Terlipressin versus placebo or no intervention for people with cirrhosis and hepatorenal syndrome

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

doi:10.1002/14651858.CD005162.pub4

Terlipresina versus placebo o ninguna intervención para pacientes con cirrosis y síndrome hepatorrenal

Contraer todo Desplegar todo

Referencias

Referencias de los estudios incluidos en esta revisión

Ir a:

estudios excluidos
estudios en curso
otras referencias
otras versiones publicadas

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.

Google Scholar

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. Gastroenterology2016; Vol. 150, issue 7:1579‐89.e2. [PUBMED: 26896734]

Google Scholar

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.

Google Scholar

Hadengue A, Gadano A, Moreau R, Giostra E, Durand F, Valla D, et al. Beneficial effects of the 2‐day administration of terlipressin in patients with cirrhosis and hepatorenal syndrome. Journal of Hepatology 1998;29:565‐70. [MEDLINE: PMID: 9824265]

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.

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. [ClinicalTrials.gov NCT00287664]

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]

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

Google Scholar

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.

Google Scholar

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]

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.

Google Scholar

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.

Google Scholar

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. [MEDLINE: PMID: 12542598]

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

Google Scholar

Zafar S, Haque I, UnTayyab G, Khan G, Chaudry N. Role of terlipressin and albumin combination versus albumin alone in hepatorenal syndrome. American Journal of Gastroenterology 2012;107:S175.

Referencias de los estudios excluidos de esta revisión

Ir a:

estudios incluidos
estudios en curso
otras referencias
otras versiones publicadas

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.

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.

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.

Google Scholar

Cavallin M, Merli M, Fasolato S, Toniutto P, Salerno F, Bernardi M, et al. Terlipressin and albumin vs midodrine plus octreotide in the treatment of hepatorenal syndrome in patients with cirrhosis: results of a controlled trial by the Italian Association for the Study of the Liver. Digestive and Liver Disease 2012;44:S10.

Cavallin M, Kamath PS, Merli M, Fasolato S, Toniutto P, Salerno F, et al. Italian Association for the Study of the Liver Study Group on Hepatorenal Syndrome. Terlipressin plus albumin versus midodrine and octreotide plus albumin in the treatment of hepatorenal syndrome: a randomized trial. Hepatology (Baltimore, Md.) 2015;62:567‐74.

Chelarescu D, Chelarescu O, Crumpie F, Staratan I. Captopril in low dose associated with octreotide in hepatorenal syndrome: a randomized study. Journal of Hepatology 2003;38:S56.

Indrabi RA, Zargar GJSA, Khan BA, Yattoo GN, Shah SH, Gulzar BM, 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.

Nguyen‐Tat M, Götz 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.

Google Scholar

Pomier‐Layrargues G, Paquin SC, Hassoun Z, Lafortune M, Tran A. Octreotide in hepatorenal syndrome: a randomized, double‐blind, placebo‐controlled, crossover study. Hepatology (Baltimore, Md.) 2003;38:238‐43.

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.

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.

Google Scholar

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(11):1946‐59.

Google Scholar

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 [高低剂量特利加压素治疗肝硬化合并1型肝肾综合征的比较]. Zhonghua Gan Zang Bing Za Zhi 2014;21:35.

Google Scholar

Referencias de los estudios en curso

Ir a:

estudios incluidos
estudios excluidos
otras referencias
otras versiones publicadas

A placebo‐controlled, double‐blind study to confirm the reversal of hepatorenal syndrome type 1 with terlipressin. Ongoing studySeptember 2010.

Referencias adicionales

Ir a:

estudios incluidos
estudios excluidos
estudios en curso
otras versiones publicadas

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. Journal of Hepatology 2015;62:968‐74. [PUBMED: 25638527]

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.

Brown P, Brunnhuber K, Chalkidou K, Chalmers I, Clarke M, Fenton M, et al. How to formulate research recommendations. BMJ (Clinical Research Ed.) 2006;333:804‐6.

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

Dobre M, Demirjian S, Sehgal AR, Navaneethan SD. Terlipressin in hepatorenal syndrome: a systematic review and meta‐analysis. International Urology and Nephrology 2011;43(1):175‐84.

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.

Freeman JG, Cobden I, Lishman AH, Record CO. Controlled trial of terlipressin ('Glypressin') versus vasopressin in the early treatment of oesophageal varices. Lancet 1982;2:66‐8.

Garcia‐Tsao G, Parikh CR, Viola A. Acute kidney injury and cirrhosis. Hepatology (Baltimore, Md.) 2008;48:2064‐77.

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. [MEDLINE: PMID: 8514039]

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

Gluud C, Nikolova D, Klingenberg SL. Cochrane Hepato‐Biliary Group. About Cochrane (Cochrane Review Groups (CRGs)) 2017, Issue 1. Art. No.: LIVER.

