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Hepatology
Hepatology
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Hepatology (Baltimore, Md.)
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38381716
HEP-23-2100
10.1097/HEP.0000000000000793
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Original Articles: Liver Failure/Cirrhosis/Portal Hypertension
Full adherence to cirrhosis quality indicators is associated with lower mortality in acute variceal bleeding: Nationwide audit
https://orcid.org/0000-0002-0727-1183
Wong Yu Jun 123wongyujun1985@gmail.com

Teng Margaret 4margaret_teng@nuhs.edu.sg

Sim Alyssa 5alyssasim@gmail.com

Thet Htay Myat 6htay_myat_thet@nuhs.edu.sg

Teoh Xuhui 7teoh.xuhui@ktph.com.sg

De Roza Marianne Anastasia 8Marianne.a.dr@gmail.com

Sen Kew Guan 9guan_sen_kew@nuhs.edu.sg

Koh Jia Hong 4jiahong.koh@mohh.com.sg

Loi Pooi Ling 10pooiling.loi@mohh.com.sg

Lim Kai kai.lim@mohh.com.sg
10
Kang Garrett 1Garrettk1991@hotmail.com

Kuang Jonathan 5dragoneti@hotmail.com

Low En Xian Sarah 6Sarah_ex1_Low@nuhs.edu.sg

HO Jing Liang 9jingliang_ho@wh.com.sg

Cher Liu Yuan Gabriel 7cher.gabriel.ly@ktph.com.sg

Sze Kenny 7sze.kenny.cp@ktph.com.sg

Wong Guan Wee 6geneil18@hotmail.com

Kwek Boon Yew Andrew 12andrew.kwek.b.e@singhealth.com.sg

Yang Wei Lyn 5wei_lyn_yang@ttsh.com.sg

Abraldes Juan G. 3juan5@ualberta.ca

Chang Jason 210jason.chang@singhealth.com.sg

1 Department of Gastroenterology & Hepatology, Changi General Hospital, Singapore
2 Duke-NUS Academic Clinical Program, SingHealth, Singapore
3 Liver unit, Division of Gastroenterology & Hepatology, University of Alberta, Canada
4 Division of Gastroenterology and Hepatology, National University Hospital, Singapore
5 Department of Gastroenterology & Hepatology, Tan Tock Seng General Hospital, Singapore
6 Department of Medicine, Division of Gastroenterology & Hepatology, Ng Teng Fong Hospital, Singapore
7 Department of General Medicine, Division of Gastroenterology, Khoo Teck Puat Hospital, Singapore
8 Department of Gastroenterology & Hepatology, Sengkang General Hospital, Singapore
9 Department of Medicine, Woodlands Health, Singapore
10 Department of Gastroenterology & Hepatology, Singapore General Hospital, Singapore
Correspondence Wong Yu Jun, Department of Gastroenterology & Hepatology, Changi General Hospital, 2 Simei St 3, Singapore, 529889. Email: eugene.wong.y.j@singhealth.com.sg
10 2024
20 2 2024
80 4 872886
4 11 2023
23 1 2024
Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.
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 and Aims:

Acute variceal bleeding (AVB) is a major complication in patients with cirrhosis. Using a nationwide AVB audit, we performed a nested cohort study to determine whether full adherence to the AVB quality indicator (QI) improves clinical outcomes in patients with cirrhosis and AVB.

Approach and Results:

We assessed real-world adherence to AVB QI among patients with cirrhosis admitted for AVB in all public hospitals in Singapore between January 2015 and December 2020. Full adherence was considered when all 5 QIs were fulfilled: prophylactic antibiotics, vasoactive agents, timely endoscopy, endoscopic hemostasis during index endoscopy, and nonselective beta-blockers after AVB. We compare 6-week mortality between the full adherence and suboptimal adherence groups using a propensity-matched cohort.

