
==== Front
Hepatol Commun
Hepatol Commun
HC9
Hepatology Communications
2471-254X
Lippincott Williams & Wilkins Hagerstown, MD

39298544
HEP4-24-0318
10.1097/HC9.0000000000000526
00001
3
Original Article
Incidence and type of adverse events in patients with cirrhosis receiving terlipressin: A systematic review and meta-analysis
Shang Yiyang 121652439647@qq.com

Wang Cai’e 12wangcaie1126@foxmail.com

Lu Huiyuan 121807589765@qq.com

Chai Lu 12chailu0309@163.com

Xu Wentao 12
Bernardi Mauro 3mauro.bernardi@unibo.it

https://orcid.org/0000-0002-9448-6739
Qi Xingshun 12xingshunqi@126.com

1 Liver Cirrhosis Study Group, Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang, China
2 Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang, China
3 Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
Correspondence Xingshun Qi, Liver Cirrhosis Study Group, Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang 110840, Liaoning Province, China. Email: xingshunqi@126.com Mauro Bernardi, Department of Medical and Surgical Sciences, University of Bologna, Policlinico di Sant'Orsola, via Albertoni 15, 40128 Bologna, Italy. Email: mauro.bernardi@unibo.it
10 2024
18 9 2024
8 10 e052626 3 2024
25 7 2024
Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/

Background:

Terlipressin has been widely used for various cirrhosis-related complications, but its safety profile remains controversial. Herein, this issue was systematically evaluated.

Methods:

All studies reporting adverse events (AEs) of terlipressin in cirrhosis were screened. Incidences were pooled using a random-effects model. Subgroup analyses were performed according to the patient’s characteristics and treatment regimens. Interaction among subgroups was evaluated.

Results:

Seventy-eight studies with 7257 patients with cirrhosis were included. The pooled incidences of any AEs, treatment-related AEs, any serious AEs (SAEs), treatment-related SAEs, treatment withdrawal due to AEs, and treatment withdrawal due to treatment-related AEs were 31%, 22%, 5%, 5%, 4%, and 4% in patients with cirrhosis receiving terlipressin, respectively. Patients with hepatorenal syndrome had higher incidences of any SAEs (29% vs. 0% vs. 0%, p interaction = 0.01) and treatment-related SAEs (8% vs. 1% vs. 7%, p interaction = 0.02) than those with variceal bleeding or ascites. Patients who received terlipressin with human albumin had higher incidences of any SAEs (18% vs. 1%, p interaction = 0.04) and treatment-related SAEs (7% vs. 0%, p interaction = 0.09) than those without albumin. Patients with total bilirubin level >4.3 mg/dL had higher incidences of any AEs (69% vs. 24%, p interaction = 0.02), any SAEs (64% vs. 0%, p interaction < 0.01), and treatment-related SAEs (8% vs. 1%, p interaction = 0.04) than those ≤4.3 mg/dL.

Conclusions:

AEs are common in patients with cirrhosis receiving terlipressin and influenced by clinical scenarios, combination with albumin, and bilirubin levels.

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OPEN-ACCESSTRUE
SDCT
==== Body
pmcINTRODUCTION

Liver cirrhosis, the terminal stage of chronic liver disease,1 is the 15th leading cause of disability-adjusted life-years and the 11th leading cause of death worldwide.2,3 Acute variceal bleeding (AVB), ascites, and hepatorenal syndrome (HRS) are potentially lethal complications of cirrhosis. Indeed, the mortality is up to 20% within 6 weeks in patients with AVB, 40% within 1 year in those developing ascites, and 46% during hospitalization in those with HRS.4,5

Terlipressin, a synthetic nonselective vasopressin 1 and 2 receptor agonist, is able to decrease hepatic venous pressure gradient and hepatic arterial resistance, promote splanchnic arterial vasoconstriction, and improve effective volemia and renal perfusion.6,7 Interestingly, terlipressin-induced vasoconstriction is also mediated by inhibiting inducible nitric oxide synthase expression in the arterial wall, a consequence of systemic inflammation.8 Therefore, it could be promising for the management of cirrhosis-related complications.

Current guidelines have recommended terlipressin combined with human albumin (HA) as the first-line choice for patients with cirrhosis with HRS-1.5,9,10 The CONFIRM trial regarding terlipressin for HRS-1 indicated that the proportion of HRS reversal was significantly higher in the terlipressin group than the placebo (39% vs. 18%) group.11 A randomized controlled trial (RCT) by Cavallin et al12 also found that terlipressin improved renal function better than midodrine and octreotide (70.4% vs. 28.6%). A recent meta-analysis of 7 RCTs showed that the use of terlipressin was associated with a higher HRS reversal rate compared to norepinephrine.13 Besides, the use of terlipressin is more convenient than norepinephrine, which needs intensive care unit monitoring.14

The European Association for the Study of the Liver and the American Association for the Study of Liver Disease recommend terlipressin, somatostatin, or octreotide as one of the first-line vasoactive drugs for patients with cirrhosis with AVB.5,15 A network meta-analysis of 50 studies confirmed comparable bleeding control and mortality among them but less blood transfusion and rebleeding in the terlipressin group.16 Besides, terlipressin might be more effective for reducing in-hospital mortality in patients with cirrhosis with acute gastrointestinal bleeding and renal dysfunction.17

It has also been shown that continuous infusion (CINF) of terlipressin could significantly improve the nutritional status and functional muscle indexes in patients with cirrhosis awaiting liver transplantation,18 suggesting that terlipressin can be widely used in patients with cirrhosis.

Considering continuously accumulated evidence about this topic, a systematic review and meta-analysis have been conducted to comprehensively evaluate the incidence of adverse events (AEs) and explore the risk factors associated with the development of AEs in patients with cirrhosis receiving terlipressin. Furthermore, the safety profile of terlipressin was compared with other vasoactive drugs in this context.

METHODS

This meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA, http://links.lww.com/HC9/B27). The registration number was CRD42023476736 in the PROSPERPO.

Literature search

We thoroughly searched the PubMed, EMBASE, and Cochrane Library databases. Search items were as follows: ((terlipressin) OR (glypressin) OR (triglycyl lysine vasopressin)) AND (cirrhosis). The last search date was June 2, 2024.

Selection criteria

The study selection was performed by 2 investigators (Yiyang Shang and Huiyuan Lu). All eligible studies investigated the safety of terlipressin in patients with cirrhosis. Exclusion criteria were as follows: (1) duplicated studies; (2) reviews or meta-analyses; (3) guidelines or consensus; (4) protocols or clinical trial registrations; (5) case reports, comments, editorials, conference proceedings, notes, or letters; (6) animal studies; (7) patients without cirrhosis; (8) terlipressin not used; (9) treatment duration of terlipressin <1 day; (10) data overlapped among studies; and (11) safety data not extractable.

Data extraction

Two investigators (Yiyang Shang and Huiyuan Lu) independently extracted the data, including first author, publication year, country, study design, enrollment period, study population, sample size, the proportion of diabetes, the proportion of encephalopathy, the proportion of atherosclerotic disease, treatment duration and mean daily dose of terlipressin, the proportion of male, mean age, mean serum total bilirubin level (TBiL) and serum albumin concentration, and number of patients who developed any AEs, treatment-related AEs, any serious AEs (SAEs), treatment-related SAEs, treatment withdrawal due to AEs, and treatment withdrawal due to treatment-related AEs. Gastrointestinal, cardiac, metabolic, vascular, and respiratory AEs were recorded by system organ class according to the Common Terminology Criteria for Adverse Events (CTCAE).19 Definitions of the above AEs were based on the definitions employed by the included studies. Any disagreement was resolved by consensus.