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

Google Scholar

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.

Hróbjartsson A, Gøtzsche PC. Is the placebo powerless? An analysis of clinical trials comparing placebo with no treatment. New England Journal of Medicine 2001;344:1594‐602.

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, M, Krag A, Gluud LL. Terlipressin versus other vasoactive drugs for hepatorenal syndrome. Cochrane Database of Systematic Reviews 2015, Issue 2. [DOI: 10.1002/14651858.CD011532]

Israelsen ME, Gluud LL, Krag A. Acute kidney injury and hepatorenal syndrome in cirrhosis. Journal of Gastroenterology and Hepatology 2015;30:236‐43.

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

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

Obritsch MD, Bestul DJ, Jung R, Fish DN, MacLaren R. The role of vasopressin in vasodilatory septic shock. Pharmacotherapy 2004;24:1050‐3.

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

The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014.

Royle P, Milne R. Literature searching for randomized controlled trials used in Cochrane reviews: rapid versus exhaustive searches. International Journal of Technology Assessment in Health Care 2003;19(4):591‐603.

Ruiz‐del‐Arbol L, Monescillo A, Arocena C, Valer P, Gines P, Moreira V, et al. Circulatory function and hepatorenal syndrome in cirrhosis. Hepatology (Baltimore, Md.) 2005;42:439‐47.

Sagi SV, Mittal S, Kasturi KS, Sood GK. Terlipressin therapy for reversal of type 1 hepatorenal syndrome: a meta‐analysis of randomized controlled trials. Journal of Gastroenterology and Hepatology 2010;25:880‐5.

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

Savović J, Jones H, Altman D, Harris R, Jűni P, Pildal J, et al. Influence of reported study design characteristics on intervention effect estimates from randomised controlled trials: combined analysis of meta‐epidemiological studies. Health Technology Assessments 2012;16:1‐82.

Shawcross DL, Davies NA, Mookerjee RP, Hayes PC, Williams R, Lee A, et al. Worsening of cerebral hyperemia by the administration of terlipressin in acute liver failure with severe encephalopathy. Hepatology (Baltimore, Md.) 2004;39:471‐5.

Stata Corp. STATA. Stata Corp, 2007.

Copenhagen Trial Unit. TSA ‐ Trial Sequential Analysis. Version 0.9 Beta. Copenhagen: Copenhagen Trial Unit, 2011.

Wood L, Egger M, Gluud LL, Schulz KF, Jüni P, Altman GD, et al. Empirical evidence of bias in treatment effect estimates in controlled trials with different interventions and outcomes: meta‐epidemiological study. BMJ (Clinical Research Ed.) 2008;336:601‐5.

Referencias de otras versiones publicadas de esta revisión

Ir a:

estudios incluidos
estudios excluidos
estudios en curso
otras referencias

Gluud LL, Kjaer MS, Christensen E. Terlipressin for hepatorenal syndrome. Cochrane Database of Systematic Reviews 2006, Issue 4. [DOI: 10.1002/14651858.CD005162]

Gluud LL, Christensen K, Christensen E, Krag A. Systematic review of randomized trials on vasoconstrictor drugs for hepatorenal syndrome. Hepatology (Baltimore, Md.) 2010;51(2):576‐84. [DOI: 10.1002/hep.23286]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Ir a:

estudios excluidos
estudios en curso

Boyer 2016

Methods	Double‐blind, multicentre RCT
Participants	Participants had cirrhosis and type 1 hepatorenal syndrome based on the 2007 International Club of Ascites criteria.
Interventions	Terlipressin/albumin versus placebo/albumin for a maximum of 14 days. The investigators discontinued treatment if serum creatinine was below 1.5 mg/dL at the initiation of renal replacement therapy or liver transplantation. Terlipressin 1 mg 4 times daily increased to 2 mg 6 times daily in non‐responders (participants without improved renal function). Albumin 20 to 40 g/day.
Outcomes	Duration of follow‐up: 90 days
Country of origin	United States and Canada
Inclusion period	October 2010 to February 2013
Proportion with type 1 hepatorenal syndrome	100%
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated random numbers
Allocation concealment (selection bias)	Low risk	Central randomisation
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Blinding of participants and personnel using placebo
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Blinding of outcome assessors using placebo
Incomplete outcome data (attrition bias) All outcomes	Low risk	All participants included in the analyses based on the intention‐to‐treat principle. Information about clinical outcomes was available for all participants.
Selective reporting (reporting bias)	Low risk	Clinically relevant outcomes reported as described in the protocol and online trial registration.
For‐profit funding	High risk	Ikaria Therapeutics LLC funded the trial.
Other bias	Low risk	No other biases identified.
Overall risk of bias (mortality)	High risk	High risk of bias
Overall risk of bias (non‐mortality outcomes)	High risk	High risk of bias

