Abstract

Background: Proton pump inhibitor (PPI) is commonly used in patients with cirrhosis. However, some studies demonstrated that PPI use was associated with adverse outcome in patients with cirrhosis. We aimed to perform a meta-analysis of cohort studies to evaluate the association between PPI use and mortality in cirrhotic patients.

Methods: Relevant studies were obtained via search of PubMed and Embase databases. A randomized-effect model was used to pool the results. Subgroup analyses were performed to evaluate the source of heterogeneity.

Results: Overall, 21 cohort studies with 20,899 patients and 7457 death events were included. The pooled results with a randomized-effect model showed that PPI use was associated with significantly increased risk of mortality in patients with cirrhosis (adjusted relative risk [RR] = RR: 1.39, P<0.001) with considerable heterogeneity (I2=73%). Subgroup analyses showed that characteristics such as patient ethnicity, sample size, definition of PPI use, and complications of patients did not affect the association. However, the association between PPI use and mortality was independent of study characteristics including patient ethnicity, sample size, complications, definition of PPI use, and follow-up duration. However, the association between PPI use and mortality in cirrhotic patients was significant in retrospective studies (RR: 1.40, P<0.001), but not in prospective studies (RR: 1.34, P=0.33).

Conclusions: PPI use may be associated with moderately increased mortality in cirrhotic patients. Although prospective cohort studies are needed to validate our findings, PPI should only prescribed to cirrhotic patients with indications for the treatment.

Introduction

Proton pump inhibitors (PPIs) are the first-line medications for the treatment of acid-related diseases, such as gastroesophageal reflux disease, peptic ulcer, and Zollinger-Ellison syndrome et al [1–3]. For patients with cirrhosis, PPIs are also commonly used. According to previous data, proportions of cirrhotic patients who were prescribed with PPIs varied from 30% to 80% [4]. However, the indications and clinical efficacy of PPIs in these patients remain to be validated, which highlights the possible overutilization of PPIs in patients with cirrhosis [5]. Subsequently, increasing evidence from epidemiological studies indicated that PPI use may be associated with adverse outcomes in cirrhotic patients, spontaneous bacterial peritonitis (SBP) [6–11], and hepatic encephalopathy (HE) [12,13]. However, it remains unknown whether PPI use affects mortality in these patients. Previous studies evaluating the association between PPI use and mortality risk in patients with cirrhosis showed inconsistent results [14–34]. An early meta-analysis published in 2015 showed that PPI use was not associated with increased mortality in patients with cirrhosis [11]. However, only four cohort studies [14,16,17,19] were included in the present study, and many related cohort studies have been published since the previous meta-analysis [18,20–34]. In addition, it remains unknown whether study design such as study design, ethnicity of the patients, definition of PPI use, or follow-up duration may affect the outcome. Therefore, we aimed to perform a meta-analysis to systematically evaluate the potential association between PPI use and mortality in patients with cirrhosis.

Methods

The meta-analysis was performed in accordance with the MOOSE (Meta-analysis of Observational Studies in Epidemiology) [35] and Cochrane’s Handbook [36] guidelines.

Literature search

Studies were identified via systematic search of electronic databases of PubMed and Embase via the following terms: (1) “proton pump inhibitor” OR “proton pump inhibitors” OR “acid suppressive therapy” OR “anti-secretory therapy” OR “PPI” OR “anti-ulcer agent” OR “antacid” OR “omeprazole” OR “esomeprazole” OR “lansoprazole” OR “pantoprazole” OR “rabeprazole” OR “ilaprazole” and (2) “cirrhosis” OR “cirrhotic” OR “liver fibrosis”. This extensive search strategy was used to avoid the potential missing of related studies. The search was limited to human studies in English. The reference lists of related original and review articles were also analyzed using a manual approach. The final literature search was performed on September 20, 2019.

Study selection

The inclusion criteria for the studies were: (1) cohort studies published in full-length articles in English; (2) included patients with cirrhosis; (3) evaluated the association between PPI use and mortality risk in these patients; and (4) reported the relative risk for the association after adjustment of potential confounding factors. Reviews, editorials, preclinical studies, and studies irrelevant to the aim of current meta-analysis were excluded.

Data extracting and quality evaluation

Literature search, data extraction, and quality assessment of the included studies were performed according to the predefined inclusion criteria by two independent authors (X.W. and X.L.). If discrepancies occurred, they were resolved by consensus of the two authors. The extracted data included: (1) name of first author, publication year and country where the study was performed; (2) study design characteristics; (3) ethnicity, characteristics, age, and gender of the participants; (4) definition of PPI use; (5) follow-up durations for cohort studies; and (6) variables that were adjusted when presenting the results. The quality of each study was evaluated using the Newcastle–Ottawa Scale [37] that ranges from 1 to 9 stars and judges each study regarding three aspects: selection of the study groups, the comparability of the groups, and the ascertainment of the outcome of interest.

Statistical analyses

We used risk ratios (RRs) and their corresponding 95% confidence intervals (CIs) as the general measure for the association between PPI use and mortality in patients with cirrhosis. Data of RRs and their corresponding stand errors (SEs) were calculated from 95% CIs or P values, and were logarithmically transformed to stabilize variance and normalized the distribution [36]. The Cochrane’s Q test and I2 test were used to evaluate the heterogeneity among the include cohort studies [38]. A significant heterogeneity was considered if I2>50%. We used a randomized-effect model to synthesize the RR data because this model is considered as a more generalized method that incorporates of the potential heterogeneity [36]. Sensitivity analyses, by removing individual study one at a time, were performed to test the robustness of the results [39]. Predefined subgroup analyses were performed to evaluate the influences of study characteristics on the outcome, including study design, patient ethnicity, patient characteristics, sample size, definition of PPI use, and follow-up durations. The potential publication bias was assessed by funnel plots with the Egger regression asymmetry test [40]. We used the RevMan (Version 5.1; Cochrane Collaboration, Oxford, U.K.). and STATA software for the meta-analysis and statistics.