Study quality assessment

Two investigators independently assessed the quality of these included studies (Yiyang Shang and Cai’e Wang). The revised Cochrane Risk of Bias tool (ROB 2) was used to assess the quality of RCTs, which includes 5 domains (ie, the process of randomization, deviation of intended interventions, missing outcome data, measurement of the outcome, and selection of the reported result).20 Each domain is divided into “low risk of bias,” “some concerns,” or “high risk of bias.” If all domains are rated to “low risk of bias,” the overall risk of bias is considered “low risk of bias”; if one or more domains are rated as “high risk of bias,” or multiple domains are rated as “some concerns,” the overall risk assessment is considered “high risk of bias”; and in other situations, the overall risk assessment is considered “some concerns.”

The Newcastle-Ottawa Scale was used to assess the quality of cohort studies, which includes 3 domains (ie, selection, comparability, and outcome).21 The total score is 9, and a score of ≥7, 4–6, and ≤3 is considered as high, moderate, and low quality, respectively.

The Joanna Briggs Institute Scale was used to assess the quality of single-arm studies, which includes 10 questions.22 If a study has a score of ≥7, 5–6, and ≤4, it would be rated as high, moderate, and low quality, respectively.

Outcomes

The primary outcomes were the incidences of AEs in patients with cirrhosis treated with terlipressin, including any AEs, treatment-related AEs, any SAEs, treatment-related SAEs, treatment withdrawal due to AEs, treatment withdrawal due to treatment-related AEs, gastrointestinal AEs, cardiac AEs, metabolic AEs, vascular AEs, and respiratory AEs.

The secondary outcome was the difference in the incidence of AEs between patients receiving terlipressin and those receiving other vasoactive drugs.

Statistical analyses

Stata version 12.0 (Stata Corp), Review Manager software version 5.3 (Cochrane Collaboration, Nordic Cochrane Centre), RStudio version 4.3.1 (R Foundation for Statistical Computing), and TSA viewer version 0.9 β (CTU) were employed in this meta-analysis. Only a random-effects model was employed. Dichotomous outcomes were expressed as ORs with 95% CIs. Heterogeneity was assessed by I² statistics and chi-squared test, where an I² value of <25%, 25%–75%, and >75% represented low, moderate, and high degree of heterogeneity, respectively, and p < 0.10 by chi-squared test was considered significant for heterogeneity. Publication bias was assessed by the Egger test, and p < 0.1 was considered a significant publication bias. Meta-regression analyses were employed to explore the sources of heterogeneity according to the prespecified variates, including the study design (RCT vs. non-RCT), publication type (full-text vs. abstract), sample size (>28 vs. ≤28), study population (AVB vs. HRS vs. ascites vs. spontaneous bacterial peritonitis vs. septic shock), proportion of diabetes (>20% vs. ≤20%), proportion of encephalopathy (>42% vs. ≤42%), route of terlipressin administration (boluses [BOL] vs. CINF), mean dose of terlipressin (>4.3 mg/d vs. ≤4.3 mg/d), duration of terlipressin described in methods or study protocol (>5.0 d vs. ≤5.0 d), mean duration of terlipressin used in reality (>7.8 d vs. ≤7.8 d), combination with HA (yes vs. no), mean age (>65 y vs. 50–65 y vs. <50 y), proportion of male (>76% vs. ≤76%), mean TBiL (>4.3 mg/dL vs. ≤4.3 mg/dL), and mean serum albumin concentration (>2.8 g/dL vs. ≤2.8 g/dL). Subgroup analyses were performed according to the aforementioned variates in both primary and secondary outcomes if more than 2 studies were included. p interaction < 0.1 was considered a statistically significant interaction. Trial sequential analysis (TSA) was conducted to identify the reliability and conclusiveness of cumulative evidence. The required information size (RIS) was estimated by using the O’Brien-Fleming method with a type I error rate of 5% and statistical power of 80%. When the cumulative Z-curve crossed the TSA monitoring boundary, the evidence would be dependable, and no further studies were required.

RESULTS

Study selection and characteristics

Overall, 2794 articles were initially identified, and 4 other publications were retrieved manually. Notably, 2 important RCTs regarding terlipressin were excluded because 1 included the patients without cirrhosis and could not specify the data in patients with cirrhosis alone, and another took all cirrhosis-related complications, such as hepatic encephalopathy, bacterial infection, and gastrointestinal bleeding, as the AEs and did not specify the incidence of any AEs.23,24 Finally, 78 studies with 7257 participants were included (Figure 1). All of the 78 studies are listed in Supplemental Material, http://links.lww.com/HC9/B28. The characteristics of the studies are summarized in Tables 1 and 2. The quality assessments of RCTs, cohort studies, and single-arm studies are summarized in Supplemental Figure S1, http://links.lww.com/HC9/B29, and Supplemental Table S1, http://links.lww.com/HC9/B30 and Supplemental Table S2, http://links.lww.com/HC9/B31, respectively. Most studies were of moderate and high quality.

FIGURE 1 Flow chart of study selection.