Hadengue 1998

Methods	Double‐blind, single‐centre RCT.
Participants	Mean age: terlipressin group: 53 years placebo group: 53 years Proportion of men: 56% Proportion with alcoholic liver disease: 78%
Interventions	Terlipressin versus placebo Terlipressin 1 mg twice daily for 2 days.
Outcomes	Duration of follow‐up: end of treatment
Country of origin	France
Inclusion period	Not described
Proportion with type 1 hepatorenal syndrome	100%
Notes	We did not include the trial in our analyses of hepatorenal syndrome because we did not have information about the outcome measure from the first period.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not described
Allocation concealment (selection bias)	Low risk	Identical coded drug containers
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Blinding of participants and personnel achieved through double‐blinding using terlipressin placebo.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Blinding of outcome assessment achieved through double‐blinding using terlipressin placebo.
Incomplete outcome data (attrition bias) All outcomes	High risk	The trial report states that the analyses excluded 3 participants.
Selective reporting (reporting bias)	Low risk	Clinically relevant outcomes reported.
For‐profit funding	High risk	The trial received funding from Ferring S.A., France.
Other bias	Low risk	No other biases identified.
Overall risk of bias (mortality)	High risk	High risk of bias
Overall risk of bias (non‐mortality outcomes)	High risk	High risk of bias

Martín‐Llahí 2008

Methods	Open, multicentre RCT
Participants	Mean age: terlipressin/albumin group: 59 years albumin group: 52 years Proportion of men: 63% Proportion with alcoholic liver disease: 72%
Interventions	Terlipressin/albumin versus albumin for a maximum of 15 days Terlipressin 1 mg 6 times daily. If no improvement in renal function was observed, the dose was increased to 2 mg 6 times daily. Albumin 1 g/kg for 24 hours then 40 g/day adjusted according to the central venous pressure.
Outcomes	Duration of follow‐up: 3 months after treatment
Country of origin	Spain
Inclusion period	January 2002 to February 2006
Proportion with type 1 hepatorenal syndrome	56%
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated random numbers
Allocation concealment (selection bias)	Low risk	Central randomisation
Blinding of participants and personnel (performance bias) All outcomes	High risk	No blinding of participants or personnel (open trial)
Blinding of outcome assessment (detection bias) All outcomes	High risk	No blinding of outcome assessment (open trial)
Incomplete outcome data (attrition bias) All outcomes	Low risk	No losses to follow‐up, and all participants included in the analyses.
Selective reporting (reporting bias)	Low risk	Clinically relevant outcome measures reported. Primary outcome measures: mortality after 3 months; and improvement in renal function.
For‐profit funding	Low risk	The trial did not receive funding from pharmaceutical companies (reported in the discussion).
Other bias	Low risk	No other biases identified.
Overall risk of bias (mortality)	Low risk	Low risk of bias
Overall risk of bias (non‐mortality outcomes)	High risk	High risk of bias

Neri 2008

Methods	Open, multicentre RCT
Participants	Mean age: terlipressin and albumin group: 59 years albumin group: 60 years Proportion of men: 40% Proportion with alcoholic liver disease: 13%
Interventions	Terlipressin/albumin versus albumin for 19 days Terlipressin 1 mg 4 times daily for 5 days then 0.5 mg 4 times daily for 14 days. Albumin 1 g/kg for 24 hours then 40 to 80 g/day.
Outcomes	Duration of follow‐up: 6 months after hospital discharge
Country of origin	Italy
Inclusion period	December 2002 to December 2005
Proportion with type 1 hepatorenal syndrome	100%
Notes	Participants with recurrence of hepatorenal syndrome after the initial treatment received terlipressin and albumin.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated list of random numbers
Allocation concealment (selection bias)	Low risk	Central randomisation
Blinding of participants and personnel (performance bias) All outcomes	High risk	No blinding of participants or personnel (open trial)
Blinding of outcome assessment (detection bias) All outcomes	High risk	No blinding of outcome assessment (open trial)
Incomplete outcome data (attrition bias) All outcomes	Low risk	No losses to follow‐up
Selective reporting (reporting bias)	Low risk	Clinically relevant outcome measures reported. Primary outcome measure: resolution of hepatorenal syndrome defined as normalisation of creatinine.
For‐profit funding	Unclear risk	Funding not reported. Email requesting information about funding sent 17 February 2016.
Other bias	Low risk	No other biases
Overall risk of bias (mortality)	High risk	High risk of bias
Overall risk of bias (non‐mortality outcomes)	High risk	High risk of bias