A total of 989 patients with AVB were included. Full adherence to all AVB QI was suboptimal (56.5%). Analysis of the propensity-matched cohort with comparable baseline characteristics showed that full adherence was associated with a lower risk of early infection (20.0% vs. 26.9%), early rebleeding (5.2% vs. 10.2%), and mortality at 6 weeks (8.2% vs. 19.7%) and 1 year (21.3% vs. 35.4%) (p<0.05 for all). While full adherence was associated with a lower 6-week mortality regardless of the MELD score, nonadherence was associated with a higher 6-week mortality despite a lower predicted risk of 6-week mortality. Despite high adherence to the recommended process measures, patients with CTP-C remain at a higher risk of rebleeding, 6-week and 1-year mortality.

Conclusions:

Full adherence to the AVB QI should be the target for quality improvement in patients with cirrhosis.

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What is known?

For patients with acute variceal bleeding (AVB), there is an association between full adherence to quality indicators and 6-week mortality.

What is new here?

In this nested cohort study, using a nationwide variceal bleeding audit that included 559 patients with cirrhosis with AVB with full adherence to quality indicators and 430 patients with suboptimal adherence to quality indicators, full adherence was associated with a significantly lower risk of mortality at 6 weeks (8.2% vs. 19.7% at 6 weeks; OR: 0.37 [95% CI: 0.22–0.60]). While full adherence was associated with lower 6-week mortality regardless of Model of End-Stage Liver Disease and Child-Turcott-Pugh (CTP) scores, nonadherence was associated with a higher 6-week mortality despite a lower predicted probability of 6-week mortality.

Implications

Full adherence to quality indicators should be the target of quality improvement in AVB.

INTRODUCTION

Acute variceal bleeding (AVB) is a devastating complication of cirrhosis.1,2 Advancements in supportive care, pharmacological agents (somatostatin analogs, terlipressin, and nonselective beta-blockers), and effective endoscopic hemostasis (such as variceal banding) have significantly improved the standard of care in managing AVB.3,4 These evidence-based recommendations have been incorporated into more recent guidelines.1,5–7 Although the overall mortality of AVB has declined over the years, the mortality among high-risk patients remains substantial.4,8

Recently, the American Association for the Study of the Liver Disease (AASLD) introduced quality indicators (QIs) to guide physicians in providing quality care to patients with cirrhosis.9 Earlier studies evaluating adherence to these QIs have been limited to small-scale, single-center studies10–12 or administrative databases.3 A prior meta-analysis reported low adherence to AVB guidelines; however, only 2 of the included studies focused on the quality of care.4,13 Large-scale nationwide audits to provide real-world representative data on guideline adherence to AVB are still lacking. Meanwhile, it remains unclear whether adherence to QI can lead to improvement in clinical outcomes in the setting of AVB, as many existing studies were underpowered to detect meaningful clinical differences owing to the limited sample size. A previous study showed variable adherence to QIs in managing AVB, but adherence did not show improved survival in patients with AVB.13 Similarly, low uptake of antibiotic prophylaxis in the AVB setting has not been shown to impact 6-week survival in patients with AVB.14,15

To address these gaps, our primary aim was to determine real-world adherence to AVB QI in Singapore. Our secondary aim was to determine whether adherence to the guidelines improves clinical outcomes, specifically mortality at 6 weeks, in patients with AVB. We hypothesized that full adherence to the AVB QI remained suboptimal, and full adherence was associated with a lower 6-week mortality rate. Using the Singapore nationwide AVB audit, we tested our hypothesis to evaluate (1) the real-world adherence of AVB QI and (2) the association between full adherence and 6-week mortality following AVB.

METHODS

Study design

This is a nested cohort study within the first Singapore nationwide AVB audit involving all public hospitals in Singapore. In Singapore, public hospitals account for 80% of the total admissions nationwide because the Ministry of Health provides subsidies for acute inpatient care at public hospitals.16 This study was also supported by the Gastroenterological Society of Singapore (GESS). Ethics approval and consent waiver was granted by the Singhealth Centralized Institutional Review Board (CIRB 2022/2364) for all participating sites. This study was conducted in accordance with the principles of the Declaration of Helsinki.