TABLE 1 Characteristics of comparative studies

Author, (year)	Type of publication	Country	Study design	Enrollment period	Study population	Intervention in groups	
Alessandria (2007)	Full-text	Italy	RCT	NA	Cirrhosis and HRS	TP group: TP + HA (n = 12)
Control group: NE + HA (n = 10)	
Boyer (2016)	Full-text	USA and Canada	RCT	2010–2013	Cirrhosis and HRS-1	TP group: TP + HA (n = 93)
Control group: Placebo + HA (n = 95)	
Cavallin (2015)	Full-text	Italy	RCT	2008–2012	Cirrhosis and HRS	TP group: TP + HA (n = 27)
Control group: MID + OCT + HA (n = 22)	
Chiu (1990)	Full-text	China	RCT	NA	Cirrhosis and AVB	TP group: TP (n = 26)
Control group: VP (n = 28)	
Choudhury (2017)	Full-text	India	RCT	2013–2014	Cirrhosis and septic shock	TP group: TP + HA + antibiotics (n = 42)
Control group: NE + HA + antibiotics (n = 42)	
Chuah (2019)	Full-text	China	Prospective cohort	2010–2015	Cirrhosis and AVB	TP group: TP + ET (n = 109)
Control group: SS + ET (n = 41)	
D’Amico (1994)	Full-text	Italy	RCT	1988–1990	Cirrhosis and upper gastrointestinal bleeding	TP group: TP (n = 84)
Control group: VP + GTN (n = 81)	
Escorsell (2000)	Full-text	Spain and France	RCT	1994–1996	Cirrhosis and AVB	TP group: TP (n = 105)
Control group: ET (n = 114)	
Feu (1996)	Full-text	Spain	RCT	1991–1992	Cirrhosis and AVB	TP group: TP (n = 80)
Control group: SS (n = 81)	
Ghosh (2013)	Full-text	India	RCT	2009–2011	Cirrhosis and HRS-2	TP group: TP + HA (n = 23)
Control group: NE + HA (n = 23)	
Goyal (2016)	Full-text	India	RCT	NA	Cirrhosis and HRS-1	TP group: TP + HA (n = 20)
Control group: NE + HA (n = 21)	
Lata (2007)	Full-text	Czech Republic	RCT	2002–2004	Cirrhosis and ascites	TP group: TP + paracentesis (n = 24)
Control group: HA + paracentesis (n = 25)	
Moreau (2002)	Full-text	France	RCT	1998–2000	Cirrhosis and ascites	TP group: TP+paracentesis (n=10)
Control group: HA+paracentesis (n=10)	
Neri (2008)	Full-text	Italy	RCT	2002-2005	Cirrhosis and HRS-1	TP group: TP + HA (n = 26)
Control group: HA (n = 26)	
Pande (2016)	Abstract	India	Retrospective cohort	2013–2016	Cirrhosis and ascites	TP group: TP + diuretics + HA (n = 42)
Control group: Diuretics+HA (n=25)	
Pedretti (1994)	Full-text	Italy	RCT	1990–1993	Cirrhosis and AVB	TP group: TP (n = 30)
Control group: OCT (n = 30)	
Prakash (2018)	Abstract	India	RCT	2015–2017	Cirrhosis and septic shock	TP group: TP + NE (n = 91)
Control group: NE (n = 93)	
Pulvirenti (2008)	Full-text	Italy	RCT	2004–2006	Cirrhosis and HRS-1	TP group: TP + HA (n = 15)
Control group: HA (n = 15)	
Salim (2017)	Full-text	Pakistan	RCT	2016	Cirrhosis and AVB	TP group: TP for 3 d (n = 25)
Control group: TP for 0.5 d (n = 65)	
Saif (2018)	Full-text	India	RCT	NA	Cirrhosis and HRS-1	TP group: TP + HA (n = 30)
Control group: NE + HA (n = 30)	
Salman (2016)	Full-text	Egypt	RCT	NA	Cirrhosis and ascites and SBP	TP group: TP + antibiotics (n = 50)/TP + antibiotics + HA (n = 50)
Control group: Antibiotics + HA (n = 50)/MID + antibiotics (n = 50)	
Seo (2006)	Full-text	Korea	RCT	2003–2005	Cirrhosis and AVB	TP group: TP + ET (n = 48)
Control group: SS + ET (n = 50)	
Seo (2014)	Full-text	Korea	RCT	2006–2010	Cirrhosis and AVB	TP group: TP + ET (n = 261)
Control group: SS + ET (n = 259)/OCT + ET (n = 260)	
Sharma (2008)	Full-text	India	RCT	2005–2006	Cirrhosis and HRS-1	TP group: TP + HA (n = 20)
Control group: NE + HA (n = 20)	
Silvain (1993)	Full-text	France	RCT	1990–1991	Cirrhosis and AVB	TP group: TP + GTN (n = 41)
Control group: OCT (n = 46)	
Singh (2012)	Full-text	India	RCT	2009–2011	Cirrhosis and HRS-1	TP group: TP + HA (n = 23)
Control group: NE + HA (n = 23)	
Soderlund (1990)	Full-text	Sweden	RCT	1985–1988	Cirrhosis and AVB	TP group: TP (n = 31)
Control group: Placebo (n = 29)	
Srivastava (2015)	Full-text	India	RCT	2005–2010	Cirrhosis and HRS-1	TP group: TP + HA (n = 20)
Control group: DA + diuretics + HA (n = 20)	
Cirrhosis and HRS-2	TP group: TP + HA (n = 20)
Control group: DA + diuretics + HA (n = 20)	
Walker (1986)	Full-text	Germany	RCT	1983–1984	Cirrhosis and AVB	TP group: TP + ET (n = 25)
Control group: Placebo + ET (n = 25)	
Walker (1992)	Full-text	Germany	RCT	1988–1991	Cirrhosis and AVB	TP group: TP (n = 25)
Control group: SS (n = 25)	
Wong (2021)	Full-text	USA and Canada	RCT	2016–2019	Cirrhosis and HRS-1	TP group: TP + HA (n = 200)
Control group: Placebo + HA (n = 99)	
Yang (2001)	Full-text	China	RCT	1996–1999	Cirrhosis and AVB	TP group: TP + HA (n = 20)
Control group: SS + HA (n = 24)/VP+HA (n = 22)	
Yang (2001)	Full-text	China	RCT	2000	Cirrhosis and HRS	TP group: TP + HA (n = 8)
Control group: Diuretics + HA (n = 7)	
Notes: All references can obtain from the Supplemental Material.

Abbreviations: AKI, acute kidney injury; AVB, acute variceal bleeding; BOL, boluses; DA, dopamine; ET, endoscopic therapy; GTN, glyceryl trinitrate; HA, human albumin; HRS, hepatorenal syndrome; INF, intravenous infusion; MID, midodrine; NA, not available; NE, noradrenaline; OCT, octreotide; RCT, randomized controlled trial; SBP, spontaneous bacterial peritonitis; SS, somatostatin; TP, terlipressin; VP, vasopressin.