Results

Literature search

The process of database search is summarized in Figure 1. Briefly, 1312 articles were found via initial literature search of the PubMed and Embase databases, and 1264 were excluded through screening of the titles and abstracts mainly because they were not relevant to the purpose of the meta-analysis. Subsequently, 48 potential relevant records underwent full-text review. Of these, 27 were further excluded because two of them did not include patients with cirrhosis, one did not analyze PPI in cirrhotic patients, 15 did not report mortality outcome, two did not provide adjusted data for the association, and the other seven were abstracts of the already included studies. Finally, 21 cohort studies were included [14–34].

Flowchart of database search and study identification

Figure 1
Flowchart of database search and study identification
Figure 1
Flowchart of database search and study identification

Study characteristics and quality evaluation

The characteristics of the included studies are summarized in Table 1. Overall, 21 cohort studies with 20,899 patients and 7457 death events were included, of which 16 were retrospective cohort studies [16–19,22–33], while the other five were prospective cohort [14,15,20,21,34]. As for the ethnicity of the patients, 12 studies included Caucasian patients [15,16,18,20–22,24,28,29,32–34], 7 included Asians [17,19,23,25,26,30,31], and the remaining 2 included patients with mixed ethnicity [14,27]. Most of the studies included patients with hospitalized patients with cirrhosis without serious clinical complications [14–18,20–24,28–30,32,34], while six studies included cirrhotic patients with SBP [19,26], HE [25], Clostridium difficile infection [27], pneumonia [31], and after transjugular intrahepatic portosystemic shunt [33], respectively. The mean ages of the patients varied from 53 to 63 years, and the proportions of male patients varied from 53% to 77%. PPI use was defined as concurrent use at the admission in 13 studies [14,16–18,20,22,25–29,31,34], and any use during follow up in eight studies [15,19,21,23,24,30,32,33]. The follow-up durations varied from within hospitalization to 60 months. Variables including age, gender, comorbidities, and scale for disease severity, such as the Child-Pugh class or the Model for End-stage liver Disease (MELD) score were adjusted when presenting the association between PPI use and mortality. The qualities of the included cohorts were generally good, with NOS scores ranging between 7 and 9 (Table 2).