Study population

The audit included all adult (≥21 years old) patients hospitalized in any of the public hospitals for AVB between January 1, 2015, and December 30, 2021. We used the procedure code for therapeutic endoscopy (SF701 or equivalent) to identify patients with AVB. We defined AVB based on the clinical features of bleeding in the gastrointestinal tract and endoscopic evidence of recent variceal bleeding. Exclusion criteria included (1) patients without cirrhosis, (2) patients who did not undergo upper gastroscopy to confirm AVB, (3) prior admission to another hospital for an index AVB episode within the study period, and (4) missing outcome data. In patients with multiple AVB episodes, only the index AVB episode during the audit period was considered.

Active bleeding was defined as active bleeding during the insertion of endoscope.1 Cirrhosis was diagnosed based on either one of the following clinical criteria: (1) radiological findings (nodular liver and/or irregular liver margin and/or splenomegaly), (2) histological features of established cirrhosis, or (3) liver stiffness measurement ≥15 kPa.17 The diagnosis of cirrhosis was verified by reviewing the medical charts of all patients, which allowed us to exclude obvious noncirrhotic portal hypertension. There were at least 2–3 reviewers from all participating sites, including the respective site principal investigators (who are all certified hepatologists in practice), with the exception of one site (which is a new hospital open in 2018, and only 25 patients were included from this center since the hospital was not operated at full capacity until late 2022.

The medical records of all patients were reviewed individually by site investigators. To ensure the accuracy of cirrhosis, we performed fidelity checks in at least 10% of patients from each institution by a second reviewer. All participating institutions used standardized templates and a unified data dictionary provided by the data-coordinating team at the Changi General Hospital, Singapore.

AVB QIs

We adopted the AVB QI from the AASLD Cirrhosis Quality Measures proposed by Kanwal et al9,18 in 2010 with refinement by their subsequent publication in 2018. All QIs chosen were graded as class I level A evidence and were deemed to be feasible for accurate data extraction from electronic health records by consensus of the steering committee meeting on August 8, 2022. Adherence to prophylactic antibiotic was included as it was supported by various professional society and meta-analysis. The 5 key QIs included were (1) prophylactic antibiotic within 24 hours of AVB, (2) i.v. somatostatin analog or terlipressin) within 24 hours of AVB, (3) early endoscopy within 12 hours of AVB, (4) endoscopic hemostasis during index endoscopy for AVB, and (5) prescription of nonselective beta-blockers for secondary prophylaxis following AVB episodes.

To determine the clinical impact of full adherence to AVB QI on the clinical outcomes of patients with AVB, we categorized patients into the “full adherence group” (defined as patients who fulfilled all the 5 QIs) versus “suboptimal adherence group” (patients who failed to fulfill all 5 QIs), and compare their clinical outcomes using a propensity-matched, nested cohort of patients with AVB.

Study outcomes

The primary outcome was 6-week mortality.1 The secondary outcomes included early rebleeding (defined as rebleeding within 5 days of index endoscopy), infection, acute-on-chronic liver failure (ACLF), and 1-year mortality. We included both infection and ACLF as secondary outcomes because they were strongly associated with poorer outcomes in patients with cirrhosis with AVB.19,20 One-year mortality was included to capture the long-term outcomes following AVB. ACLF was retrospectively defined based on the European Association for the Study of the Liver-Chronic Liver Failure Consortium criteria.21 Adherence of AVB QI was determined in all patients, while the impact of adherence on clinical outcomes was analyzed in propensity-matched cohort. To ascertain the effect of adherence on the occurrence of ACLF, we intentionally excluded patients with ACLF within the first 24 hours of admission. The presence of infection was defined based on clinical, radiological, or microbiological evidence of infection, as described by Piano et al22.

Sample size calculation

The sample size was calculated using Kelsey et al23 approach. By assuming the prevalence of primary outcome (6-week mortality) in suboptimal adherence group to be 20%,4 the OR 0.5 with full adherence, 80% power, and equal distribution between full and suboptimal adherence groups, the minimum sample size required to determine the impact of full adherence and 6-week mortality was 520 patients.