TABLE 2 Characteristics of noncomparative studies

Author, (year)	Type of publication	Country	Study design	Enrollment period	Study population	TP groups	
Abdel-Razik (2020)	Full-text	Egypt	Prospective	2015–2019	Cirrhosis and HRS-1	TP + HA (n = 42)	
Angeli (2009)	Abstract	Italy	RCT	NA	Cirrhosis and HRS-1	TP CINF + HA (n = 19)
TP BOL + HA (n = 18)	
Amara (2023)	Abstract	India	NA	2022	Cirrhosis and HRS-AKI	TP + HA (n = 102)	
Arcidiacono (1992)	Full-text	Italy	Prospective	1990–1991	Cirrhosis and AVB	TP (n = 219)	
Arora (2021)	Abstract	India	Retrospective	2020–2021	Cirrhosis and HRS-AKI	TP (n = 160)	
Arora (2023)	Full-text	India	RCT	2016–2018	Cirrhosis and AVB	TP CINF (n = 55)
TP BOL (n = 55)	
Azam (2012)	Full-text	Pakistan	RCT	2006–2008	Cirrhosis and AVB	TP for 3 d (n = 65)
TP for 1 d (n = 65)	
Bajaj (2020)	Abstract	USA	Prospective	NA	Cirrhosis and ascites	TP (n = 6)	
Bruha (2002)	Full-text	Czech Republic	RCT	1996–1998	Cirrhosis and AVB/portal hypertensive gastropathy bleeding	TP high dose (n = 45)
TP low dose (n = 41)	
Bruha (2009)	Full-text	Czech Republic	RCT	2004–2005	Cirrhosis and AVB	TP for 5 d (n = 15)
TP for 10d (n = 10)	
Cavallin (2016)	Full-text	Italy	RCT	2007–2014	Cirrhosis and HRS-1	TP CINF + HA (n = 34)
TP BOL + HA (n = 37)	
Chang (1991)	Full-text	China	RCT	1988–1989	Cirrhosis and AVB	TP low dose (n = 21)
TP high dose (n = 19)	
Cheng (2019)	Full-text	China	Retrospective	2012–2018	Cirrhosis and AKI	TP + HA (n = 19)	
Choudhury (2014)	Abstract	India	Retrospective	NA	Cirrhosis and AVB/HRS	TP (n = 332)	
Choudhury (2016)	Abstract	India	Prospective	NA	Cirrhosis and AVB/HRS-AKI/septic shock	TP (n = 424)	
Choudhury (2018)	Abstract	India	RCT	NA	Cirrhosis and AVB	TP CINF (n = 25)
TP BOL (n = 25)	
Fiaccadori (1993)	Full-text	Italy	Prospective	1990–1993	Cirrhosis and AVB	TP (n = 546)	
Fimiani (2011)	Full-text	Italy	Prospective	NA	Cirrhosis and ascites	TP + diuretics + HA (n = 26)	
Halimi (2002)	Full-text	France	Retrospective cohort	NA	Cirrhosis and HRS	TP CINF (n = 5)
TP BOL (n = 13)	
Hinz (2013)	Full-text	Germany	Retrospective	NA	Cirrhosis and HRS	TP + HA (n = 21)	
Hu (2008)	Full-text	China	RCT	2003–2006	Cirrhosis and AVB	TP new brand (n = 19)
TP (n = 22)	
Jain (2023)	Abstract	India	RCT	NA	Septic shock	TP CINF (n = 55)
TP BOL (n = 57)	
Kim (2005)	Full-text	Korea	RCT	1999–2001	Cirrhosis and AVB	TP + ET (n = 36)	
Licata (2013)	Full-text	Italy	Retrospective	2001–2012	Cirrhosis and HRS	TP + HA (n = 28)	
Linhares (2020)	Abstract	Brazil	Prospective/Retrospective	2018–2019	Cirrhosis and HRS	TP + HA (n = 18)	
Ma (2024)	Full-text	Spain	Prospective cohort	2019–2021	Cirrhosis and HRS-AKI	TP + HA (n = 23)	
Moreau (2002)	Full-text	France	Retrospective	1996–2000	Cirrhosis and HRS-1	TP + HA (n = 99)	
Mulkay (2001)	Full-text	Belgium	Prospective	1997–1999	Cirrhosis and HRS-1	TP + HA (n = 12)	
Muñoz (2009)	Full-text	Mexico	Prospective	2006–2008	Cirrhosis and HRS-1	TP + HA (n = 13)	
Narahara (2012)	Full-text	Japan	Prospective	2007–2009	Cirrhosis and HRS-1	TP + HA (n = 8)	
Nazar (2010)	Full-text	Spain	Prospective	1998–2007	Cirrhosis and HRS-1	TP + HA (n=39)	
Ortega (2002)	Full-text	Spain	Prospective cohort	1999–2001	Cirrhosis and HRS	TP (n = 8)
TP + HA (n = 13)	
Premkumar (2022)	Abstract	India	Prospective	NA	Cirrhosis and HRS-AKI	TP (n = 65)	
Premkumar (2024)	Full-text	India	Prospective	2021–2023	Cirrhosis and HRS-AKI	TP + HA (n = 140)	
Reddy (2022)	Abstract	USA	Prospective	NA	Cirrhosis and HRS-AKI	TP (n = 32)	
Rodríguez (2014)	Full-text	Italy	Prospective	2011–2013	Cirrhosis and HRS-1 and Sepsis	TP + antibiotics + HA (n = 18)	
Saner (2004)	Full-text	Germany	Prospective	NA	Cirrhosis and HRS	TP + gelafundin (n = 7)	
Singh (2023)	Full-text	India	RCT	2018–2019	Cirrhosis and HRS-1	TP+HA (n = 30)
TP + NE + HA (n = 30)	
Slyvka (2021)	Full-text	Ukraine	RCT	2013–2019	Cirrhosis and HRS-AKI	TP 3 mg/d+HA (n=86)
TP varied dose + HA (n = 89)	
Solanki (2003)	Full-text	India	RCT	NA	Cirrhosis and HRS-1	TP + HA (n = 12)	
Triantos (2010)	Full-text	UK	Retrospective	NA	Cirrhosis and Renal failure	TP + HA (n = 45)	
Vaishnav (2023)	Abstract	India	RCT	NA	Cirrhosis and AVB	TP for 3 d (n = 75)
TP for 1d (n = 74)	
Uriz (2000)	Full-text	Spain	Prospective	NA	Cirrhosis and HRS	TP + HA (n = 9)	
Wan (2014)	Full-text	China	Retrospective cohort	2010–2012	Cirrhosis and HRS-1	TP low dose (n = 29)
TP high dose (n = 27)	
Weinberg (2024)	Abstract	NA	RCT	NA	Cirrhosis and ascites	TP + diuretics (n = 10)	
Notes: All references can obtain from the Supplemental Material.

Abbreviations: AKI, acute kidney injury; AVB, acute variceal bleeding; BOL, boluses; CINF, continuous infusion; HA, human albumin; HRS, hepatorenal syndrome; NA, not available; RCT, randomized controlled trial; TP, terlipressin.

The characteristics of patients and terlipressin treatment are summarized in Supplemental Table S3, http://links.lww.com/HC9/B32.

Incidence of AEs in patients with cirrhosis receiving terlipressin

The frequency of AEs is summarized in Supplemental Table S4, http://links.lww.com/HC9/B33.

Any AEs

Thirty studies reported the incidence of any AEs in patients with cirrhosis receiving terlipressin. The pooled incidence of any AEs was 31% (95% CI = 20%–42%) with significant heterogeneity (I 2=96.7%; p < 0.01) (Figure 2A). Meta-regression analyses suggested that the route of terlipressin administration, duration of terlipressin described in methods or study protocol, proportion of male, and mean TBiL might be the potential sources of heterogeneity (Table 3). There was no significant publication bias (p = 0.396).

FIGURE 2 Forest plots of the incidence of any AEs (A) and treatment-related AEs (B) in patients receiving terlipressin. Abbreviations: ALB, serum albumin concentration; AEs, adverse events; AVB, acute variceal bleeding; BOL, boluses; CINF, continuous infusion; HA, human albumin; HRS, hepatorenal syndrome; RCT, randomized controlled trial; TBiL, total serum bilirubin concentration.

TABLE 3 Results of meta-regression analyses regarding AEs

Covariates	Any AEs	Treatment-related AEs	Any SAEs	Treatment-related SAEs	Treatment withdrawal due to AEs	Treatment withdrawal due to treatment-related AEs	
Study design (RCT vs. non-RCT)	0.218	0.433	0.710	0.311	0.061	<0.001	
Publication type (full-text vs. abstract)	0.611	0.022	—	0.149	0.092	0.634	
Sample size (>28 vs. ≤28)	0.407	0.234	0.278	0.325	0.388	0.073	
Study population (AVB vs. HRS vs. ascites vs. SBP vs. septic shock)	0.742	0.002	0.227	0.210	0.621	0.001	
Proportion of diabetes (>21% vs. ≤21%)	0.466	0.555	0.701	/	0.315	0.989	
Proportion of encephalopathy (>42% vs. ≤42%)	0.227	0.428	0.020	0.940	0.471	0.963	
Route of terlipressin administration (BOL vs. CINF)	0.076	0.443	0.770	0.408	0.052	0.997	
Mean dose of terlipressin (mg/d) (>4.3 vs. ≤4.3)	0.978	0.134	—	0.154	0.637	0.441	
Duration of terlipressin described in methods or study protocol (d) (>5 vs. ≤5)	0.002	0.019	<0.001	0.048	0.091	0.347	
Mean duration of terlipressin used in reality (d) (>7.8 vs. ≤7.8)	0.277	0.351	0.133	0.879	0.316	0.575	
Combination with HA (yes vs. no)	0.294	0.821	0.002	0.148	0.692	0.597	
Mean age (y) (>65 vs. 50–65 vs. <50)	0.311	0.198	0.626	0.441	0.357	0.004	
Proportion of male (>76% vs. ≤76%)	0.001	0.107	0.286	0.929	0.790	0.401	
Mean TBiL (mg/dL) (>4.3 vs. ≤4.3)	<0.001	0.391	<0.001	0.139	0.498	/	
Mean ALB (g/dL) (>2.8 vs. ≤2.8)	0.752	0.557	0.117	0.044	0.964	0.912	
Notes: p < 0.10 was considered a potential source of heterogeneity.

Abbreviations: AEs, adverse events; ALB, serum albumin concentration; AVB, acute variceal bleeding; BOL, boluses; CINF, continuous infusion; HA, human albumin; HRS, hepatorenal syndrome; RCT, randomized controlled trial; SAEs, serious AEs; SBP, spontaneous bacterial peritonitis; TBiL, total serum bilirubin concentration.

The results of subgroups are summarized in Figure 2A.