Table 1
Characteristics of the included studies
StudyCountryDesignEthnicityPatient characteristicsSample sizeMean ageMaleDefinitions of PPI useFollow-up durationsDeath (n)Variables adjustedNOS
Years%Months
van Vlerken 2012 The Netherlands PC Caucasian Cirrhotic patients with ascites 84 55.0 67.0 Any PPI use within follow-up 28 17 Age, gender, and Child-Pugh class 
Bajaj 2012 US PC Mixed Cirrhotic patients 207 55.0 59.9 Current PPI use at admission 49 Age, gender, MELD score, albumin, serum sodium, SOFA score 
de Vos 2013 Belgium RC Caucasian Cirrhotic patients with ascites 51 57.5 68.6 Current use for at least 2 weeks by medical record review 12 40 Age, gender, INR, MELD score, and Child-Pugh class 
Min 2014 Korea RC Asian Cirrhotic patients with SBP 134 58 73.9 Any PPI use during hospitalization Within hospitalization 41 Age, gender, serum sodium, MELD score, and Child-Pugh class 
Kwon 2014 Korea RC Asian Cirrhotic patients with ascites 533 62.3 75.4 Current use of PPI within 30 days before admission 175 Age, gender, and MELD score 
Mandorfer 2014 Austria RC Caucasian Cirrhotic patients with ascites 607 57.5 70.0 Current use on admission by medical record review 10 358 Age, gender, and MELD score 
Dultz 2015 Germany PC Caucasian Cirrhotic patients 272 57.0 66.9 Current PPI use at admission 86 Age, gender, etiology of cirrhosis, and MELD Score 
Merli 2015 Italy PC Caucasian Cirrhotic patients 400 61.5 70.3 Any PPI use during hospitalization Within hospitalization 39 Age, gender, and MELD score 
Cole 2016 U.K. RC Caucasian Cirrhotic patients 198 56.0 65.2 Current PPI use at discharge 23 38 Age, gender, and MELD score 
Kim 2017 Korea RC Asian Cirrhotic patients with a previous SBP 307 57.6 77.1 Any PPI use for at least 1 week during follow-up Within hospitalization 91 Age, gender, etiology of liver disease, serum sodium, SCr, and Child-Pugh class 
Miozzo 2017 Brazil RC Caucasian Cirrhotic patients 258 53.6 58.2 Any PPI use during follow-up 30 155 Age, gender, and MELD score 
Hung 2018a China RC Asian Cirrhotic patients with SBP 2574 60.9 71.8 Current PPI use during hospitalization 12 1785 Age, gender, and MELD score 
Hung 2018b China RC Asian Cirrhotic patients with HE 5020 62.5 68.0 Current PPI use during hospitalization 12 3210 Age, gender, etiology of cirrhosis, and MELD score 
Smith 2018 US RC Mixed Cirrhotic patients with CDI 400 58.5 60.0 Current PPI use at admission 30 44 Age, gender, serum albumin, and MELD score 
Tergast 2018 Germany RC Caucasian Cirrhotic patients with ascites 613 56.1 62.0 Current PPI use within 7 days before admission 121 Age, gender, and MELD score 
Janka 2019 Hungary RC Caucasian Cirrhotic patients 350 56.0 53.7 Regular use of PPI for at least 80% of follow-up periods based on medical chart review 60 147 Age, gender, and MELD score 
Nardelli 2019 Italy PC Caucasian Cirrhotic patients 310 62.2 71.3 Current PPI use at least 4 weeks before admission 14 112 Age, gender, serum albumin, serum sodium, and MELD score 
Lewis 2019 US RC Caucasian Cirrhotic patients after TIPS 2284 56.4 66. 1 Any PPI use at follow-up 13 115 Age, gender, and MELD score 
Dam 2019 Denmark RC Caucasian Cirrhotic patients 1198 57.5 70.0 Current PPI use at admission 81 Age, gender, MELD score, history of variceal bleeding, and history of HE 
Hung 2019 China RC Asian Cirrhotic patients with pneumonia 4804 63.0 71.2 Current PPI use during hospitalization 638 Age, gender, etiology of cirrhosis, and MELD score 
De Roza 2019 Singapore RC Asian Cirrhotic patients 295 62.8 68.1 Any PPI use at follow-up 115 Age, gender, etiology of cirrhosis, history of variceal bleeding and HE, and MELD score 
StudyCountryDesignEthnicityPatient characteristicsSample sizeMean ageMaleDefinitions of PPI useFollow-up durationsDeath (n)Variables adjustedNOS
Years%Months
van Vlerken 2012 The Netherlands PC Caucasian Cirrhotic patients with ascites 84 55.0 67.0 Any PPI use within follow-up 28 17 Age, gender, and Child-Pugh class 
Bajaj 2012 US PC Mixed Cirrhotic patients 207 55.0 59.9 Current PPI use at admission 49 Age, gender, MELD score, albumin, serum sodium, SOFA score 
de Vos 2013 Belgium RC Caucasian Cirrhotic patients with ascites 51 57.5 68.6 Current use for at least 2 weeks by medical record review 12 40 Age, gender, INR, MELD score, and Child-Pugh class 
Min 2014 Korea RC Asian Cirrhotic patients with SBP 134 58 73.9 Any PPI use during hospitalization Within hospitalization 41 Age, gender, serum sodium, MELD score, and Child-Pugh class 
Kwon 2014 Korea RC Asian Cirrhotic patients with ascites 533 62.3 75.4 Current use of PPI within 30 days before admission 175 Age, gender, and MELD score 
Mandorfer 2014 Austria RC Caucasian Cirrhotic patients with ascites 607 57.5 70.0 Current use on admission by medical record review 10 358 Age, gender, and MELD score 
Dultz 2015 Germany PC Caucasian Cirrhotic patients 272 57.0 66.9 Current PPI use at admission 86 Age, gender, etiology of cirrhosis, and MELD Score 
Merli 2015 Italy PC Caucasian Cirrhotic patients 400 61.5 70.3 Any PPI use during hospitalization Within hospitalization 39 Age, gender, and MELD score 
Cole 2016 U.K. RC Caucasian Cirrhotic patients 198 56.0 65.2 Current PPI use at discharge 23 38 Age, gender, and MELD score 
Kim 2017 Korea RC Asian Cirrhotic patients with a previous SBP 307 57.6 77.1 Any PPI use for at least 1 week during follow-up Within hospitalization 91 Age, gender, etiology of liver disease, serum sodium, SCr, and Child-Pugh class 
Miozzo 2017 Brazil RC Caucasian Cirrhotic patients 258 53.6 58.2 Any PPI use during follow-up 30 155 Age, gender, and MELD score 
Hung 2018a China RC Asian Cirrhotic patients with SBP 2574 60.9 71.8 Current PPI use during hospitalization 12 1785 Age, gender, and MELD score 
Hung 2018b China RC Asian Cirrhotic patients with HE 5020 62.5 68.0 Current PPI use during hospitalization 12 3210 Age, gender, etiology of cirrhosis, and MELD score 
Smith 2018 US RC Mixed Cirrhotic patients with CDI 400 58.5 60.0 Current PPI use at admission 30 44 Age, gender, serum albumin, and MELD score 
Tergast 2018 Germany RC Caucasian Cirrhotic patients with ascites 613 56.1 62.0 Current PPI use within 7 days before admission 121 Age, gender, and MELD score 
Janka 2019 Hungary RC Caucasian Cirrhotic patients 350 56.0 53.7 Regular use of PPI for at least 80% of follow-up periods based on medical chart review 60 147 Age, gender, and MELD score 
Nardelli 2019 Italy PC Caucasian Cirrhotic patients 310 62.2 71.3 Current PPI use at least 4 weeks before admission 14 112 Age, gender, serum albumin, serum sodium, and MELD score 
Lewis 2019 US RC Caucasian Cirrhotic patients after TIPS 2284 56.4 66. 1 Any PPI use at follow-up 13 115 Age, gender, and MELD score 
Dam 2019 Denmark RC Caucasian Cirrhotic patients 1198 57.5 70.0 Current PPI use at admission 81 Age, gender, MELD score, history of variceal bleeding, and history of HE 
Hung 2019 China RC Asian Cirrhotic patients with pneumonia 4804 63.0 71.2 Current PPI use during hospitalization 638 Age, gender, etiology of cirrhosis, and MELD score 
De Roza 2019 Singapore RC Asian Cirrhotic patients 295 62.8 68.1 Any PPI use at follow-up 115 Age, gender, etiology of cirrhosis, history of variceal bleeding and HE, and MELD score 

Abbreviations: CDI, Clostridium difficile Infection; DM, diabetes mellitus; HE, hepatic encephalopathy; INR, international normalized ratio; MELD, Model for End-stage liver Disease; NOS, the Newcastle–Ottawa Score; PC, prospective cohort; PPI, proton pump inhibitor; RC, retrospective cohort; SCr, serum creatinine; SBP, spontaneous bacterial peritonitis; TIPS, transjugular intrahepatic portosystemic shunt.