Statistical analysis

Propensity-matched analysis

To adjust for potential baseline differences between the full and suboptimal adherence groups, we performed propensity score matching using the nearest neighbor method (1:1 ratio), without replacement, with a maximum caliper width of 0.1 of the SD of the propensity score determined by logistic regression.24 Propensity score matching was performed using the following covariates: age, MELD score,25 presence of PVT,26 HCC,27,28 cirrhotic etiology (viral vs. nonviral),29 ascites,30 hematemesis,31 and race.32 The difference in baseline characteristics between the full and suboptimal adherence groups was considered balanced when the absolute standard mean difference was <0.1.33 In addition, we graphically compared the distribution of propensity scores on jitter plot and histogram.33 The matched cohort was subsequently used to compare the clinical outcomes between the full and suboptimal adherence groups. Continuous variables were compared using the Student t test or Mann-Whitney test, and categorical variables were compared using the Chi-square or Fisher exact test, depending on the normality of data distribution, assessed using the Kolmogorov-Smirnov test. The complete data set was used to determine real-world adherence to the AVB QI. Patients with missing clinical outcome data were excluded from the matched propensity score analysis. The optimal full-matching algorithm was used for the sensitivity analysis.

To predict the treatment effect of full adherence, we first estimated the effect of full adherence against the predicted 6-week mortality, which was estimated using both the calibrated MELD model by Reverter et al25 and the calibrated CTP score by Fortune et al.30 We subsequently compared the calibration curve between the predicted and observed 6-week mortality between the full adherence group (vs. suboptimal adherence group) using various model performance metrics, including the C-for-benefit, Eavg-for-benefit, E90-for-benefit, and Brier score.34

Sensitivity and subgroup analysis

Several sensitivity analyses were conducted. First, to reduce the confounding effect of the severity of cirrhosis and HCC on clinical outcomes, we performed a sensitivity analysis in patients with advanced cirrhosis (defined as a CTP score≥7) and patients without HCC.28 We used absolute standardized differences to compare baseline differences between the full and suboptimal adherence groups within these subsets of the cohort. Second, we excluded patients who died within the first 7 or 14 days of presentation. Third, we examine the effect of removing extreme observations by trimming the propensity scores at the 95th, 5th, 85th, 15th, 75th, and 25th percentiles. Fourth, we changed the width of the maximum caliper from 0.1 to 0.05, 0.01 and 0.2 of the SD of the logit of the propensity score. Fifth, we adjusted for propensity score as a variable using all patients in the prematching cohort. Sixth, we used N:1 matching in addition to 1:1 matching. Finally, we calculated the E-value to quantify the degree to which the result may still be influenced by residual confounding from unmeasured covariates (E-value calculator [evalue-calculator.com]).35

Statistical analysis was performed using SPSS version 26.0 (Armonk, NY, IBM Corp) and R software version 4.0 (R Foundation for Statistical Computing) with package “MatchIt,”36 “Hmisc,”37 and “rms.”38 All statistical tests were two-sided, and a p-value <0.05 was considered statistically significant.

RESULTS

Baseline characteristics

This nationwide audit included 989 patients with AVB hospitalized in all public hospitals in Singapore between January 1, 2015, and December 30, 2021 (Supplemental Figure S1, http://links.lww.com/HEP/I286). The baseline characteristics are summarized in Table 1. The overall rate of early rebleeding at 5 days, 6-week, and 1-year mortality rates was 7.1% (70/989) (95% CI: 5.6%–8.9%), 13.8% [133/966] (95% CI: 12%–16%), and 27.9% [266/955] (95% CI: 23.0%-30.1%), respectively. 24% (95% CI: 21.8%–27.3%) developed a bacterial infection during their admission for AVB. The types of infections are summarized in Supplemental Table S1, http://links.lww.com/HEP/I286. ACLF occurred in 6.8% (61/893) of patients, of which 4.3% (38/893) had ACLF at presentation and 2.6% (23/893) developed ACLF beyond 24 hours after admission.

