authors declared no conflict of interests and the trial did not receive funding from for‐profit organisations.

Overall risk of bias (non‐mortality outcomes)

High risk

Overall risk of bias (mortality)

Low risk

Copaci 2013

Methods

Open‐label, single‐centre randomised clinical trial.

Participants

Criteria used to define hepatorenal syndrome: not reported.

Type 1 hepatorenal syndrome = 36 participants included.

Type 2 hepatorenal syndrome = 4 participants included.

Demographics:

Terlipressin group: not available.

Other vasoactive drug group: not available.

Interventions

Terlipressin:

Administration form: continuous intravenous infusion.

Dose: dose titration regimen.

Initial dose 4 mg/24 hours. With no response, dose increased stepwise to 12 mg/24 hours. Response defined as a reduction in serum creatinine of ≥ 50% from baseline or reversal of hepatorenal syndrome.

Other vasoactive drug:octreotide.

Administration form: subcutaneously bolus injection.

Dose: dose titration regimen.

Initial dose 100 mg/8 hours. With no response, dose increased to 200 mg/8 hours. Response defined as a reduction in serum creatinine of ≥ 50% from baseline or reversal of hepatorenal syndrome.

Cointervention: both arms treated with albumin; 1 g/kg bodyweight at day 1, followed by 20 g/day to 40 g/day.

Outcomes

No description. Data on reversal of hepatorenal syndrome and mortality available.

Treatment duration

Treatment duration: data not available.

Follow‐up: 30 days.

Country of origin

Romania.

Inclusion period

Data not available.

Notes

Abstract.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

No description.

Allocation concealment (selection bias)

Unclear risk

No description.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

No blinding of participants or personnel.

Blinding of outcome assessment (detection bias)
All outcomes

High risk

No blinding of outcome assessment.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No missing outcome data and all participants accounted for.

Selective reporting (reporting bias)

Low risk

Clinically relevant outcomes defined and reported. No differences between trial registration/protocol and published paper identified.

For‐profit bias

Unclear risk

No description.

Overall risk of bias (non‐mortality outcomes)

High risk

Overall risk of bias (mortality)

High risk

Ghosh 2013

Methods

Open‐label, single‐centre randomised clinical trial.

Participants

Criteria used to define hepatorenal syndrome:Salerno 2007 (Appendix 2).

Type 2 hepatorenal syndrome = 46 participants included.

Demographics:

Terlipressin group: mean age 46 years, 87% men, alcohol‐related cirrhosis 65%.

Other vasoactive drug group: mean age 48 years, 70% men, alcohol‐related cirrhosis 70%.

Interventions

Terlipressin:

Administration form: intravenous bolus injection.

Dose: dose titration regimen.

Initial dose 0.5 mg/6 hours. With no response, dose increased primarily to 1 mg/6 hours and then to 2 mg/6 hours. Response defined as a reduction in serum creatinine of 1 mg/dL after 3 days of treatment.

Other vasoactive drug:noradrenaline.

Administration form: continuous intravenous infusion.

Dose: dose titration regimen.

Initial dose 0.5 mg/hour. Dose increased in steps of 0.5 mg/hour every 4 hours until mean arterial pressure increased to ≥ 10 mmHg compared to baseline or an increase in urine output to > 200 mL/4 hours. Maximum dose 3 mg/hour.

Cointervention: both arms treated with albumin 20 g/day to 40 g/day. Treatment temporarily stop if central venous pressure exceeded 18 cmH2O.

Outcomes

Primary: reversal of hepatorenal syndrome.

Secondary: 3 months mortality.

Treatment duration

Treatment duration: until reversal of hepatorenal syndrome, death, or a maximum of 15 days.

Follow‐up: 3 months.

Country of origin

India.

Inclusion period

January 2009 to December 2011.

Notes

Full paper.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated allocation sequence.

Allocation concealment (selection bias)

Low risk

Serially numbered opaque sealed envelopes.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

No blinding of participants or personnel.

Blinding of outcome assessment (detection bias)
All outcomes

High risk

No blinding of outcome assessment.

Incomplete outcome data (attrition bias)
All outcomes

High risk

Investigators excluded 12 participants from analyses after randomisation. Reasons for exclusions/withdrawals included sepsis (7), severe coronary artery disease (1), hepatocellular carcinoma (1), diabetic nephropathy (1), and refusal to participate (2). Authors did not provide information about allocation group.