Treatment-related AEs

Thirty-eight studies reported the incidence of treatment-related AEs in patients with cirrhosis receiving terlipressin. The pooled incidence of treatment-related AEs was 22% (95% CI = 16%–29%) with significant heterogeneity (I 2 = 92.5%; p < 0.01) (Figure 2B). Meta-regression analyses demonstrated that the publication type, study population, and duration of terlipressin described in methods or study protocol might be the potential sources of heterogeneity (Table 3). There was no significant publication bias (p = 0.404).

The results of subgroups are summarized in Figure 2B.

Any SAEs

Eighteen studies reported the incidence of any SAEs in patients with cirrhosis receiving terlipressin. The pooled incidence of any SAEs was 5% (95% CI = 0%–16%) with significant heterogeneity (I 2 = 96.6%; p < 0.01) (Figure 3A). Meta-regression analyses demonstrated that the duration of terlipressin described in methods or study protocol, combination with HA, and mean TBiL might be the potential sources of heterogeneity (Table 3). There was no significant publication bias (p = 0.122).

FIGURE 3 Forest plots of the incidence of any SAEs (A) and treatment-related SAEs (B) in patients receiving terlipressin. Abbreviations: ALB, serum albumin concentration; AEs, adverse events; AVB, acute variceal bleeding; BOL, boluses; CINF, continuous infusion; HA, human albumin; HRS, hepatorenal syndrome; RCT, randomized controlled trial; SAE, serious adverse event; TBiL, total serum bilirubin concentration.

The results of subgroups are summarized in Figure 3A.

Treatment-related SAEs

Twenty-three studies reported the incidence of treatment-related SAEs in patients with cirrhosis receiving terlipressin. The pooled incidence of treatment-related SAEs was 5% (95% CI = 1%–10%) with significant heterogeneity (I 2 = 81.4%; p < 0.01) (Figure 3B). Meta-regression analyses demonstrated that the duration of terlipressin described in methods or study protocol and mean serum albumin concentration might be the potential sources of heterogeneity (Table 3). There was no significant publication bias (p = 0.963).

The results of subgroups are summarized in Figure 3B.

Treatment withdrawal due to AEs

Thirty-two studies reported the incidence of treatment withdrawal due to AEs in patients with cirrhosis receiving terlipressin. The pooled incidence of treatment withdrawal due to AEs was 4% (95% CI = 1%–7%) with significant heterogeneity (I 2 = 84.7%; p < 0.01) (Figure 4A). Meta-regression analyses demonstrated that the study design, publication type, route of terlipressin administration, and duration of terlipressin described in methods or study protocol might be the potential sources of heterogeneity (Table 3). There was no significant publication bias (p = 0.247).

FIGURE 4 Forest plots of the incidence of treatment withdrawal due to AEs (A) and treatment withdrawal due to treatment-related AEs (B) in patients receiving terlipressin. Abbreviations: ALB, serum albumin concentration; AEs, adverse events; AVB, acute variceal bleeding; BOL, boluses; CINF, continuous infusion; HA, human albumin; HRS, hepatorenal syndrome; RCT, randomized controlled trial; SBP, spontaneous bacterial peritonitis; TBiL, total serum bilirubin concentration.

The results of subgroups are summarized in Figure 4A.

Treatment withdrawal due to treatment-related AEs

Thirty-seven studies reported the incidence of treatment withdrawal due to treatment-related AEs in patients with cirrhosis receiving terlipressin. The pooled incidence of treatment withdrawal due to treatment-related AEs was 4% (95% CI = 1%–8%) with significant heterogeneity (I 2 = 86.2%; p < 0.01) (Figure 4B). Meta-regression analyses demonstrated that the study design, sample size, study population, and mean age might be the potential sources of heterogeneity (Table 3). There was no significant publication bias (p = 0.379).

The results of subgroups are summarized in Figure 4B.

Gastrointestinal, cardiac, metabolic, vascular, and respiratory AEs

Diarrhea. Twenty-four studies reported the incidence of diarrhea in patients with cirrhosis receiving terlipressin. The pooled incidence of diarrhea was 10% (95% CI = 6%–14%) with significant heterogeneity (I 2 = 83.1%; p < 0.01) (Figure 5A). Meta-regression analyses demonstrated that the duration of terlipressin described in methods or study protocol might be the potential sources of heterogeneity (Supplemental Table S5, http://links.lww.com/HC9/B34). There was significant publication bias (p = 0.010).

FIGURE 5 Forest plots of the incidence of diarrhea (A) and abdominal pain (B) in patients receiving terlipressin. Abbreviations: ALB, serum albumin concentration; AVB, acute variceal bleeding; BOL, boluses; CINF, continuous infusion; HA, human albumin; HRS, hepatorenal syndrome; RCT, randomized controlled trial; SBP, spontaneous bacterial peritonitis; TBiL, total serum bilirubin concentration.

The results of subgroups are summarized in Figure 5A.

Abdominal pain. Forty studies reported the incidence of abdominal pain in patients with cirrhosis receiving terlipressin. The pooled incidence of abdominal pain was 9% (95% CI = 7%–12%) with significant heterogeneity (I 2 = 78.1%; p < 0.01) (Figure 5B). Meta-regression analyses demonstrated that the duration of terlipressin described in methods or study protocol might be the potential sources of heterogeneity (Supplemental Table S5, http://links.lww.com/HC9/B34). There was significant publication bias (p = 0.072).

The results of subgroups are summarized in Figure 5B.

Nausea. Seven studies reported the incidence of nausea in patients with cirrhosis receiving terlipressin. The pooled incidence of nausea was 4% (95% CI = 0%–11%) with significant heterogeneity (I 2 = 92.0%; p < 0.01) (Figure 6A). Meta-regression analyses did not find the source of heterogeneity (Supplemental Table S5, http://links.lww.com/HC9/B34). There was no significant publication bias (p = 0.945).

FIGURE 6 Forest plots of the incidence of nausea (A) and vomiting (B) in patients receiving terlipressin. Abbreviations: ALB, serum albumin concentration; AVB, acute variceal bleeding; BOL, boluses; CINF, continuous infusion; HA, human albumin; HRS, hepatorenal syndrome; RCT, randomized controlled trial; SBP, spontaneous bacterial peritonitis; TBiL, total serum bilirubin concentration.

The results of subgroups are summarized in Figure 6A.

Vomiting. Seven studies reported the incidence of vomiting in patients with cirrhosis receiving terlipressin. The pooled incidence of vomiting was 4% (95% CI = 1%–8%) with significant heterogeneity (I 2 = 79.2%; p < 0.01) (Figure 6B). Meta-regression analyses did not find the source of heterogeneity (Supplemental Table S5, http://links.lww.com/HC9/B34). There was no significant publication bias (p = 0.627).

The results of subgroups are summarized in Figure 6B.

Intestinal ischemia. Eight studies reported the incidence of intestinal ischemia in patients with cirrhosis receiving terlipressin. The pooled incidence of intestinal ischemia was 1% (95% CI = 1%–3%) with significant heterogeneity (I 2 = 49.6%; p = 0.04) (Figure 7A). Meta-regression analyses did not find the source of heterogeneity (Supplemental Table S5, http://links.lww.com/HC9/B34). There was no significant publication bias (p = 0.128).

FIGURE 7 Forest plots of the incidence of intestinal ischemia (A) and peripheral ischemia (B) in patients receiving terlipressin. Abbreviations: ALB, serum albumin concentration; AVB, acute variceal bleeding; BOL, boluses; CINF, continuous infusion; HA, human albumin; HRS, hepatorenal syndrome; RCT, randomized controlled trial; TBiL, total serum bilirubin concentration.

The results of subgroups are summarized in Figure 7A.