TABLE 1 Baseline characteristics of all patients with cirrhosis with acute variceal bleeding—total cohort and propensity score matched cohort

	Total cohort (n=989)	1:1 Propensity-matched cohorta (n=610)	
Baseline characteristics	Total (n=989), n (%)	Full adherence (n=559), n (%)	Suboptimal adherence (n=430), n (%)	p	Full adherence (n=305), n (%)	Suboptimal adherence (n=305), n (%)	p	
Ageb	61 (12)	61 (12)	60 (13)	0.512	62 (12)	61 (11)	0.805	
Maleb	734 (74.2)	418 (74.8)	265 (72.8)	0.660	225 (73.8)	220 (72.1)	0.715	
Raceb	—	—	—	—	—	—	—	
 Chinese	611 (61.8)	343 (61.4)	221 (60.7)	0.383	202 (66.2)	192 (63.0)	0.165	
 Malay	210 (21.5)	112 (20.0)	84 (23.1)	—	53 (17.4)	74 (24.3)	—	
 Indian	107 (10.8)	66 (11.8)	39 (10.7)	—	34 (11.1)	27 (8.9)	—	
 Others	61 (6.2)	38 (6.8)	20 (5.5)	—	16 (5.2)	12 (3.9)	—	
Etiologyb	—	—	—	—	—	—	—	
 HBV	211 (21.3)	126 (22.5)	73 (20.1)	0.010	66 (21.6)	60 (21.4)	0.132	
 HCV	154 (15.6)	87 (15.6)	59 (16.2)	—	43 (14.1)	49 (16.1)	—	
 Alcohol	186 (18.8)	121 (21.6)	59 (16.2)	—	67 (22.0)	43 (14.1)	—	
 NASH	228 (23.1)	118 (21.1)	94 (25.8)	—	64 (21.0)	85 (27.5)	—	
 Cryptogenic	125 (12.6)	72 (12.9)	47 (12.9)	—	44 (14.4)	39 (12.8)	—	
 Autoimmune	39 (3.9)	16 (2.9)	20 (5.5)	—	9 (3.0)	14 (4.6)	—	
 Others	46 (4.7)	19 (3.4)	12 (3.3)	—	12 (3.9)	13 (4.3)	—	
Liver-related complicationsb	
 Prior variceal bleeding	180 (18.2)	108 (19.3)	72 (16.7)	0.765	55 (18.0)	49 (16.1)	0.591	
 Ascites	283 (28.6)	145 (25.9)	138 (32.1)	0.039	89 (29.2)	94 (30.8)	0.886	
 HE	261 (26.3)	147 (26.3)	114 (26.5)	0.765	82 (26.9)	81 (26.6)	0.996	
 HCC	241 (24.4)	131 (23.4)	110 (25.6)	0.455	75 (24.6)	82 (26.9)	0.579	
 Portal vein thrombosis	159 (16.1)	89 (15.9)	70 (16.3)	0.879	82 (15.6)	43 (15.3)	0.745	
CTP scoreb	7 (6–8)	7 (6–8)	7 (6–8)	0.350	7 (1.2)	7 (1.4)	0.085	
CTP class	—	—	—	—	—	—	—	
 A	379 (38.3)	218 (39.0)	161 (37.4)	—	115 (37.7)	121 (39.7)	0.878	
 B	536 (54.2)	306 (54.7)	230 (53.5)	—	169 (55.4)	163 (53.4)	—	
 C	74 (7.5)	35 (6.3)	39 (9.1)	—	21 (6.9)	21 (6.9)	—	
MELD scoreb	13.5 (5.9)	13.4 (5.6)	14.1 (6.9)	0.087	13.3 (5.8)	13.5 (6.2)	0.630	
Laboratory resultsb	
 Bilirubin (mmol/L)	23 (14–42)	23 (14–40)	22 (13–34)	0.819	23 (14–41)	20 (13–43)	0.149	
 Albumin (g/L)	30 (26–33)	29 (26–33)	30 (26–34)	0.067	30 (26–33)	30 (25–33)	0.812	
 Alanine aminotransferase (U/L)	33 (22–53)	32 (23–51)	33 (22–56)	0.915	32 (22–52)	33 (22–58)	0.782	
 INR (mean; SD)	1.3 (1.1–1.5)	1.3 (1.2–1.4)	1.4 (1.1–1.5)	0.352	1.3 (1.2–1.4)	1.2 (1.1–1.4)	0.523	
 Hemoglobin	8.3 (6.7–10.3)	9.6 (6.6–10.3)	8.2 (6.7–10.2)	0.213	8.4 (6.7–10.1)	8.2 (6.8–10.1)	0.921	
 Platelet (×109/L)	126 (90–176)	126 (92–173)	125 (87–178)	0.960	124 (93–180)	130 (990–177)	0.959	
 Creatinine (mmol/L)	79 (63–109)	79 (62–106)	80 (64–111)	0.682	79 (63–104))	81 (65–139)	0.953	
Severity of bleedingb	
 Hypotension	201 (20.3)	109 (19.5)	92 (21.4)	0.463	57 (18.7)	66 (21.6)	0.419	
 Hematemesis	632 (63.9)	419 (75.0)	213 (49.5)	<0.0001	182 (59.7)	179 (58.7)	0.869	
 Active bleeding during endoscopy	179 (18.1)	99 (17.7)	80 (18.6)	0.717	52 (17.0)	58 (19.0)	0.599	
a Matched for age, MELD score, presence of HCC, PVT, ascites, hematemesis, etiology of cirrhosis, and race.