Table 2
Details of study quality evaluation by the Newcastle–Ottawa Scale
StudyRepresentativeness of the exposed cohortSelection of the non-exposed cohortAscertainment of exposureOutcome not present at baselineControl for age and genderControl for other confounding factorsAssessment of outcomeEnough long follow-up durationAdequacy of follow-up of cohortsTotal
van Vlerken 2012 0 1 0 1 1 1 1 1 1 7 
Bajaj 2012 1 1 0 1 1 1 1 1 1 8 
de Vos 2013 0 1 1 1 1 1 0 1 1 7 
Min 2014 0 1 1 1 1 1 1 0 1 7 
Kwon 2014 1 1 0 1 1 1 1 1 1 8 
Mandorfer 2014 1 1 1 1 1 1 1 1 0 8 
Dultz 2015 1 1 0 1 1 1 1 1 1 8 
Merli 2015 1 1 1 1 1 1 0 0 1 7 
Cole 2016 0 1 0 1 1 1 1 1 1 7 
Kim 2017 1 0 0 1 1 1 1 1 1 7 
Miozzo 2017 0 1 0 1 1 1 1 1 1 7 
Hung 2018a 1 0 0 1 1 1 1 1 1 7 
Hung 2018b 1 0 0 1 1 1 1 1 1 7 
Smith 2018 0 1 0 1 1 1 1 1 1 7 
Tergast 2018 1 1 1 1 1 1 0 1 1 8 
Janka 2019 0 1 1 0 1 1 1 1 1 7 
Nardelli 2019 1 1 1 1 1 1 1 1 1 9 
Lewis 2019 0 1 1 1 1 1 1 1 1 8 
Dam 2019 1 1 0 1 1 1 1 0 1 7 
Hung 2019 1 0 0 1 1 1 1 1 1 7 
De Roza 2019 1 1 1 1 1 1 1 0 1 8 
StudyRepresentativeness of the exposed cohortSelection of the non-exposed cohortAscertainment of exposureOutcome not present at baselineControl for age and genderControl for other confounding factorsAssessment of outcomeEnough long follow-up durationAdequacy of follow-up of cohortsTotal
van Vlerken 2012 0 1 0 1 1 1 1 1 1 7 
Bajaj 2012 1 1 0 1 1 1 1 1 1 8 
de Vos 2013 0 1 1 1 1 1 0 1 1 7 
Min 2014 0 1 1 1 1 1 1 0 1 7 
Kwon 2014 1 1 0 1 1 1 1 1 1 8 
Mandorfer 2014 1 1 1 1 1 1 1 1 0 8 
Dultz 2015 1 1 0 1 1 1 1 1 1 8 
Merli 2015 1 1 1 1 1 1 0 0 1 7 
Cole 2016 0 1 0 1 1 1 1 1 1 7 
Kim 2017 1 0 0 1 1 1 1 1 1 7 
Miozzo 2017 0 1 0 1 1 1 1 1 1 7 
Hung 2018a 1 0 0 1 1 1 1 1 1 7 
Hung 2018b 1 0 0 1 1 1 1 1 1 7 
Smith 2018 0 1 0 1 1 1 1 1 1 7 
Tergast 2018 1 1 1 1 1 1 0 1 1 8 
Janka 2019 0 1 1 0 1 1 1 1 1 7 
Nardelli 2019 1 1 1 1 1 1 1 1 1 9 
Lewis 2019 0 1 1 1 1 1 1 1 1 8 
Dam 2019 1 1 0 1 1 1 1 0 1 7 
Hung 2019 1 0 0 1 1 1 1 1 1 7 
De Roza 2019 1 1 1 1 1 1 1 0 1 8 

Association between PPI use and mortality in patients with cirrhosis

Meta-analysis with a randomized-effect model including 21 studies showed that use of PPI was significantly associated with mortality in cirrhotic patients (RR: 1.39, 95% CI: 1.19–1.62, P<0.001; Figure 2) with significant heterogeneity (P for Cochrane’s Q test < 0.001, I2=73%). Results of sensitivity analyses by omitting one dataset at a time did not significantly change the results (RR: 1.31–1.43, P all < 0.001; Table 3). Subgroup analyses according to the study design showed that the association between PPI use and mortality risk in patients with cirrhosis was significant in retrospective cohort studies (16 studies, RR: 1.40, 95% CI: 1.20–1.64, P<0.001), but not in prospective cohort studies (five studies, RR: 1.34, 95% CI: 0.75–2.40, P=0.33; Table 4). However, the difference between the subgroups was not significant (P=0.88). The association between PPI use and mortality in cirrhotic patients was significant and not affected by study characteristics including patient ethnicity, with or without severe complications, sample size, definition of PPI use, or follow-up durations (Table 4).

Forest plots for the meta-analysis of the association between PPI use and mortality in cirrhotic patients

Figure 2
Forest plots for the meta-analysis of the association between PPI use and mortality in cirrhotic patients
Figure 2
Forest plots for the meta-analysis of the association between PPI use and mortality in cirrhotic patients
Table 3
Results of sensitivity analysis
Studies omittedRR95% CII2P for effect
van Vlerken 2012 1.37 1.18–1.60 74% <0.001 
Bajaj 2012 1.42 1.21–1.66 73% <0.001 
de Vos 2013 1.41 1.20–1.66 74% <0.001 
Min 2014 1.38 1.18–1.62 74% <0.001 
Kwon 2014 1.37 1.17–1.60 73% <0.001 
Mandorfer 2014 1.42 1.21–1.67 73% <0.001 
Dultz 2015 1.36 1.17–1.59 73% <0.001 
Merli 2015 1.43 1.23–1.67 71% <0.001 
Cole 2016 1.39 1.19–1.63 74% <0.001 
Kim 2017 1.38 1.18–1.62 74% <0.001 
Miozzo 2017 1.43 1.22–1.67 70% <0.001 
Hung 2018a 1.40 1.18–1.67 74% <0.001 
Hung 2018b 1.41 1.19–1.68 74% <0.001 
Smith 2018 1.38 1.18–1.62 74% <0.001 
Tergast 2018 1.37 1.17–1.60 74% <0.001 
Janka 2019 1.36 1.16–1.59 72% <0.001 
Nardelli 2019 1.37 1.17–1.60 73% <0.001 
Lewis 2019 1.31 1.14–1.50 62% <0.001 
Dam 2019 1.42 1.22–1.67 73% <0.001 
Hung 2019 1.40 1.19–1.67 74% <0.001 
De Roza 2019 1.36 1.17–1.59 73% <0.001 
Studies omittedRR95% CII2P for effect
van Vlerken 2012 1.37 1.18–1.60 74% <0.001 
Bajaj 2012 1.42 1.21–1.66 73% <0.001 
de Vos 2013 1.41 1.20–1.66 74% <0.001 
Min 2014 1.38 1.18–1.62 74% <0.001 
Kwon 2014 1.37 1.17–1.60 73% <0.001 
Mandorfer 2014 1.42 1.21–1.67 73% <0.001 
Dultz 2015 1.36 1.17–1.59 73% <0.001 
Merli 2015 1.43 1.23–1.67 71% <0.001 
Cole 2016 1.39 1.19–1.63 74% <0.001 
Kim 2017 1.38 1.18–1.62 74% <0.001 
Miozzo 2017 1.43 1.22–1.67 70% <0.001 
Hung 2018a 1.40 1.18–1.67 74% <0.001 
Hung 2018b 1.41 1.19–1.68 74% <0.001 
Smith 2018 1.38 1.18–1.62 74% <0.001 
Tergast 2018 1.37 1.17–1.60 74% <0.001 
Janka 2019 1.36 1.16–1.59 72% <0.001 
Nardelli 2019 1.37 1.17–1.60 73% <0.001 
Lewis 2019 1.31 1.14–1.50 62% <0.001 
Dam 2019 1.42 1.22–1.67 73% <0.001 
Hung 2019 1.40 1.19–1.67 74% <0.001 
De Roza 2019 1.36 1.17–1.59 73% <0.001 

Abbreviations: CI, confidence interval; RR, risk ratio.