Peripheral ischemia. Fourteen studies reported the incidence of peripheral ischemia in patients with cirrhosis receiving terlipressin. The pooled incidence of peripheral ischemia was 2% (95% CI = 0%–5%) with significant heterogeneity (I 2 = 79.2%; p < 0.01) (Figure 7B). Meta-regression analyses did not find the source of heterogeneity (Supplemental Table S5, http://links.lww.com/HC9/B34). There was no significant publication bias (p = 0.143).

The results of subgroups are summarized in Figure 7B.

Chest pain. Eighteen studies reported the incidence of chest pain in patients with cirrhosis receiving terlipressin. The pooled incidence of chest pain was 2% (95% CI = 1%–3%) with significant heterogeneity (I 2 = 50.3%; p < 0.01) (Supplemental Figure S2A, http://links.lww.com/HC9/B29). Meta-regression analyses did not find the source of heterogeneity (Supplemental Table S5, http://links.lww.com/HC9/B34). There was no significant publication bias (p = 0.784).

The results of subgroups are summarized in Supplemental Figure S2A, http://links.lww.com/HC9/B29.

Ventricular extrasystoles. Eleven studies reported the incidence of ventricular extrasystoles in patients with cirrhosis receiving terlipressin. The pooled incidence of ventricular extrasystoles was 2% (95% CI = 1%–4%) without significant heterogeneity (I 2 = 0%; p = 0.66) (Supplemental Figure S2B, http://links.lww.com/HC9/B29). There was no significant publication bias (p = 0.351).

The results of subgroups are summarized in Supplemental Figure S2B, http://links.lww.com/HC9/B29.

Atrial fibrillation. Ten studies reported the incidence of atrial fibrillation in patients with cirrhosis receiving terlipressin. The pooled incidence of atrial fibrillation was 2% (95% CI = 1%–3%) without significant heterogeneity (I 2 = 0%; p = 0.50) (Supplemental Figure S3A, http://links.lww.com/HC9/B29). There was no significant publication bias (p = 0.371).

The results of subgroups are summarized in Supplemental Figure S3A, http://links.lww.com/HC9/B29.

Myocardial infarction. Nine studies reported the incidence of hyponatremia in patients with cirrhosis receiving terlipressin. The pooled incidence of hyponatremia was 0% (95% CI = 0%–1%) without significant heterogeneity (I 2 = 0%; p = 0.91) (Supplemental Figure S3B, http://links.lww.com/HC9/B29). There was no significant publication bias (p = 0.632).

The results of subgroups are summarized in Supplemental Figure S3B, http://links.lww.com/HC9/B29.

Arterial hypertension. Seven studies reported the incidence of arterial hypertension in patients with cirrhosis receiving terlipressin. The pooled incidence of arterial hypertension was 1% (95% CI = 0%–3%) without significant heterogeneity (I 2 = 26.0%; p = 0.21) (Supplemental Figure S4A, http://links.lww.com/HC9/B29). There was significant publication bias (p = 0.057).

The results of subgroups are summarized in Supplemental Figure S4A, http://links.lww.com/HC9/B29.

Hyponatremia. Eleven studies reported the incidence of hyponatremia in patients with cirrhosis receiving terlipressin. The pooled incidence of hyponatremia was 9% (95% CI = 4%–17%) with significant heterogeneity (I 2 = 89.2%; p < 0.01) (Supplemental Figure S4B, http://links.lww.com/HC9/B29). Meta-regression analyses did not find the source of heterogeneity (Supplemental Table S5, http://links.lww.com/HC9/B34). There was significant publication bias (p = 0.084).

The results of subgroups are summarized in Supplemental Figure S4B, http://links.lww.com/HC9/B29.

Dyspnea. Four studies reported the incidence of dyspnea in patients with cirrhosis receiving terlipressin. The pooled incidence of dyspnea was 9% (95% CI = 3%–16%) without significant heterogeneity (I 2 = 80.3%; p < 0.01) (Supplemental Figure S5A, http://links.lww.com/HC9/B29). Meta-regression analyses did not find the source of heterogeneity (Supplemental Table S5, http://links.lww.com/HC9/B34). There was no significant publication bias (p = 0.847).

The results of subgroups are summarized in Supplemental Figure S5A, http://links.lww.com/HC9/B29.

Pulmonary edema. Seven studies reported the incidence of pulmonary edema in patients with cirrhosis receiving terlipressin. The pooled incidence of pulmonary edema was 7% (95% CI = 5%–10%) without significant heterogeneity (I 2 = 0%; p = 0.73) (Supplemental Figure S5B, http://links.lww.com/HC9/B29). There was significant publication bias (p = 0.077).

The results of subgroups are summarized in Supplemental Figure S5B, http://links.lww.com/HC9/B29.

Respiratory failure. Five studies reported the incidence of respiratory failure in patients with cirrhosis receiving terlipressin. The pooled incidence of respiratory failure was 4% (95% CI = 0%–14%) with significant heterogeneity (I 2 = 92.9%; p < 0.01) (Figure 8A). Meta-regression analyses did not find the source of heterogeneity (Supplemental Table S5, http://links.lww.com/HC9/B34). There was no significant publication bias (p = 0.399).

FIGURE 8 Forest plots of the incidence of respiratory failure (A) and bronchospasm (B) in patients receiving terlipressin. Abbreviations: AVB, acute variceal bleeding; BOL, boluses; CINF, continuous infusion; HA, human albumin; HRS, hepatorenal syndrome; RCT, randomized controlled trial; SBP, spontaneous bacterial peritonitis; TBiL, total serum bilirubin concentration.

The results of subgroups are summarized in Figure 8A.

Bronchospasm. Four studies reported the incidence of bronchospasm in patients with cirrhosis receiving terlipressin. The pooled incidence of bronchospasm was 2% (95% CI = 0%–4%) without significant heterogeneity (I 2 = 0%; p = 0.75) (Figure 8B). There was no significant publication bias (p = 0.656).

The results of subgroups are summarized in Figure 8B.

Difference in the incidence of AEs between terlipressin versus noradrenaline

Any AEs

Three studies reported the incidence of any AEs in the terlipressin group and noradrenaline group. Meta-analysis demonstrated that the terlipressin group had a significantly higher incidence of any AEs than the noradrenaline group (OR = 2.98, 95% CI = 1.05–8.42, p = 0.04) without significant heterogeneity (I 2 = 0.00%; p = 0.80) (Supplemental Figure S6, http://links.lww.com/HC9/B29). There was no significant publication bias (p = 0.324).

The results of subgroups are summarized in Table 4.

TABLE 4 Difference in the incidence of any AEs between patients receiving terlipressin versus noradrenaline

Variates	No. studies	Odds ratio (95% CI)	Heterogeneity	p interaction	
I 2 (%)	p	
Overall	3	2.98 (1.05–8.42)	0.0	0.80		
Mean duration of terlipressin used in reality (d)	0.76	
 >7.8	2	2.63 (0.72–9.68)	0.0	0.55		
 ≤7.8	1	3.71 (0.66-20.76)	—	—		
Mean age (y)	0.67	
 50–65	2	2.65 (0.83–8.53)	—	—		
 <50	1	4.63 (0.48–45.09)	0.0	0.88		
Mean ALB (g/dL)	0.72	
 >2.8	1	4.63 (0.48–45.09)	—	—		
 ≤2.8	2	2.65 (0.83–8.53)	0.0	0.61		
Abbreviations: AEs, adverse events; ALB, serum albumin concentration.

In TSA, the cumulative Z-curves neither crossed the TSA monitoring boundary nor reached the RIS (n = 270) (Supplemental Figure S7, http://links.lww.com/HC9/B29).