b Categorical variables reported in number (%), continuous variables reported in mean ± SD or median (interquartile range).

Abbreviation: CTP, Child-Turcotte-Pugh.

Adherence with QIs

The real-world adherence with the individual QI was generally high, with nearly all patients receiving prophylactic antibiotics (91.7%), vasoactive agents (91.7%), endoscopic hemostasis during index endoscopy (91.1%), and timely endoscopy (80.4%) within 12 hours of AVB. However, only 78.6% received nonselective beta-blockers before discharge, and full adherence to all QI was only observed in 56.5% (Figure 1).

FIGURE 1 Proportion of patients adhering to the acute variceal bleeding quality indicators. The adherence to beta-blocker and full adherence to all quality indicators remained suboptimal in real-world settings. *NSBB group defined as the prescription of NSBB before discharge. Full adherence was defined as adherence to all 5 quality indicators. Abbreviation: NSBB, nonselective beta-blocker.

Although patients with full adherence tended to have more severe presentation (hematemesis: 75.0% vs. 49.5%, p<0.001; intubation: 40.5% vs. 30.0%, p=0.001), they were less likely to require salvage therapy, such as balloon tamponade (2.3% vs. 8.5%, p<0.0001) or TIPS (2.8% vs. 4.3%, p=0.069). The proportion of patients with full adherence (vs. suboptimal adherence) was comparable across different CTP-class, HCC status, and PVT status (p>0.05 for all). Full adherence was lower in transplant center versus nontransplant center (49.8% vs. 59.9%, p=0.003), specifically in the domain of having endoscopic hemostasis performed during index endoscopy (86.8% vs. 93.3%, p=0.001) and initiation of beta-blocker prior to discharge (73.0% vs. 81.4%, p=0.003).

Comparison between the unmatched and matched cohort

Unmatched cohort

In the unmatched cohort (n=989), the full adherence group was less likely to have baseline ascites (25.9% [145/559] vs. 32.1% [138/430], p=0.039) or autoimmune-related cirrhosis (2.9% [16/559] vs. 5.3% [23/430], p=0.049). Regarding the clinical outcomes, there was a significant difference in terms of the risk of infection (21.3% vs. 28.6%, p=0.008), early rebleeding (5.4% vs. 9.3%, p=0.017), 6-week mortality (8.4% vs. 20.7%, p<0.001), and 1-year mortality (22.3% vs. 35.0%, p<0.001) between the full and suboptimal adherence group (Figure 2A).