Pulvirenti 2008

Methods	Open, single‐centre RCT.
Participants	Mean age: terlipressin group: 58 years albumin group: 61 years Proportion of men: 37% Proportion with alcoholic liver disease: 13%
Interventions	Terlipressin/albumin versus albumin for a maximum of 15 days Terlipressin 1 mg/hour for the first day, then 0.5 mg/8 hours for the next 12 days. Albumin 1 g/kg/day for 5 days.
Outcomes	Duration of follow‐up: 180 days after treatment
Country of origin	Italy
Inclusion period	June 2004 to March 2006
Proportion with type 1 hepatorenal syndrome	100%
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated list of random numbers
Allocation concealment (selection bias)	Low risk	Central randomisation
Blinding of participants and personnel (performance bias) All outcomes	High risk	No blinding of participants or personnel (open trial)
Blinding of outcome assessment (detection bias) All outcomes	High risk	No blinding of outcome assessment (open trial)
Incomplete outcome data (attrition bias) All outcomes	Low risk	No losses to follow‐up
Selective reporting (reporting bias)	Low risk	Clinically relevant outcome measures reported.
For‐profit funding	Unclear risk	Funding not reported. Email requesting information about funding sent 17 February 2016.
Other bias	Low risk	No other biases
Overall risk of bias (mortality)	High risk	High risk of bias
Overall risk of bias (non‐mortality outcomes)	High risk	High risk of bias

Sanyal 2008

Methods	Double‐blind, multicentre RCT
Participants	Mean age: terlipressin/albumin group: 51 years placebo/albumin group: 53 years Proportion of men: 71% Proportion with alcoholic liver disease: 36%
Interventions	Terlipressin/albumin versus placebo/albumin for a maximum of 14 days Terlipressin 1 mg 4 times daily increased to 2 mg 4 times daily if serum creatinine had not decreased by at least 30%. Albumin 100 g for 24 hours then 25 g daily.
Outcomes	Duration of follow‐up: 6 months
Country of origin	United States, Germany, and Russia
Inclusion period	June 2004 to September 2006
Proportion with type 1 hepatorenal syndrome	100%
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated random numbers
Allocation concealment (selection bias)	Low risk	Central randomisation
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Blinding of participants and personnel achieved through double‐blinding using terlipressin placebo.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Blinding of outcome assessment achieved through double‐blinding using terlipressin placebo.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Intention‐to‐treat analyses including all participants randomised are reported. No outcomes reported after censoring.
Selective reporting (reporting bias)	Low risk	Clinically relevant outcome measures reported. Primary outcome measure: treatment success at day 14 defined as normalisation of serum creatinine on 2 measurements with at least 48‐hour intervals and no dialysis, death, or recurrence of hepatorenal syndrome type 1 before day 15
For‐profit funding	High risk	Industry funding (Orphan Therapeutics)
Other bias	Low risk	No other biases
Overall risk of bias (mortality)	High risk	High risk of bias
Overall risk of bias (non‐mortality outcomes)	High risk	High risk of bias

Solanki 2003

Methods	Open, single‐centre RCT
Participants	Mean age: terlipressin/albumin group: 51 years albumin group: 52 years Proportion of men: 71% Proportion with alcoholic liver disease: 33%
Interventions	Terlipressin/albumin versus placebo/albumin for 15 days Terlipressin 1 mg twice daily. Albumin 20 g daily.
Outcomes	Duration of follow‐up: end of treatment
Country of origin	India
Inclusion period	Not described
Proportion with type 1 hepatorenal syndrome	100%
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random‐number table
Allocation concealment (selection bias)	Low risk	Centralised randomisation through an independent statistician
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	The authors state that the trial is single‐blind, but do not describe the method of blinding.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	The authors state that the trial is single‐blind, but do not describe the method of blinding.
Incomplete outcome data (attrition bias) All outcomes	Low risk	There were no losses to follow‐up.
Selective reporting (reporting bias)	Low risk	Clinically relevant outcome measures reported.
For‐profit funding	Unclear risk	Funding not reported.
Other bias	Low risk	No other biases
Overall risk of bias (mortality)	High risk	High risk of bias
Overall risk of bias (non‐mortality outcomes)	High risk	High risk of bias

Yang 2001

Methods	Open, single‐centre RCT
Participants	Participant characteristics (n = 50) not reported.
Interventions	Terlipressin versus no intervention for 15 days Terlipressin 1 mg twice daily.
Outcomes	Duration of follow‐up: 15 days
Country of origin	China
Inclusion period	Not reported
Proportion with type 1 hepatorenal syndrome	100%
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not described
Allocation concealment (selection bias)	Unclear risk	Not described
Blinding of participants and personnel (performance bias) All outcomes	High risk	No blinding of participants or personnel (open trial)
Blinding of outcome assessment (detection bias) All outcomes	High risk	No blinding of outcome assessment (open trial)
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Unclear reporting of losses to follow‐up
Selective reporting (reporting bias)	Low risk	Clinically relevant outcome measures reported. Primary outcome measure: reversal of hepatorenal syndrome
For‐profit funding	Unclear risk	Funding not reported.
Other bias	Low risk	No other biases
Overall risk of bias (mortality)	High risk	High risk of bias
Overall risk of bias (non‐mortality outcomes)	High risk	High risk of bias