Treatment-related AEs

Three studies reported the incidence of treatment-related AEs in the terlipressin group and oradrenaline group. Terlipressin group had a significantly higher incidence of treatment-related AEs (OR = 2.32, 95% CI = 1.02–5.27, p = 0.05) without significant heterogeneity (I 2 = 0.00%; p = 0.77) (Supplemental Figure S8, http://links.lww.com/HC9/B29). The publication bias could not be evaluated due to an insufficient number of studies.

The results of subgroups are summarized in Table 5.

TABLE 5 Difference in the incidence of treatment withdrawal due to treatment-related AEs between patients receiving terlipressin versus noradrenaline

Variates	No. Studies	Odds ratio (95% CI)	Heterogeneity	p interaction	
I 2 (%)	p	
Overall	3	2.32 (1.02–5.27)	0.0%	0.77		
Sample size	0.77	
 >28	2	2.49 (0.95–6.52)	—	—		
 ≤28	1	1.89 (0.38–9.27)	—	—		
Study population	0.77	
 HRS	2	1.89 (0.38–9.27)	—	—		
 Septic shock	1	2.49 (0.95–6.52)	—	—		
Route of terlipressin administration	0.77	
 BOL	2	1.89 (0.38–9.27)	—	—		
 CINF	1	2.49 (0.95–6.52)	—	—		
Abbreviations: AEs, adverse events; BOL, boluses; CINF, continuous infusion.

In TSA, the cumulative Z-curve neither crossed the TSA monitoring boundary nor reached the RIS (n = 481) (Supplemental Figure S9, http://links.lww.com/HC9/B29).

Any SAEs

One study reported the incidence of any SAEs in the terlipressin group and noradrenaline group. Both groups reported no events.

Treatment-related SAEs

Three studies reported the incidence of treatment-related SAEs in the terlipressin group and noradrenaline group. Both groups reported no events.

Treatment withdrawal due to AEs

Two studies reported the incidence of treatment withdrawal due to AEs in the terlipressin group and noradrenaline group. There was no significant difference in the incidence of treatment withdrawal due to AEs between the 2 groups (OR = 3.14, 95% CI = 0.14–72.9, p = 0.48). The heterogeneity and publication bias could not be evaluated due to an insufficient number of studies.

Treatment withdrawal due to treatment-related AEs

Three studies reported the incidence of treatment withdrawal due to treatment-related AEs in the terlipressin group and noradrenaline group. Both groups reported no events.

Difference between terlipressin versus somatostatin

Any AEs

Four studies reported the incidence of any AEs in the terlipressin group and somatostatin group. There was no significant difference in the incidence of any AEs between the 2 groups (OR = 1.98, 95% CI = 0.76–5.14, p = 0.16) with significant heterogeneity (I 2 = 58.0%; p = 0.09) (Supplemental Table S6, http://links.lww.com/HC9/B35). There was no significant publication bias (p = 0.878).

The results of subgroups are summarized in Supplemental Table S6, http://links.lww.com/HC9/B35.

In TSA, the cumulative Z-curve crossed the TSA monitoring boundary, but the total sample size did not reach the RIS (n = 751) (Supplemental Figure S10, http://links.lww.com/HC9/B29).

Treatment-related AEs

Three studies reported the incidence of treatment-related AEs in the terlipressin group and somatostatin group. There was no significant difference in the incidence of treatment-related AEs between the 2 groups (OR = 0.75, 95% CI = 0.05–10.89, p = 0.84) with significant heterogeneity (I 2 = 69.0%; p = 0.07) (Supplemental Table S7, http://links.lww.com/HC9/B36). The publication bias could not be evaluated due to an insufficient number of studies.

The results of subgroups are summarized in Supplemental Table S7, http://links.lww.com/HC9/B36.

In TSA, the cumulative Z-curve neither crossed the TSA monitoring boundary nor reached the RIS (n = 1323) (Supplemental Figure S11, http://links.lww.com/HC9/B29).

Any SAEs

One study reported the incidence of any SAEs in the terlipressin group and somatostatin group. Both groups reported no events.

Treatment-related SAEs

One study reported the incidence of treatment-related SAEs in the terlipressin group and somatostatin group. Both groups reported no events.

Treatment withdrawal due to AEs

Four studies reported the incidence of treatment withdrawal due to AEs in the terlipressin group and somatostatin group. There was no significant difference in the incidence of treatment withdrawal due to AEs between the 2 groups (OR = 3.08, 95% CI = 0.12–76.6, p = 0.49). The heterogeneity and publication bias could not be evaluated due to an insufficient number of studies.

Treatment withdrawal due to treatment-related AEs

Four studies reported the incidence of treatment withdrawal due to AEs in the terlipressin group and somatostatin group. There was no significant difference in the incidence of treatment withdrawal due to AEs between the 2 groups (OR = 3.08, 95% CI = 0.12–76.6, p = 0.49). The heterogeneity and publication bias could not be evaluated due to an insufficient number of studies.

Difference between terlipressin versus octreotide

Any AEs

Two studies reported the incidence of any AEs in the terlipressin group and octreotide group. Terlipressin group had a significantly higher incidence of any AEs (OR = 7.30, 95% CI = 4.00–13.34, p < 0.01) without significant heterogeneity (I 2 = 0.00%; p = 0.41). The publication bias could not be evaluated due to an insufficient number of studies.

Treatment-related AEs

One study reported the incidence of treatment-related AEs in the terlipressin group and somatostatin group. There was no significant difference in the incidence of treatment-related AEs between the 2 groups (OR = 0.71, 95% CI = 0.23–2.19, p = 0.55). The heterogeneity and publication bias could not be evaluated due to an insufficient number of studies.

Any SAEs

One study reported the incidence of any SAEs in the terlipressin group and octreotide group. Both groups reported no events.

Treatment-related SAEs

No study reported the incidence of treatment-related SAEs in the terlipressin group and octreotide group.

Treatment withdrawal due to AEs

One study reported the incidence of treatment withdrawal due to AEs in the terlipressin group and octreotide group. Both groups reported no events.

Treatment withdrawal due to treatment-related AEs

Two studies reported the incidence of treatment withdrawal due to treatment-related AEs in the terlipressin group and octreotide group. There was no significant difference in the incidence of treatment withdrawal due to treatment-related AEs between the 2 groups (OR = 5.89, 95% CI = 0.27–126.3, p = 0.26). The heterogeneity and publication bias could not be evaluated due to an insufficient number of studies.

Difference between terlipressin versus other vasoactive drugs in advanced liver disease

Any AEs in patients with MELD score ≥15

Four studies reported the incidence of any AEs in the terlipressin group and other vasoactive drugs group in patients whose MELD score is ≥15. Terlipressin group had a significantly higher incidence of any AEs (OR = 3.46, 95% CI = 2.13–5.64, p < 0.01) without significant heterogeneity (I 2 = 0.00%; p = 0.97). There was no significant publication bias (p = 0.735).

Treatment-related AEs in patients with MELD score ≥15

Four studies reported the incidence of treatment-related AEs in the terlipressin group and other vasoactive drugs group in patients whose MELD score is ≥15. There was no significant difference in the incidence of treatment-related AEs between them (OR = 1.77, 95% CI = 0.89–3.54, p < 0.01) without significant heterogeneity (I 2 = 0.00%; p = 0.48). There was no significant publication bias (p = 0.670).

Any AEs in patients with Child score ≥10

Three studies reported the incidence of any AEs in the terlipressin group and other vasoactive drugs group in patients whose Child score is ≥10. Terlipressin group had a significantly higher incidence of any AEs (OR = 2.91, 95% CI = 1.03–8.24, p = 0.04) without significant heterogeneity (I 2 = 0.00%; p = 0.77). There was no significant publication bias (p = 0.426).