FIGURE 2 Clinical outcomes among acute variceal bleeding patients according to (A) unmatched cohort and (B) propensity-matched cohort. Full adherence was associated with a lower risk of infection, early rebleeding, and mortality in both the matched and unmatched cohort. #Full adherence: define as adherence to all quality indicators. Abbreviation: ACLF, acute-on-chronic liver failure.

Propensity score matched cohort

The propensity score matched cohort included 305 matched pairs (610 patients), where both groups were balanced in baseline characteristics by 1:1 nearest neighbor matching (Table 1, Supplemental Figures S2–S4, http://links.lww.com/HEP/I286). Regarding the clinical outcomes, the full adherence group was associated with a lower risk of infection (20.0% [61/305] vs. 26.9% [82/305], p=0.045), lower risk of early rebleeding (5.2% [16/305] vs. 10.2% [31/305], p=0.023), lower mortality at 6 weeks (8.2% [25/305] vs. 19.7% [60/305], p<0.001), and 1 year (21.3% [65/305] vs. 35.4% [108/305], p<0.001), respectively (Figure 2B).

With optimal matching, the baseline characteristics were comparable (Supplemental Figure S5, http://links.lww.com/HEP/I286). Again, the full adherence group was associated with a lower risk of infection (19.8% [93/469] vs. 29.1% [109/375], p=0.002), lower risk of early rebleeding (5.3% [25/469] vs. 9.3% [35/375], p=0.025), lower risk of mortality at 6 weeks (7.5% [35/469] vs. 20.3%[76/375], p<0.001), and 1 year (20.7% [97/469] vs. 34.7% [130/375], p<0.001), respectively. The reduction in 6-week mortality was consistent in various sensitivity analyses, including trimming the propensity score distribution, changing the caliper width, and changing the adjustment method, as summarized in Table 2. By adjusting for the same variables in logistic regression, full adherence was associated with a lower adjusted odds of 6-week mortality (OR: 0.36, 95% CI: 0.24–0.54) (Table 2).

TABLE 2 Association between adherence to quality indicators with clinical outcomes in patients with cirrhosis with acute variceal bleeding