Zafar 2012

Methods	Open, multicentred RCT.
Participants	Participant characteristics not reported.
Interventions	Terlipressin/albumin versus albumin for 10 days (range 8 to 12 days) Terlipressin (1 mg/4 hourly). Albumin (1 g/kg followed by 20 to 40 g/day).
Outcomes	Not reported
Country of origin	Pakistan
Inclusion period	Not reported
Proportion with type 1 hepatorenal syndrome	Not reported
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not described
Allocation concealment (selection bias)	Unclear risk	Not described
Blinding of participants and personnel (performance bias) All outcomes	High risk	No blinding of participants or personnel (open trial)
Blinding of outcome assessment (detection bias) All outcomes	High risk	No blinding of outcome assessment (open trial)
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Not described
Selective reporting (reporting bias)	Low risk	Clinically relevant outcome measures reported.
For‐profit funding	Unclear risk	Not described
Other bias	Low risk	No other biases
Overall risk of bias (mortality)	High risk	High risk of bias
Overall risk of bias (non‐mortality outcomes)	High risk	High risk of bias

RCTs: randomised clinical trial

Characteristics of excluded studies [ordered by study ID]

Ir a:

estudios incluidos
estudios en curso

Study	Reason for exclusion
Alessandria 2007	RCT on noradrenaline/albumin versus terlipressin/albumin for hepatorenal syndrome.
Angeli 2008	RCT comparing different modes of administering terlipressin/albumin for hepatorenal syndrome.
Cavallin 2012	RCT on terlipressin/albumin versus midodrine/octreotide/albumin for hepatorenal syndrome.
Cavallin 2015	RCT comparing terlipressin versus midodrine/octreotide for people with hepatorenal syndrome.
Chelarescu 2003	RCT comparing captopril/octreotide versus octreotide published in abstract form.
Indrabi 2013	RCT on noradrenalin/albumin versus terlipressin/albumin for hepatorenal syndrome.
Nguyen‐Tat 2015	Observational study on terlipressin for hepatorenal syndrome.
Pomier 2003	Cross‐over trial on octreotide for hepatorenal syndrome.
Sharma 2008	RCT on noradrenalin/albumin versus terlipressin/albumin for hepatorenal syndrome.
Silawat 2011	RCT on dopamine versus terlipressin/albumin for hepatorenal syndrome.
Wan 2014	RCT comparing low and high‐dose of terlipressin for hepatorenal syndrome type 1.

Characteristics of ongoing studies [ordered by study ID]

Ir a:

estudios incluidos
estudios excluidos

NCT01143246

Trial name or title	A placebo‐controlled, double‐blind study to confirm the reversal of hepatorenal syndrome type 1 with terlipressin
Methods	Study type: interventional Study design: allocation: randomised Endpoint classification: safety/efficacy study Intervention model: parallel assignment Masking: double‐blind (participant, investigator) Primary purpose: treatment
Participants	Cirrhosis, ascites, and hepatorenal syndrome type 1
Interventions	Drug: terlipressin Blinded terlipressin reconstituted with 5 mL of sterile 0.9% sodium chloride solution for injection will be administered intravenously as a slow bolus injection over 2 minutes at a dose of 1 mg (1 vial) every 6 hours (4 mg/day). Other name: Lucassin Drug: placebo Lyophilised mannitol reconstituted with 5 mL of sterile 0.9% sodium chloride solution administered intravenously as a slow bolus injection over 2 minutes at a dose of 1 mg (1 vial) every 6 hours (4 mg/day).
Outcomes	Confirmed hepatorenal syndrome reversal: the percentage of participants with 2 serum creatinine values of ≤ 133 µmol/L (1.5 mg/dL) at least 48 hours apart, on treatment, and without intervening renal replacement therapy or liver transplant.
Starting date	September 2010
Contact information	Diane Stebbins [email protected]
Notes	Estimated enrolment: 180

Data and analyses

Open in table viewer

Comparison 1. Terlipressin alone or with albumin versus no intervention or albumin