Treatment-related AEs in patients with Child score ≥10

Three studies reported the incidence of any AEs in the terlipressin group and other vasoactive drugs group in patients whose Child score is ≥10. Terlipressin group had a significantly higher incidence of treatment-related AEs (OR = 2.32, 95% CI = 1.02–5.27, p = 0.05) without significant heterogeneity (I 2 = 0.00%; p = 0.77). The publication bias could not be evaluated due to an insufficient number of studies.

DISCUSSION

This is a systematic review and meta-analysis exploring comprehensively the safety of terlipressin administration for patients with cirrhosis in different clinical scenarios. Up to now, at least 18 systematic reviews and meta-analyses also reported the safety profile of terlipressin in cirrhosis.16,25–41 However, most of them selected patients affected by only 1 or 2 specific cirrhosis-related complications and only evaluated specific types of AEs (ie, any AEs and any SAEs). Therefore, the safety profile of terlipressin administration in cirrhosis was insufficiently assessed. The present meta-analysis overcame most of these shortcomings, specifically (1) it included a more comprehensive patient population, including patients with cirrhosis affected by AVB, HRS, ascites, spontaneous bacterial peritonitis, and septic shock; (2) contrary to previous studies, it also assessed treatment-related SAEs; (3) it used TSA to evaluate whether the cumulative evidence of AEs was reliable and conclusive; and (4) it attempted to identify the risk factors for terlipressin-associated AEs.

Based on the data from the studies included in the meta-analysis, we found that the pooled incidences of any AEs, treatment-related AEs, any SAEs, treatment-related SAEs, treatment withdrawal due to AEs, treatment withdrawal due to treatment-related AEs in patients with cirrhosis receiving terlipressin were 31%, 22%, 5%, 5%, 4%, and 4%, respectively. The terlipressin group had higher incidences of any AEs than the noradrenaline group and octreotide group, but there were no significant differences between terlipressin and somatostatin groups.

Terlipressin is employed to treat different cirrhosis-related complications. The present meta-analysis demonstrated that the most common gastrointestinal and respiratory systems AEs were diarrhea (10%) and dyspnea (9%) in patients with cirrhosis. Patients with HRS had higher incidences of any AEs, any SAEs, and treatment-related SAEs than those with AVB or ascites. In the present meta-analysis, the pooled incidence of respiratory failure was 4%, while in the CONFIRM trial, which enrolled patients with HRS-1, the incidence of respiratory failure was 10.5%, and 11% of patients died of respiratory disorders within 90 days.11 There are some explanations for this difference, as follows. First, terlipressin is usually combined with HA to treat HRS because this combination is more effective than terlipressin alone.42,43 However, this combination regimen might aggravate the incidence of respiratory AEs, namely pulmonary edema, because of central blood volume expansion by HA coupled with the increase in systemic vascular resistance induced by terlipressin.44 Second, patients with HRS often require a longer treatment duration of terlipressin than those with other cirrhosis-related complications, such as AVB.4,5,45 In the light of our subgroup analyses, the treatment duration is a relevant factor since the duration of terlipressin administration described in the methods or study protocol >5 days was associated with a greater incidence of AEs. Third, the underlying cirrhosis is usually more advanced and severe in patients developing HRS than in those with AVB. Altogether, these aspects suggest that patients with cirrhosis treated with terlipressin merit careful screening and monitoring with continuous pulse oximetry and clinical assessment for respiratory failure, particularly in the cases where HA is combined, to allow prompt treatment discontinuation when respiratory symptoms develop.

The present meta-analysis found that the incidence of AEs was significantly higher in patients with a baseline TBiL level of >4.3 mg/dL. This finding is not surprising, as TBiL is a common component in the most widely used prognostic models for patients with liver cirrhosis.46 Indeed, the TBiL level parallels the MELD score, and a high MELD score represents a more severe hepatic impairment and a worse prognosis. Thus, this might explain why patients with cirrhosis showing a high TBiL level have a higher incidence of AEs. Moreover, our meta-analysis also found that the use of terlipressin has a higher incidence of any AEs than other vasoactive drugs in patients with advanced liver disease. Therefore, the measurement of TBiL level may help to evaluate the risk of developing AEs in patients with cirrhosis treated with terlipressin.

CINF and BOL are 2 routes of terlipressin administration in clinical practice. Our meta-analysis demonstrated that terlipressin administered by CINF in patients with cirrhosis had a lower incidence of any AEs than that administered by BOL, but the difference was not statistically significant. The better safety of CINF can be due to the pharmacokinetics and pharmacodynamics of terlipressin. It has been shown that the elimination rate of terlipressin increases with a rise in its plasma concentration.47 The plasma concentration of terlipressin infused through BOL could not be maintained over a long period of time, while it was more stable through CINF. The dosage of terlipressin to maintain an equal decrease in portal pressure at a fixed interval may be lower through CINF than BOL. Indeed, the interval of terlipressin administrated through BOL is 4–6 hours, but its efficacy lasts <4 hours.48 Therefore, CINF should be preferred to enhance the efficacy of terlipressin.

The present meta-analysis has several limitations. First, most of these included studies did not specify the definitions of AEs, which may affect the reliability of our conclusions. Second, most patients received complex treatments. Thus, it is sometimes unclear whether terlipressin or other drugs were responsible for AEs. Third, a considerable proportion of the included studies were non-RCTs, which lowers their quality. Fourth, we did not assess the difference in the incidence of SAEs between the 2 routes of terlipressin administration due to a lack of relevant data. Fifth, we could not perform subgroup analyses according to the atherosclerotic disease due to the lack of sufficient data.

CONCLUSIONS

According to our systematic review and meta-analysis, AEs are common among patients with cirrhosis receiving terlipressin. The safety of terlipressin may be mainly affected by the clinical context of terlipressin use, duration of terlipressin therapy, combination with HA, and baseline TBiL level. However, a better insight into the risk factors for the occurrence of AEs in patients with cirrhosis receiving terlipressin requires further investigation with prospective studies.

Supplementary Material

AUTHOR CONTRIBUTIONS

Yiyang Shang: reviewed and searched the literature, extracted and collated the data, discussed the findings, and drafted the manuscript. Cai’e Wang: revised the manuscript, discussed the findings, and gave critical comments. Huiyuan Lu: searched the literature, and extracted and collated the data. Lu Chai and Wentao Xu: discussed the findings and gave critical comments. Mauro Bernardi: reviewed the literature, interpreted and discussed the findings, gave critical comments, and revised the manuscript. Xingshun Qi: conceived the work, reviewed the literature, interpreted and discussed the findings, and revised the manuscript. All authors have made an intellectual contribution to the manuscript and approved the submission.

FUNDING INFORMATION

The study was partially supported by the Outstanding Youth Foundation of Liaoning Province (no. 2022-YQ-07).

CONFLICTS OF INTEREST

The authors have no conflicts to report.

Yiyang Shang, Cai’e Wang, Huiyuan Lu, Lu Chai, and Wentao Xu are co-first authors.

Abbreviations: AE, adverse event; AVB, acute variceal bleeding; CINF, continuous infusion; CTCAE, common terminology criteria for adverse events; HA, human albumin; HRS, hepatorenal syndrome; PRISMA, preferred reporting items for systematic reviews and meta-analyses; RCT, randomized controlled trial; RIS, required information size; SAE, serious AE; TBiL, total bilirubin level; TSA, trial sequential analysis.

Supplemental Digital Content is available for this article. Direct URL citations are provided in the HTML and PDF versions of this article on the journal's website, www.hepcommjournal.com.
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