Table 4
Subgroup analyses for the meta-analysis of the association between PPI use and mortality in patients with cirrhosis
CharacteristicsDataset numberRR (95% CI)P for subgroup effectI2P for subgroup difference
Study design      
  PC 1.34 [0.75, 2.40] 0.33 79%  
  RC 16 1.40 [1.20, 1.64] <0.001 73% 0.88 
Ethnicity      
  Caucasian 12 1.42 [1.07, 1.90] 0.02 83%  
  Asian 1.32 [1.18, 1.48] <0.001 17% 0.63 
Patient characteristics      
  With complications or after procedure 1.50 [1.19, 1.89] 0.001 79%  
  Without complications 15 1.34 [1.08, 1.67] 0.008 71% 0.49 
Number of participants      
  >500 11 1.33 [1.03, 1.72] 0.03 71%  
  ≤500 10 1.45 [1.18, 1.78] 0.004 76% 0.61 
Definition of PPI use      
  Current PPI use at admission 13 1.28 [1.13, 1.46] <0.001 48%  
  Any PPI use during follow-up 1.60 [1.02, 2.53] 0.04 86% 0.35 
Follow-up durations      
  ≤1 month 1.19 [1.01, 1.40] 0.04 70%  
  >1 month 15 1.42 [1.20, 1.68] <0.001 76% 0.15 
CharacteristicsDataset numberRR (95% CI)P for subgroup effectI2P for subgroup difference
Study design      
  PC 1.34 [0.75, 2.40] 0.33 79%  
  RC 16 1.40 [1.20, 1.64] <0.001 73% 0.88 
Ethnicity      
  Caucasian 12 1.42 [1.07, 1.90] 0.02 83%  
  Asian 1.32 [1.18, 1.48] <0.001 17% 0.63 
Patient characteristics      
  With complications or after procedure 1.50 [1.19, 1.89] 0.001 79%  
  Without complications 15 1.34 [1.08, 1.67] 0.008 71% 0.49 
Number of participants      
  >500 11 1.33 [1.03, 1.72] 0.03 71%  
  ≤500 10 1.45 [1.18, 1.78] 0.004 76% 0.61 
Definition of PPI use      
  Current PPI use at admission 13 1.28 [1.13, 1.46] <0.001 48%  
  Any PPI use during follow-up 1.60 [1.02, 2.53] 0.04 86% 0.35 
Follow-up durations      
  ≤1 month 1.19 [1.01, 1.40] 0.04 70%  
  >1 month 15 1.42 [1.20, 1.68] <0.001 76% 0.15 

Abbreviations: CI, confidence interval; PPI, proton pump inhibitor; PR, prospective cohort; RC, retrospective cohort; RR, risk ratio.

Publication bias

The funnel plots regarding the association between PPI use and mortality in cirrhotic patients were shown in Figure 3. The funnel plots were symmetry on visual inspection, suggesting low chance of significant publication bias. Results of Egger’s regression test also suggested that no significant publication bias (P=0.65).

Funnel plots for the meta-analysis of the association between PPI use and mortality in cirrhotic patients

Figure 3
Funnel plots for the meta-analysis of the association between PPI use and mortality in cirrhotic patients
Figure 3
Funnel plots for the meta-analysis of the association between PPI use and mortality in cirrhotic patients

Discussion

Results of this meta-analysis showed that PPI use was associated with moderately increased mortality in patients with cirrhosis. The association between PPI use and mortality in cirrhotic patients seemed to be independent of demographic factors and scales indicating the disease severity because we included data after adjustment of these confounding factors. Moreover, sensitivity analyses by omitting one study at a time indicated the robustness of the outcome. Subgroup analyses also suggested that the association between PPI use and mortality in cirrhotic patients was consistent in different subgroups according to study characteristics including patient ethnicity, sample size, with or without patient complications, definition of PPI use, and follow-up durations. Although the association between PPI use and mortality was significant in subgroup of retrospective studies but not in subgroups of prospective studies, the difference between the subgroups was not significant. Taken together, these results indicated that PPI use may be associated with increased mortality risk in patients with cirrhosis. Although these findings should be validated in large-scale prospective studies, considering the potential overutilization of PPI in cirrhotic patients, carefully selection of cirrhotic patients with appropriate indications for PPI therapy is recommended before using the medication.

An early meta-analysis published in 2016 failed to show a significant association between PPI use and mortality risk in cirrhotic patients [11]. As mentioned by the authors, the limited number of available studies and sample size may lead to statistical inadequacy of the meta-analysis to reach a positive outcome. Our meta-analysis, by including 21 available cohort studies with 20,899 patients, showed that PPI use was associated with increased mortality in cirrhotic patients. Despite of the large number of studies included, our study has the following strengths. First, we only included article published in peer-reviewed journal, which therefore is of low risk of selection bias. Second, RRs data after adjustment of multiple confounding factors were included and combined, which therefore may provide an independent association between PPI use and mortality risk in cirrhosis patients. Third, we performed exhausting sensitivity and subgroup analyses to evaluate the potential influences of individual study and study characteristics on the outcome. These studies confirmed the robustness of the meta-analysis result, which was not likely to be driven by a single study or affected by study characteristics including patient ethnicity, sample size, with or without complications, definition of PPI, and follow-up durations. Although we found that the association between PPI use and mortality risk was significant in retrospective studies but not in prospective studies, difference between the subgroups was not statistically. Moreover, only five prospective cohorts were available. Therefore, it was likely that the non-significant association between PPI use and mortality risk in subgroup of prospective cohorts may probably be attributed to limited studies available. Since retrospective cohort studies is exposed to recall bias [41], large-scale prospective cohort studies are needed to validate our findings. Collectively, results of this meta-analysis support that PPI is associated with increased mortality in cirrhotic patients. Considering the potential overutilization of PPIs in patients with cirrhosis [5], as well as the potential safety consideration related to the long-term use of PPIs [3], decision for the prescription of PPIs in cirrhotic patients should only be made after carefully evaluating the appropriate indications and balancing the benefits and potential risk of adverse outcomes in these patients.

