Feature Articles

The Comparative Effectiveness of Vasoactive Treatments for Hepatorenal Syndrome: A Systematic Review and Network Meta-Analysis*

Pitre, Tyler MD¹; Kiflen, Michel MSc^2,3; Helmeczi, Wryan MD⁴; Dionne, Joanna C. PhD^5,6; Rewa, Oleksa MD⁷; Bagshaw, Sean M. MD⁷; Needham-Nethercott, Natalie MD^8,9; Alhazzani, Waleed MD^5,6; Zeraatkar, Dena PhD^6,10; Rochwerg, Bram MD^5,6

Author Information

¹ Department of Internal Medicine, McMaster University, Hamilton, ON, Canada.

² Department of Medicine, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada.

³ Population Health Research Institute, McMaster University, Hamilton, ON, Canada.

⁴ Division of Internal Medicine, University of Ottawa, Ottawa, ON, Canada.

⁵ Department of Medicine (Division of Critical Care), McMaster University, Hamilton, ON, Canada.

⁶ Department of Health Research Methods, Evidence & Impact, McMaster University, Hamilton, ON, Canada.

⁷ Department of Critical Care Medicine, Faculty of Medicine and Dentistry, University of Alberta and Alberta Health Services, Edmonton, AB, Canada.

⁸ Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada.

⁹ Department of Critical Care, Grand River Hospital, Kitchener, ON, Canada.

¹⁰ Department of Bioinformatics, Harvard Medical School, Harvard University, Cambridge, MA.

*See also p. 1533.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal).

Drs. Zeraatkar and Rochwerg are senior authors.

Dr. Pitre is the main author; he developed the study idea and design and helped collect the data and perform the statistical analysis under supervision of Dr. Zeraatkar. He wrote the first draft of the article. Mr. Kiflen helped collect data, rate the risk of bias, and write the article. Dr. Helmeczi helped collect data, helped write the article, and provide other supportive tasks. Drs. Dionne, Rewa, Bagshaw, Needham-Nethercott, and Alhazzani provided clinical expertise in developing the methods, interpreting the results, and writing/copy-editing the article. Drs. Zeraatkar and Rochwerg cosupervised the study, providing key methodological and statistical support, as well as approving and extensively editing the final article.

Dr. Rewa discloses payments or Honoria from Baxter Healthcare and participates on a data safety monitor board for Leadiant Biosciences, and received payments. Dr. Bagshaw discloses payments or Honoria from Baxter Health and participates on a data safety monitoring board for I-SPY COVID, and received payments. Dr. Rewa received funding from Leading Biosciences. Dr. Bagshaw received funding from BioPorto. The remaining authors have disclosed that they do not have any potential conflicts of interest.

Registration: OSF: https://osf.io/nq9k2.

For information regarding this article, E-mail: [email protected]

Critical Care Medicine 50(10):p 1419-1429, October 2022. | DOI: 10.1097/CCM.0000000000005595

Abstract

OBJECTIVE:

Hepatorenal syndrome (HRS) is associated with high rates of morbidity and mortality. Evidence examining commonly used drug treatments remains uncertain. We assessed the comparative effectiveness of inpatient treatments for HRS by performing a network meta-analysis of randomized clinical trials (RCTs).

DATA SOURCES:

We searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Medline In-Process & Other Non-Indexed Citations, Scopus, and Web of Science from inception.

STUDY SELECTION AND DATA EXTRACTION:

Pairs of reviewers independently identified eligible RCTs that enrolled patients with type 1 or 2 HRS. Pairs of reviewers independently extracted data.

DATA SYNTHESIS:

We assessed risk of bias using the Cochrane tool for RCTs and certainty of evidence using the Grading of Recommendations, Assessment, Development and Evaluations approach. Our main outcomes are all-cause mortality, HRS reversal, and serious adverse events. Of 3,079 citations, we included 26 RCTs examining 1,736 patients. Based on pooled analysis, terlipressin increases HRS reversal compared with placebo (142 reversals per 1,000 [95% CI, >87.7 to >210.9]; high certainty). Norepinephrine (112.7 reversals per 1,000 [95% CI, 52.6 to >192.3]) may increase HRS reversal compared with placebo (low certainty). The effect of midodrine+octreotide (67.8 reversals per 1,000 [95% CI, <2.8 to >177.4]; very low) on HRS reversal is uncertain. Terlipressin may reduce mortality compared with placebo (93.7 fewer deaths [95% CI, 168.7 to <12.5]; low certainty). Terlipressin probably increases the risk of serious adverse events compared with placebo (20.4 more events per 1,000 [95% CI, <5.1 to >51]; moderate certainty).

CONCLUSIONS:

Terlipressin increases HRS reversal compared with placebo. Terlipressin may reduce mortality. Until access to terlipressin improves, initial norepinephrine administration may be more appropriate than initial trial with midodrine+octreotide. Our review has the potential to inform future guideline and practice in the treatment of HRS.