Selective reporting (reporting bias)

Low risk

Clinically relevant outcomes defined and reported. No differences between trial registration/protocol and published paper identified.

For‐profit bias

Unclear risk

No description.

Overall risk of bias (non‐mortality outcomes)

High risk

Overall risk of bias (mortality)

High risk

Goyal 2016

Methods

Open‐label, single‐centre randomised clinical trial.

Participants

Criteria used to define hepatorenal syndrome:Salerno 2007 (Appendix 2).

Type 1 hepatorenal syndrome = 41 participants included.

Demographics:

Terlipressin group: mean age 56.9 years, 85% men, alcohol‐related cirrhosis 75%.

Other vasoactive drug group: mean age 54.7 years, 95.2% men, alcohol‐related cirrhosis 61.9%.

Interventions

Terlipressin:

Administration form: intravenous bolus injection.

Dose: dose titration regimen.

Initial dose 0.5 mg/6 hours. With no response, dose increased stepwise to maximum of 2 mg/6 hours. Response defined as a reduction in serum creatinine of 1 mg/dL after 3 days of treatment.

Other vasoactive drug:noradrenaline (+furosemide).

Noradrenaline

Administration form: continuous intravenous infusion

Dose: dose titration regimen.

Initial dose 0.5 mg/hour. Dose increased in steps of 0.5 mg/hour every 4 hours until mean arterial pressure increased to ≥ 10 mmHg compared to baseline or an increase in urine output to > 200 mL/4 hours. Maximum dose 3 mg/hour.

Furosemide

Administration form: continuous intravenous infusion.

Dose: dose titration regimen.

Furosemides added, if urine output < 200 mL/4 hours despite reaching an increase in mean arterial pressure of ≥ 10 mmHg.

Initial dose 0.001 mg/kg/minute and adjusted to maintain a urine output of > 40 mL/hour.

Cointervention: both arms treated with intravenous third‐generation cephalosporins and albumin 20 g/day to 40 g/day. Administration stopped temporarily if central venous pressure increased > 12 cm/H2O or if serum albumin > 4 g/L.

Outcomes

Primary: reversal of hepatorenal syndrome.

Secondary: 14 days mortality.

Treatment duration

Treatment duration: until reversal of hepatorenal syndrome, death, or a maximum of 14 days.

Follow‐up: 14 days.

Country of origin

India.

Inclusion period

3 years.

Notes

Full paper.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

No description.

Allocation concealment (selection bias)

Unclear risk

No description.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

No blinding of participants or personnel.

Blinding of outcome assessment (detection bias)
All outcomes

High risk

No blinding of outcome assessment.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No missing outcome data and all participants included in analyses.

Selective reporting (reporting bias)

Low risk

Clinically relevant outcomes defined and reported. No differences between trial registration/protocol and published paper identified.

For‐profit bias

Unclear risk

No description.

Overall risk of bias (non‐mortality outcomes)

High risk

Overall risk of bias (mortality)

High risk

Indrabi 2013

Methods

Open‐label randomised clinical trial.

Participants

Criteria used to define hepatorenal syndrome: no description.

Type 1 hepatorenal syndrome = 60 participants included.

Demographics: no description.

Interventions

Terlipressin:

Administration form: intravenous.

Other vasoactive drug:noradrenaline.

Administration form: intravenous.

Cointervention: both arms treated with albumin. Dose not reported.

Outcomes

No description. Data on reversal of hepatorenal syndrome and mortality available.

Treatment duration

Treatment duration: no description.

Follow‐up: 90 days or death.

Country of origin

India.

Inclusion period

No description.

Notes

Full paper.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

No description.

Allocation concealment (selection bias)

Unclear risk

No description.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

No blinding of participants or personnel.

Blinding of outcome assessment (detection bias)
All outcomes

High risk

No blinding of outcome assessment.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No description.

Selective reporting (reporting bias)

Low risk

Clinically relevant outcomes described and reported. No differences between trial registration/protocol and published paper identified.

For‐profit bias

Unclear risk

No description.

Overall risk of bias (non‐mortality outcomes)

High risk

Overall risk of bias (mortality)

High risk

Sharma 2008

Methods

Open‐label, single‐centre randomised clinical trial.

Participants

Criteria used to define hepatorenal syndrome:Arroyo 1996 (Appendix 2).

Type 1 hepatorenal syndrome = 40 participants included.

Demographics:

Terlipressin group: mean age 48 years, 85% men, alcohol‐related cirrhosis 60%.