The reasons and mechanisms for the increased mortality risk associated with PPI use in cirrhotic patients may be multifactorial. First, PPIs, by suppressing gastric acids, may cause bacterial overgrowth in both stomach and intestine [42,43]. Subsequently, the impaired intestinal epithelial barrier in patients with cirrhosis [44] may facilitate the translocation of the overgrown bacteria to mesenteric lymph nodes, which finally leads to SBP and other infections [45]. Moreover, PPIs may also contribute to the gut dysbiosis that generally exists in patients with cirrhosis, whereas altered gut microbiota can induce or exacerbate HE [46,47], another complication that has been related to increased mortality risk in cirrhotic patients [12]. In addition, studies in overall population showed that PPI use may be associated with increased risks of cardiovascular adverse events [48], stroke [49], and fractures [50], which may also lead to increased mortality. Studies regarding the safety of PPI use in various populations, particularly the long-term use of PPI, should be performed to confirm these mechanisms.

Our study has limitations which should be considered when interpreting the results. First, significant heterogeneity exists among the included studies. Although exploring subgroup analyses were performed to evaluate the potential source of heterogeneity, the results of subgroup analyses should be interpreted with caution since the numbers of available studies were limited for each stratum of subgroups. Moreover, since the individual patient data were not available, we could only perform subgroup analyses based on study-level data. The influences of patient and study characteristics on the association between PPI use and mortality in cirrhotic patients should be further analyzed in future studies. Second, although we included studies with adjusted data for the association between PPI use and mortality, we could not exclude the existence of residual factors which may confound the association. Third, a causative association between PPI use and mortality in cirrhotic patients should not be derived based on our finding since the present study was a meta-analysis of observational studies. Randomized controlled trials should be considered to validate the influence of PPI on clinical outcomes in cirrhosis patients. Finally, we could not determine whether the dosages, durations, or individual PPI medications may affect the clinical outcomes of cirrhotic patients differently. Future studies are also warranted in this regard.

Conclusions

In conclusion, results of our meta-analysis indicated that PPI use may be associated with increased mortality risk in cirrhotic patients. Although these findings should be validated in large-scale prospective studies, considering the potential overutilization of PPI in cirrhotic patients, carefully selection of cirrhotic patients with appropriate indications for PPI therapy is recommended before using the medication.

Competing Interests

The authors declare that there are no competing interests associated with the manuscript.

Funding

The authors declare that there are no sources of funding to be acknowledged.

Author Contribution

X.W. and X.L. conceived and designed the study. X.W. and D.Z. selected the studies and collected the data. X.W., D.Z., Y.Y., and L.L. analyzed data, and all authors interpreted the results. XW and XL drafted and revised the paper. All authors revised the draft paper. All authors read and approved the final version of the manuscript.