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality Show forest plot	9	534	Risk Ratio (M‐H, Random, 95% CI)	0.85 [0.73, 0.98]
Open in figure viewer Analysis 1.1 Comparison 1 Terlipressin alone or with albumin versus no intervention or albumin, Outcome 1 Mortality.
1.1 Type 1 hepatorenal syndrome	7	438	Risk Ratio (M‐H, Random, 95% CI)	0.78 [0.63, 0.98]
1.2 Type 1 or 2 hepatorenal syndrome	2	96	Risk Ratio (M‐H, Random, 95% CI)	0.92 [0.75, 1.14]
2 Mortality in randomised clinical trials evaluating terlipressin and albumin Show forest plot	7	510	Risk Ratio (M‐H, Random, 95% CI)	0.82 [0.67, 1.01]
Open in figure viewer Analysis 1.2 Comparison 1 Terlipressin alone or with albumin versus no intervention or albumin, Outcome 2 Mortality in randomised clinical trials evaluating terlipressin and albumin.
3 Hepatorenal syndrome Show forest plot	7	510	Risk Ratio (M‐H, Random, 95% CI)	0.63 [0.48, 0.82]
Open in figure viewer Analysis 1.3 Comparison 1 Terlipressin alone or with albumin versus no intervention or albumin, Outcome 3 Hepatorenal syndrome.
3.1 Type 1 hepatorenal syndrome	6	449	Risk Ratio (M‐H, Random, 95% CI)	0.64 [0.47, 0.87]
3.2 Type 2 hepatorenal syndrome	1	11	Risk Ratio (M‐H, Random, 95% CI)	0.39 [0.14, 1.08]
3.3 Type 1 or 2 hepatorenal syndrome	1	50	Risk Ratio (M‐H, Random, 95% CI)	0.65 [0.46, 0.92]
4 Serious adverse events, total number Show forest plot	9	534	Risk Ratio (M‐H, Random, 95% CI)	0.91 [0.68, 1.21]
Open in figure viewer Analysis 1.4 Comparison 1 Terlipressin alone or with albumin versus no intervention or albumin, Outcome 4 Serious adverse events, total number.
5 Serious adverse events, types Show forest plot	5		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.5 Comparison 1 Terlipressin alone or with albumin versus no intervention or albumin, Outcome 5 Serious adverse events, types.
5.1 Cardovascular adverse events	4	234	Risk Ratio (M‐H, Random, 95% CI)	7.26 [1.70, 31.05]
5.2 Circulatory overload	1	46	Risk Ratio (M‐H, Random, 95% CI)	1.75 [0.59, 5.17]
5.3 Gastrointestinal bleeding	1	46	Risk Ratio (M‐H, Random, 95% CI)	0.67 [0.22, 2.05]
5.4 Hepatic encephalopathy	1	46	Risk Ratio (M‐H, Random, 95% CI)	1.0 [0.68, 1.47]
5.5 Respiratory distress/acidosis	2	300	Risk Ratio (M‐H, Random, 95% CI)	1.97 [0.84, 4.60]
5.6 Bacterial inflections	1	46	Risk Ratio (M‐H, Random, 95% CI)	0.75 [0.39, 1.43]
6 Non‐serious adverse events Show forest plot	5		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.6 Comparison 1 Terlipressin alone or with albumin versus no intervention or albumin, Outcome 6 Non‐serious adverse events.
6.1 Total number	5	406	Risk Ratio (M‐H, Random, 95% CI)	1.25 [0.58, 2.68]
6.2 Abdominal pain	4	294	Risk Ratio (M‐H, Random, 95% CI)	1.54 [0.97, 2.43]
6.3 Chest pain	1	52	Risk Ratio (M‐H, Random, 95% CI)	5.00 [0.25, 99.34]
6.4 Livedo reticularis	1	112	Risk Ratio (M‐H, Random, 95% CI)	3.00 [0.12, 72.10]
6.5 Diarrhoea	2	240	Risk Ratio (M‐H, Random, 95% CI)	5.76 [2.19, 15.15]

Figure 1

Study flow diagram.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Figure 2

Methodological quality summary: review authors' judgments about each methodological quality item for each included study.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Figure 3

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

Ir a la figura de la revisiónAbrir en una pestaña nueva

Figure 4

Trial Sequential Analysis of eight randomised clinical trials (525 participants) evaluating terlipressin versus placebo or no intervention for people with hepatorenal syndrome on mortality. Data from Hadengue 1998 is not included due to lack of events. The analysis is made with power 90%, alpha 3%, a relative risk reduction (RRR) of 25%, a control group risk (CGR) of mortality of 61.5%, and a model variance ‐based heterogeneity correction of 30%. The risk ratio is 0.85 (95% confidence interval 0.70 to 1.02). The cumulative Z‐curve (blue line) does not cross the diversity‐adjusted trial monitoring boundary for benefit.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Figure 5

Trial Sequential Analysis of seven randomised clinical trials (510 participants) evaluating terlipressin versus placebo/no intervention for people with hepatorenal syndrome on lack of reversal of hepatorenal syndrome. The analysis is 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 88%, and a heterogeneity correction of 70%. The risk ratio is 0.64 (95% confidence interval 0.46 to 0.89). The cumulative Z‐curve (blue line) crosses the diversity‐adjusted trial monitoring boundary for benefit during the fourth trial.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Figure 6