Other vasoactive drug group: mean age 48 years, 85% men, alcohol‐related cirrhosis 70%.

Interventions

Terlipressin:

Administration form: intravenous bolus injection.

Dose: dose titration regimen.

Initial dose 0.5 mg/6 hours. With no response, dose increased stepwise to a maximum 2 mg/6 hours. Response defined as a reduction in serum creatinine of 1 mg/dL after 3 days of treatment.

Other vasoactive drug:noradrenaline.

Administration form: continuous intravenous infusion.

Dose: dose titration regimen.

Initial dose 0.5 mg/hour. Dose increased in steps of 0.5 mg/hour every 4 hours until mean arterial pressure increased to ≥ 10 mmHg compared to baseline or an increase in urine output to > 200 mL/4 hours. Maximum dose 3 mg/hour.

Cointervention: both arms treated with albumin 20 g/day to 40 g/day. Treatment temporarily stop if central venous pressure exceeded 18 cmH2O.

Participants with tense ascites had 3 L to 5 L paracentesis combined with infusions of 8 g of albumin for each litre of ascitic fluid removed.

Outcomes

Primary outcome: reversal of hepatorenal syndrome.

Secondary outcomes: 30 days survival.

Treatment duration

Treatment duration: until reversal of hepatorenal syndrome, death, or a maximum of 15 days.

Follow‐up: 30 days.

Country of origin

India.

Inclusion period

August 2005 to December 2006.

Notes

Full paper.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated allocation sequence.

Allocation concealment (selection bias)

Unclear risk

No description.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

No blinding of participants or personnel.

Blinding of outcome assessment (detection bias)
All outcomes

High risk

No blinding of outcome assessment.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No missing outcome data. All participants included in analyses.

Selective reporting (reporting bias)

Low risk

Clinically relevant outcomes reported. No differences between trial registration/protocol and published paper identified.

For‐profit bias

Low risk

Authors declared no conflict of interests and trial did not receive funding from for‐profit organisations.

Overall risk of bias (non‐mortality outcomes)

High risk

Overall risk of bias (mortality)

High risk

Singh 2012

Methods

Open‐label, single‐centre randomised clinical trial.

Participants

Criteria used to define hepatorenal syndrome:Salerno 2007 (Appendix 2).

Type 1 hepatorenal syndrome = 46 participants included.

Demographics:

Terlipressin group: mean age 51 years, 83% men, alcohol‐related cirrhosis 43%.

Other vasoactive drug group: mean age 48 years, 83% men, alcohol‐related cirrhosis 52%.

Interventions

Terlipressin:

Administration form: intravenous bolus injection.

Dose: dose titration regimen.

Initial dose 0.5 mg/6 hours. With no response, dose increased stepwise to maximum 2 mg/6 hours. Response defined as a reduction in serum creatinine of 1 mg/dL after 3 days of treatment.

Other vasoactive drug:noradrenaline.

Administration form: continuous intravenous infusion.

Dose: dose titration regimen.

Initial dose 0.5 mg/hour. Dose increased in steps of 0.5 mg/hour every 4 hours until mean arterial pressure increased to > 10 mmHg compared to baseline or an increase in urine output to > 200 mL/4 hours. Maximum dose 3 mg/hour.

Cointervention: both arms treated with albumin 20 g/day to 40 g/day. Treatment temporarily stopped if central venous pressure exceeded 18 cmH2O.

Participants with tense ascites had 3 L to 5 L paracentesis combined with infusions of 8 g of albumin for each litre of ascitic fluid removed.

Outcomes

Primary outcome: reversal of hepatorenal syndrome.

Secondary outcomes: 30 days survival.

Treatment duration

Treatment duration: until reversal of hepatorenal syndrome, death, or a maximum of 15 days.

Follow‐up: 30 days.

Country of origin

India.

Inclusion period

January 2009 to 2011 October.

Notes

Full paper.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated allocation list.

Allocation concealment (selection bias)

Low risk

Serially numbered opaque sealed envelopes.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

No blinding of participants or personnel.

Blinding of outcome assessment (detection bias)
All outcomes

High risk

No blinding of outcome assessment.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No missing outcome data and all participants included in analyses.

Selective reporting (reporting bias)

Low risk

Clinically relevant outcomes reported. No differences between trial registration/protocol and published paper identified.

For‐profit bias

Low risk

Authors declared no conflict of interests and trial did not receive funding from for‐profit organisations.