Abbreviations

     
  • CDI

    Clostridium difficile Infection

  •  
  • DM

    diabetes mellitus

  •  
  • HE

    hepatic encephalopathy

  •  
  • INR

    international normalized ratio

  •  
  • MELD

    Model for End-stage liver Disease

  •  
  • NOS

    the Newcastle–Ottawa Score

  •  
  • PC

    prospective cohort

  •  
  • PPI

    proton pump inhibitor

  •  
  • RC

    retrospective cohort

  •  
  • SBP

    spontaneous bacterial peritonitis

  •  
  • SCr

    serum creatinine

  •  
  • TIPS

    transjugular intrahepatic portosystemic shunt

References

References
1.
Vaezi
M.F.
,
Yang
Y.X.
and
Howden
C.W.
(
2017
)
Complications of Proton Pump Inhibitor Therapy
.
Gastroenterology
153
,
35
48
[PubMed]
2.
Weersink
R.A.
,
Bouma
M.
,
Burger
D.M.
et al.
(
2018
)
Safe use of proton pump inhibitors in patients with cirrhosis
.
Br. J. Clin. Pharmacol.
84
,
1806
1820
[PubMed]
3.
Corley
D.A.
(
2019
)
Safety and Complications of Long-Term Proton Pump Inhibitor Therapy: Getting Closer to the Truth
.
Gastroenterology
157
,
604
607
[PubMed]
4.
Chavez-Tapia
N.C.
,
Tellez-Avila
F.I.
,
Garcia-Leiva
J.
and
Valdovinos
M.A.
(
2008
)
Use and overuse of proton pump inhibitors in cirrhotic patients
.
Med. Sci. Monit.
14
,
CR468
CR472
[PubMed]
5.
Heidelbaugh
J.J.
,
Kim
A.H.
,
Chang
R.
and
Walker
P.C.
(
2012
)
Overutilization of proton-pump inhibitors: what the clinician needs to know
.
Therap. Adv. Gastroenterol.
5
,
219
232
[PubMed]
6.
Trikudanathan
G.
,
Israel
J.
,
Cappa
J.
and
O'Sullivan
D.M.
(
2011
)
Association between proton pump inhibitors and spontaneous bacterial peritonitis in cirrhotic patients - a systematic review and meta-analysis
.
Int. J. Clin. Pract.
65
,
674
678
[PubMed]
7.
Siple
J.F.
,
Morey
J.M.
,
Gutman
T.E.
,
Weinberg
K.L.
and
Collins
P.D.
(
2012
)
Proton pump inhibitor use and association with spontaneous bacterial peritonitis in patients with cirrhosis and ascites
.
Ann. Pharmacother.
46
,
1413
1418
[PubMed]
8.
Deshpande
A.
,
Pasupuleti
V.
,
Thota
P.
et al.
(
2013
)
Acid-suppressive therapy is associated with spontaneous bacterial peritonitis in cirrhotic patients: a meta-analysis
.
J. Gastroenterol. Hepatol.
28
,
235
242
[PubMed]
9.
Khan
M.A.
,
Kamal
S.
,
Khan
S.
,
Lee
W.M.
and
Howden
C.W.
(
2015
)
Systematic review and meta-analysis of the possible association between pharmacological gastric acid suppression and spontaneous bacterial peritonitis
.
Eur. J. Gastroenterol. Hepatol.
27
,
1327
1336
[PubMed]
10.
Xu
H.B.
,
Wang
H.D.
,
Li
C.H.
et al.
(
2015
)
Proton pump inhibitor use and risk of spontaneous bacterial peritonitis in cirrhotic patients: a systematic review and meta-analysis
.
Genet. Mol. Res.
14
,
7490
7501
[PubMed]
11.
Yu
T.
,
Tang
Y.
,
Jiang
L.
,
Zheng
Y.
,
Xiong
W.
and
Lin
L.
(
2016
)
Proton pump inhibitor therapy and its association with spontaneous bacterial peritonitis incidence and mortality: A meta-analysis
.
Dig. Liver Dis.
48
,
353
359
[PubMed]
12.
Ma
Y.J.
,
Cao
Z.X.
,
Li
Y.
and
Feng
S.Y.
(
2019
)
Proton pump inhibitor use increases hepatic encephalopathy risk: A systematic review and meta-analysis
.
World J. Gastroenterol.
25
,
2675
2682
[PubMed]
13.
Tantai
X.X.
,
Yang
L.B.
,
Wei
Z.C.
et al.
(
2019
)
Association of proton pump inhibitors with risk of hepatic encephalopathy in advanced liver disease: A meta-analysis
.
World J. Gastroenterol.
25
,
2683
2698
[PubMed]
14.
Bajaj
J.S.
,
O'Leary
J.G.
,
Reddy
K.R.
et al.
(
2012
)
Second infections independently increase mortality in hospitalized patients with cirrhosis: the North American consortium for the study of end-stage liver disease (NACSELD) experience
.
Hepatology
56
,
2328
2335
[PubMed]
15.
van Vlerken
L.G.
,
Huisman
E.J.
,
van Hoek
B.
et al.
(
2012
)
Bacterial infections in cirrhosis: role of proton pump inhibitors and intestinal permeability
.
Eur. J. Clin. Invest.
42
,
760
767
[PubMed]
16.
de Vos
M.
,
De Vroey
B.
,
Garcia
B.G.
et al.
(
2013
)
Role of proton pump inhibitors in the occurrence and the prognosis of spontaneous bacterial peritonitis in cirrhotic patients with ascites
.
Liver Int.
33
,
1316
1323
[PubMed]
17.
Kwon
J.H.
,
Koh
S.J.
,
Kim
W.
et al.
(
2014
)
Mortality associated with proton pump inhibitors in cirrhotic patients with spontaneous bacterial peritonitis
.
J. Gastroenterol. Hepatol.
29
,
775
781
[PubMed]
18.
Mandorfer
M.
,
Bota
S.
,
Schwabl
P.
et al.
(
2014
)
Proton pump inhibitor intake neither predisposes to spontaneous bacterial peritonitis or other infections nor increases mortality in patients with cirrhosis and ascites
.
PLoS ONE
9
,
e110503
[PubMed]
19.
Min
Y.W.
,
Lim
K.S.
,
Min
B.H.
et al.
(
2014
)
Proton pump inhibitor use significantly increases the risk of spontaneous bacterial peritonitis in 1965 patients with cirrhosis and ascites: a propensity score matched cohort study
.
Aliment. Pharmacol. Ther.
40
,
695
704
[PubMed]
20.
Dultz
G.
,
Piiper
A.
,
Zeuzem
S.
,
Kronenberger
B.
and
Waidmann
O.
(
2015
)
Proton pump inhibitor treatment is associated with the severity of liver disease and increased mortality in patients with cirrhosis
.
Aliment. Pharmacol. Ther.
41
,
459
466
[PubMed]
21.
Merli
M.
,
Lucidi
C.
,
Di Gregorio
V.
et al.
(
2015
)
The chronic use of beta-blockers and proton pump inhibitors may affect the rate of bacterial infections in cirrhosis
.
Liver Int.
35
,
362
369
[PubMed]
22.
Cole
H.L.
,
Pennycook
S.
and
Hayes
P.C.
(
2016
)
The impact of proton pump inhibitor therapy on patients with liver disease
.
Aliment. Pharmacol. Ther.
44
,
1213
1223
[PubMed]
23.
Kim
J.H.
,
Lim
K.S.
,
Min
Y.W.
et al.
(
2017
)
Proton pump inhibitors do not increase the risk for recurrent spontaneous bacterial peritonitis in patients with cirrhosis