Trial Sequential Analysis of four randomised clinical trials (234 participants) evaluating terlipressin versus placebo or no intervention for people with hepatorenal syndrome on cardiovascular adverse events. The analysis is 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 risk ratio is 7.26 (95% confidence interval 1.70 to 31.05). The diversity‐adjusted trial monitoring boundary for harm is not included in the figure due to insufficient information. The estimated required information size is 4831 participants. Accordingly, with an accrued number of participants of 234, only 4.8% of the required number of participants has been achieved.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.1

Comparison 1 Terlipressin alone or with albumin versus no intervention or albumin, Outcome 1 Mortality.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.2

Comparison 1 Terlipressin alone or with albumin versus no intervention or albumin, Outcome 2 Mortality in randomised clinical trials evaluating terlipressin and albumin.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.3

Comparison 1 Terlipressin alone or with albumin versus no intervention or albumin, Outcome 3 Hepatorenal syndrome.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.4

Comparison 1 Terlipressin alone or with albumin versus no intervention or albumin, Outcome 4 Serious adverse events, total number.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.5

Comparison 1 Terlipressin alone or with albumin versus no intervention or albumin, Outcome 5 Serious adverse events, types.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.6

Comparison 1 Terlipressin alone or with albumin versus no intervention or albumin, Outcome 6 Non‐serious adverse events.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Summary of findings for the main comparison. Terlipressin versus placebo or no intervention for hepatorenal syndrome

Terlipressin versus placebo or no intervention for hepatorenal syndrome. Administration of albumin allowed if administered to both the intervention and comparison group
Patient or population: people with hepatorenal syndrome Setting: hospital Intervention: terlipressin alone or terlipressin plus albumin Comparison: placebo or no intervention or albumin
Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments
	Risk with placebo or no intervention	Risk with terlipressin
Mortality	Study population		RR 0.85 (0.73 to 0.98)	534 (9 RCTs)	⊕⊕⊝⊝ LOW¹	Downgraded because of i) clinical heterogeneity and ii) the results of the Trial Sequential Analysis
	688 per 1000	536 per 1000 (433 to 660)
	Moderate
	625 per 1000	488 per 1000 (394 to 600)
Hepatorenal syndrome	Study population		RR 0.63 (0.48 to 0.82)	510 (7 RCTs)	⊕⊕⊝⊝ LOW	Downgraded because of i) clinical heterogeneity and ii) all trials are judged as 'high risk of bias'.
	879 per 1000	510 per 1000 (431 to 606)
	Moderate
	875 per 1000	507 per 1000 (429 to 604)
Serious adverse events	Study population		RR 0.91 (0.68 to 1.21)	534 (9 RCTs)	⊕⊕⊝⊝ LOW	Downgraded because of i) clinical heterogeneity and ii) all RCTs are judged as high risk of bias.
	85 per 1000	212 per 1000 (131 to 344)
Serious cardiovascular adverse events	Study population		RR 7.26 (1.70 to 31.05)	234 (4 RCTs)	⊕⊕⊝⊝ LOW	Downgraded because of i) clinical heterogeneity and ii) all RCTs are judged as high risk of bias
	16 per 1000	111 per 1000
Abdominal pain	Study population		RR 1.54 (0.97 to 2.43)	294 (4 RCTs)	⊕⊕⊝⊝ LOW¹	Downgraded because of i) clinical heterogeneity and ii) all RCTs are judged as high risk of bias
	149 per 1000	229 per 1000
Diarrhoea	Study population		RR 5.76 (2.19 to 15.15)	240 (2 RCTs)	⊕⊕⊝⊝ LOW	Downgraded because of i) clinical heterogeneity and ii) all RCTs are judged as high risk of bias
	33 per 1000	190 per 1000
*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.
¹Not confirmed in analyses of randomised clinical trials (RCTs) with a low risk of bias.

Summary of findings for the main comparison. Terlipressin versus placebo or no intervention for hepatorenal syndrome

Ir a la tabla de la revisión

Comparison 1. Terlipressin alone or with albumin versus no intervention or albumin

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality Show forest plot	9	534	Risk Ratio (M‐H, Random, 95% CI)	0.85 [0.73, 0.98]

1.1 Type 1 hepatorenal syndrome	7	438	Risk Ratio (M‐H, Random, 95% CI)	0.78 [0.63, 0.98]
1.2 Type 1 or 2 hepatorenal syndrome	2	96	Risk Ratio (M‐H, Random, 95% CI)	0.92 [0.75, 1.14]
2 Mortality in randomised clinical trials evaluating terlipressin and albumin Show forest plot	7	510	Risk Ratio (M‐H, Random, 95% CI)	0.82 [0.67, 1.01]