Overall risk of bias (non‐mortality outcomes)

High risk

Overall risk of bias (mortality)

Low risk

Srivastava 2015

Methods

Open‐label, single‐centre randomised clinical trial.

Participants

Criteria used to define hepatorenal syndrome:Salerno 2007 (Appendix 2).

Type 1 hepatorenal syndrome = 40 participants included.

Type 2 hepatorenal syndrome = 40 participants included.

Demographics: type 1 hepatorenal syndrome.

Terlipressin group: mean age 46 years, 83% men, alcohol‐related cirrhosis 50%.

Other vasoactive drug group: mean age 39 years, 83% men, alcohol‐related cirrhosis 50%.

Demographics: type 2 hepatorenal syndrome.

Terlipressin group: mean age 45 years, 83% men, alcohol‐related cirrhosis 53%.

Other vasoactive drug group: mean age 43 years, 83% men, alcohol‐related cirrhosis 55%.

Interventions

Terlipressin:

Administration form: intravenous bolus injection.

Dose: fixed dose 0.5 mg/6 hours.

Other vasoactive drug:dopamine and furosemide.

Administration form: continuous intravenous infusion.

Dose: fixed doses of dopamine 2 μg/kg/minute and furosemide 0.01 mg/kg/hour.

Cointervention: both arms treated with albumin 20 g/day.

Outcomes

Primary outcomes: reversal of hepatorenal syndrome, 15 and 30 days' survival.

Secondary outcomes: cost of treatment.

Treatment duration

Treatment duration: 5 days.

Follow‐up: 30 days.

Country of origin

India.

Inclusion period

February 2005 to June 2010.

Notes

Full paper.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated random numbers.

Allocation concealment (selection bias)

Unclear risk

No description.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

No blinding of participants or personnel.

Blinding of outcome assessment (detection bias)
All outcomes

High risk

No blinding of outcome assessment.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No missing outcome data and all participants included in analyses.

Selective reporting (reporting bias)

High risk

Number of participants with (or without) reversal of hepatorenal syndrome not reported.

For‐profit bias

Low risk

Authors declared no conflict of interests. The randomised clinical trial received financial support from the Indian Council of Medical Research and did not receive funding from for‐profit organisations.

Overall risk of bias (non‐mortality outcomes)

High risk

Overall risk of bias (mortality)

High risk

Characteristics of excluded studies [ordered by study ID]

Jump to:

Study

Reason for exclusion

Boyer 2016

Comparing terlipressin with placebo.

Cavallin 2015

Compared bolus injections of terlipressin with continuous infusions of terlipressin.

Hadengue 1998

Compared terlipressin with placebo.

Martín‐Llahí 2008

Compared terlipressin with placebo.

Neri 2008

Compared terlipressin with placebo.

Nguyen‐Tat 2015

Observational study. No information about harms.

Pulvirenti 2008

Compared terlipressin with placebo.

Sanyal 2008

Compared terlipressin with placebo.

Silawat 2011

Quasi‐randomised trial. No information about harms.

Solanki 2003

Compared terlipressin with placebo.

Tavakkoli 2012

Compared noradrenaline with midodrine and octreotide.

Wan 2014

Compared high dose of terlipressin with low dose of terlipressin.

Yang 2001

Compared terlipressin with placebo.

Data and analyses

Open in table viewer
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]

Analysis 1.1

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

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

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]

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 2 Mortality: type of vasoactive drug.

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]

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 3 Mortality: type of hepatorenal syndrome.

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

Analysis 1.4

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

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

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]

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 5 Hepatorenal syndrome: type of vasoactive drug.

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]

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 6 Hepatorenal syndrome: type hepatorenal syndrome.

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]

Analysis 1.7

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

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

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]

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 8 Serious adverse events, type of vasoactive drug.

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

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 9 Serious adverse events, type of event.

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]

Analysis 1.10

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

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

11 Non‐serious adverse event: types Show forest plot

6

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 1.11

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

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

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]

Study flow diagram.
Figures and Tables -
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.
Figures and Tables -
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.
Figures and Tables -
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.
Figures and Tables -
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.
Figures and Tables -
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.
Figures and Tables -
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.
Figures and Tables -
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.
Figures and Tables -
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.
Figures and Tables -
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.
Figures and Tables -
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.
Figures and Tables -
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.
Figures and Tables -
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.
Figures and Tables -
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.
Figures and Tables -
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.
Figures and Tables -
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.
Figures and Tables -
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.
Figures and Tables -
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