.
J. Gastroenterol. Hepatol.
32
,
1064
1070
[PubMed]
24.
Miozzo
S.A.S.
,
John
J.A.
,
Appel-da-Silva
M.C.
,
Dossin
I.A.
,
Tovo
C.V.
and
Mattos
A.A.
(
2017
)
Influence of proton pump inhibitors in the development of spontaneous bacterial peritonitis
.
World J. Hepatol.
9
,
1278
1285
[PubMed]
25.
Hung
T.H.
,
Lee
H.F.
,
Tseng
C.W.
and
Tsai
C.C.
(
2018
)
Effect of proton pump inhibitors in hospitalization on mortality of patients with hepatic encephalopathy and cirrhosis but no active gastrointestinal bleeding
.
Clin. Res. Hepatol. Gastroenterol.
42
,
353
359
[PubMed]
26.
Hung
T.H.
,
Tseng
C.W.
,
Lee
H.F.
and
Tsai
C.C.
(
2018
)
Effect of Proton Pump Inhibitors on Mortality in Patients with Cirrhosis and Spontaneous Bacterial Peritonitis
.
Ann. Hepatol.
17
,
933
939
[PubMed]
27.
Smith
E.Z.
,
Northup
P.G.
and
Argo
C.K.
(
2018
)
Predictors of Mortality in Cirrhosis Inpatients With Clostridium difficile Infection
.
J. Clin. Gastroenterol.
52
,
747
751
[PubMed]
28.
Tergast
T.L.
,
Wranke
A.
,
Laser
H.
et al.
(
2018
)
Dose-dependent impact of proton pump inhibitors on the clinical course of spontaneous bacterial peritonitis
.
Liver Int.
38
,
1602
1613
[PubMed]
29.
Dam
G.
,
Vilstrup
H.
,
Andersen
P.K.
,
Bossen
L.
,
Watson
H.
and
Jepsen
P.
(
2019
)
Effect of proton pump inhibitors on the risk and prognosis of infections in patients with cirrhosis and ascites
.
Liver Int.
39
,
514
521
[PubMed]
30.
De Roza
M.A.
,
Kai
L.
,
Kam
J.W.
et al.
(
2019
)
Proton pump inhibitor use increases mortality and hepatic decompensation in liver cirrhosis
.
World J. Gastroenterol.
25
,
4933
4944
[PubMed]
31.
Hung
T.H.
,
Tseng
C.W.
,
Tsai
C.C.
and
Lee
H.F.
(
2019
)
Effect of proton pump inhibitors on mortality of cirrhotic patients with pneumonia
.
PLoS ONE
14
,
e0216041
[PubMed]
32.
Janka
T.
,
Tornai
T.
,
Borbely
B.
et al.
(
2020
)
Deleterious effect of proton pump inhibitors on the disease course of cirrhosis
.
Eur. J. Gastroenterol. Hepatol.
32
,
257
264
33.
Lewis
D.S.
,
Lee
T.H.
,
Konanur
M.
et al.
(
2019
)
Proton Pump Inhibitor Use Is Associated with an Increased Frequency of New or Worsening Hepatic Encephalopathy after Transjugular Intrahepatic Portosystemic Shunt Creation
.
J. Vasc. Interv. Radiol.
30
,
163
169
[PubMed]
34.
Nardelli
S.
,
Gioia
S.
,
Ridola
L.
,
Farcomeni
A.
,
Merli
M.
and
Riggio
O.
(
2019
)
Proton Pump Inhibitors Are Associated With Minimal and Overt Hepatic Encephalopathy and Increased Mortality in Patients With Cirrhosis
.
Hepatology
70
,
640
649
[PubMed]
35.
Stroup
D.F.
,
Berlin
J.A.
,
Morton
S.C.
et al.
(
2000
)
Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group
.
JAMA
283
,
2008
2012
[PubMed]
36.
Higgins
J.
and
Green
S.
(
2011
)
Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0
.
The Cochrane Collaboration
37.
Wells
G.A.
,
Shea
B.
,
O'Connell
D.
et al.
(
2010
)
The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses
.
38.
Higgins
J.P.
and
Thompson
S.G.
(
2002
)
Quantifying heterogeneity in a meta-analysis
.
Stat. Med.
21
,
1539
1558
[PubMed]
39.
Patsopoulos
N.A.
,
Evangelou
E.
and
Ioannidis
J.P.
(
2008
)
Sensitivity of between-study heterogeneity in meta-analysis: proposed metrics and empirical evaluation
.
Int. J. Epidemiol.
37
,
1148
1157
[PubMed]
40.
Egger
M.
,
Davey Smith
G.
,
Schneider
M.
and
Minder
C.
(
1997
)
Bias in meta-analysis detected by a simple, graphical test
.
BMJ
315
,
629
634
[PubMed]
41.
Coughlin
S.S.
(
1990
)
Recall bias in epidemiologic studies
.
J. Clin. Epidemiol.
43
,
87
91
[PubMed]
42.
Fujimori
S.
(
2015
)
What are the effects of proton pump inhibitors on the small intestine?
World J. Gastroenterol.
21
,
6817
6819
[PubMed]
43.
Sieczkowska
A.
,
Landowski
P.
,
Zagozdzon
P.
,
Kaminska
B.
and
Lifschitz
C.
(
2017
)
The association of proton pump inhibitor therapy and small bowel bacterial overgrowth in children
.
Eur. J. Gastroenterol. Hepatol.
29
,
1190
1191
[PubMed]
44.
Pijls
K.E.
,
Jonkers
D.M.
,
Elamin
E.E.
,
Masclee
A.A.
and
Koek
G.H.
(
2013
)
Intestinal epithelial barrier function in liver cirrhosis: an extensive review of the literature
.
Liver Int.
33
,
1457
1469
[PubMed]
45.
Runyon
B.A.
,
Squier
S.
and
Borzio
M.
(
1994
)
Translocation of gut bacteria in rats with cirrhosis to mesenteric lymph nodes partially explains the pathogenesis of spontaneous bacterial peritonitis
.
J. Hepatol.
21
,
792
796
[PubMed]
46.
Bajaj
J.S.
,
Cox
I.J.
,
Betrapally
N.S.
et al.
(
2014
)
Systems biology analysis of omeprazole therapy in cirrhosis demonstrates significant shifts in gut microbiota composition and function
.
Am. J. Physiol. Gastrointest. Liver Physiol.
307
,
G951
G957
[PubMed]
47.
Gupta
A.
,
Dhiman
R.K.
,
Kumari
S.
et al.
(
2010
)
Role of small intestinal bacterial overgrowth and delayed gastrointestinal transit time in cirrhotic patients with minimal hepatic encephalopathy
.
J. Hepatol.
53
,
849
855
[PubMed]
48.
Hu
W.
,
Tong
J.
,
Kuang
X.
,
Chen
W.
and
Liu
Z.
(
2018
)
Influence of proton pump inhibitors on clinical outcomes in coronary heart disease patients receiving aspirin and clopidogrel: A meta-analysis
.
Medicine (Baltimore).
97
,
e9638
[PubMed]
49.
Malhotra
K.
,
Katsanos
A.H.
,
Bilal
M.
,
Ishfaq
M.F.
,
Goyal
N.
and
Tsivgoulis
G.
(
2018
)
Cerebrovascular Outcomes With Proton Pump Inhibitors and Thienopyridines: A Systematic Review and Meta-Analysis
.
Stroke
49
,
312
318
[PubMed]
50.
Poly
T.N.
,
Islam
M.M.
,
Yang
H.C.
,
Wu
C.C.
and
Li
Y.J.
(
2019
)
Proton pump inhibitors and risk of hip fracture: a meta-analysis of observational studies
.
Osteoporos. Int.
30
,
103
114
[PubMed]
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