3 Hepatorenal syndrome Show forest plot	7	510	Risk Ratio (M‐H, Random, 95% CI)	0.63 [0.48, 0.82]

3.1 Type 1 hepatorenal syndrome	6	449	Risk Ratio (M‐H, Random, 95% CI)	0.64 [0.47, 0.87]
3.2 Type 2 hepatorenal syndrome	1	11	Risk Ratio (M‐H, Random, 95% CI)	0.39 [0.14, 1.08]
3.3 Type 1 or 2 hepatorenal syndrome	1	50	Risk Ratio (M‐H, Random, 95% CI)	0.65 [0.46, 0.92]
4 Serious adverse events, total number Show forest plot	9	534	Risk Ratio (M‐H, Random, 95% CI)	0.91 [0.68, 1.21]

5 Serious adverse events, types Show forest plot	5		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

5.1 Cardovascular adverse events	4	234	Risk Ratio (M‐H, Random, 95% CI)	7.26 [1.70, 31.05]
5.2 Circulatory overload	1	46	Risk Ratio (M‐H, Random, 95% CI)	1.75 [0.59, 5.17]
5.3 Gastrointestinal bleeding	1	46	Risk Ratio (M‐H, Random, 95% CI)	0.67 [0.22, 2.05]
5.4 Hepatic encephalopathy	1	46	Risk Ratio (M‐H, Random, 95% CI)	1.0 [0.68, 1.47]
5.5 Respiratory distress/acidosis	2	300	Risk Ratio (M‐H, Random, 95% CI)	1.97 [0.84, 4.60]
5.6 Bacterial inflections	1	46	Risk Ratio (M‐H, Random, 95% CI)	0.75 [0.39, 1.43]
6 Non‐serious adverse events Show forest plot	5		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

6.1 Total number	5	406	Risk Ratio (M‐H, Random, 95% CI)	1.25 [0.58, 2.68]
6.2 Abdominal pain	4	294	Risk Ratio (M‐H, Random, 95% CI)	1.54 [0.97, 2.43]
6.3 Chest pain	1	52	Risk Ratio (M‐H, Random, 95% CI)	5.00 [0.25, 99.34]
6.4 Livedo reticularis	1	112	Risk Ratio (M‐H, Random, 95% CI)	3.00 [0.12, 72.10]
6.5 Diarrhoea	2	240	Risk Ratio (M‐H, Random, 95% CI)	5.76 [2.19, 15.15]

Comparison 1. Terlipressin alone or with albumin versus no intervention or albumin

Ir a la tabla de la revisión

	Idioma de la Revisión Cochrane Escoja su idioma de preferencia para las revisiones Cochrane y otros contenidos. Las secciones sin una traducción aparecerán en inglés.

	Idioma de la web Escoja su idioma de preferencia para la web de la Biblioteca Cochrane.

Idioma de la Revisión Cochrane

Idioma de la web

Referencias

Referencias de los estudios incluidos en esta revisión

Boyer 2016 {published data only}

Hadengue 1998 {published data only}

Martín‐Llahí 2008 {published data only}

Neri 2008 {published data only}

Pulvirenti 2008 {published data only}

Sanyal 2008 {published data only}

Solanki 2003 {published data only}

Yang 2001 {published data only}

Zafar 2012 {published data only}

Referencias de los estudios excluidos de esta revisión

Alessandria 2007 {published data only}

Angeli 2008 {published data only}

Cavallin 2012 {published data only}

Cavallin 2015 {published data only}

Chelarescu 2003 {published data only}

Indrabi 2013 {published data only}

Nguyen‐Tat 2015 {published data only}

Pomier 2003 {published data only}

Sharma 2008 {published data only}

Silawat 2011 {published data only (unpublished sought but not used)}

Wan 2014 {published data only}

Referencias de los estudios en curso

NCT01143246 {unpublished data only}

Referencias adicionales

Angeli 2015

Arroyo 1996

Brown 2006

Cardenas 2003

Dobre 2010

Fabrizi 2009

Freeman 1982

Garcia‐Tsao 2008

Gines 1993

Gines 2003

Gluud 2017

GRADEpro [Computer program]

Higgins 2011

Hróbjartsson 2001

ICH‐GCP 1997

Israelsen 2015a

Israelsen 2015b

Krag 2008

Moller 2004

Obritsch 2004

Pasqualetti 1998

RevMan 2014 [Computer program]

Royle 2003

Ruiz del Arbol 2005

Sagi 2010

Salerno 2007

Savović 2012

Shawcross 2004

STATA [Computer program]

TSA 2011 [Computer program]

Wood 2008

Referencias de otras versiones publicadas de esta revisión

Gluud 2006

Gluud 2010

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Characteristics of excluded studies [ordered by study ID]

Characteristics of ongoing studies [ordered by study ID]

Data and analyses

Copiar o descargar referencia

Idioma de la Revisión Cochrane

Idioma de la web

Instituciones a las que se accedió previamente

Usuarios institucionales

Instituciones a las que se accedió previamente

Otras opciones de acceso