	Patients	OR for full adherence compared to suboptimal adherence (95% CI)	
Sensitivity analyses	Full adherence	Suboptimal adherence	Infection	ACLF	Early rebleeding	6-wk mortality	1-y mortality	
1:1 nearest neighbor matching	305	305	0.68 (0.47–0.99)	0.40 (0.08–2.06)	0.49 (0.26–0.92)	0.37 (0.22–0.60)	0.49 (0.34–0.71)	
1: N full optimal matching	469	375	0.60 (0.44–0.83)	0.23 (0.05–1.10)	0.55 (0.32–0.93)	0.32 (0.21–0.49)	0.49 (0.36–0.67)	
Optimal matching	375	375	0.63 (0.45–0.88)	0.28 (0.06–1.37)	0.66 (0.39–1.14)	0.38 (0.35–0.59)	0.57 (0.41–0.78)	
Changing caliper width from	—	—	—	—	—	—	—	
 0.1 to 0.2 of the SD of the logit of PS	317	317	0.58 (0.40–0.84)	0.20 (0.02–1.70)	0.48 (0.25–0.92)	0.33 (0.20–0.54)	0.55 (0.39–0.78)	
 0.1 to 0.05 of the SD of the logit of PS	301	301	0.59 (0.40–0.87)	0.20 (0.02–1.70)	0.52 (0.26–1.01)	0.29 (0.17–0.50)	0.57 (0.40–0.82)	
 0.1 to 0.01 of the SD of the logit of PS	248	248	0.60 (0.39–0.92)	0.20 (0.02–1.70)	0.39 (0.17–0.86)	0.26 (0.14–0.48)	0.50 (0.33–0.75)	
Adjusting to propensity score in logistic regressiona	559	430	0.71 (0.52–0.96)	0.53 (0.22–1.26)	0.49 (0.29–0.82)	0.36 (0.24–0.54)	0.55 (0.41–0.74)	
Trimming PS distribution tail to	—	—	—	—	—	—	—	
 95th and 5th percentiles	512	372	0.79 (0.58–1.01)	0.40 (0.08–2.07)	0.64 (0.38–1.07)	0.37 (0.24–0.57)	0.58 (0.42–0.78)	
 85th and 15th percentiles	460	326	0.81 (0.58–1.13)	0.40 (0.08–2.06)	0.64 (0.36–1.11)	0.38 (0.24–0.58)	0.54 (0.39–0.75)	
 75th and 25th percentiles	410	278	0.81 (0.57–1.16)	0.40 (0.08–2.06)	0.63 (0.35–1.14)	0.38 (0.24–0.61)	0.54 (0.38–0.76)	
Sensitivity analysis	—	—	—	—	—	—	—	
 Excluding Child-Pugh class A	224	224	1.00 (0.66–1.52)	0.50 (0.12–2.02)	0.70 (0.37–1.31)	0.49 (0.31–0.81)	0.58 (0.39–0.88)	
 Excluding patients with HCC	257	257	0.51 (0.34–0.78)	1.19 (0.07–19.1)	0.42 (0.20–0.86)	0.31 (0.17–0.59)	0.51 (0.33–0.79)	
 Excluding those who died within 7 days	305	305	0.58 (0.40–0.85)	0.50 (0.09–2.73)	0.65 (0.34–1.25)	0.36 (0.21–0.60)	0.53 (0.42–0.85)	
 Excluding those who died within 14 days	296	296	0.62 (0.42–0.91)	0.75 (0.17–3.37)	0.52 (0.26–1.04)	0.34 (0.19–0.61)	0.56 (0.39–0.82)	
a Adjusting for age, MELD, HCC, PVT, prior variceal bleeding, HE, hematemesis, and albumin.

Abbreviations: ACLF, acute-on-chronic liver failure; PS, propensity score.

To determine whether full adherence remained prognostic even after an event-free period, we performed landmark analysis. After excluding patients who died within 7 and 14 days of the index AVB, the benefit of early rebleeding was no longer significant. Nevertheless, full adherence group remained significantly associated with a lower risk of infection (7 days: OR=0.58, 95% CI: 0.40–0.85; 14 days: OR: 0.62, 95% CI: 0.42–0.91), lower 6-week mortality (7 days: OR=0.36, 95% CI: 0.21–0.60; 14 days: OR=0.34, 95% CI: 0.19–0.61) (Table 2).

Despite having full adherence to all the QI, patients with CTP-class C remained at a higher risk of early rebleeding (23.8% vs. 3.9%, p=0.003) and death (6-week mortality: 38.1% vs. 6.0%, p<0.001; 1-year mortality: 47.6% vs. 19.4%, p=0.005) compared to patients with CTP-class A or B (Figure 3).

FIGURE 3 Clinical outcomes in patients with full adherence to quality indicators of acute variceal bleeding (n=305), stratified CTP class. Despite full adherence, patients with CTP-class C remained at a higher risk of early rebleeding (23.8% vs. 3.9%, p=0.003), and death (6-week mortality: 38.1% vs. 6.0%, p<0.001; 1-year mortality: 47.6% vs. 19.4%, p=0.005) compared to patients in CTP-class A or B. Abbreviations: ACLF, acute-on-chronic liver failure; CTP, Child-Turcotte-Pugh.

Prediction of the treatment effect of full adherence

The observed probability of 6-week mortality was significantly lower in the full adherence group than in the suboptimal adherence group across the full spectrum of MELD and CTP scores (Figure 4A, B). The c-statistics of the calibrated MELD score for predicting 6-week mortality in the 3 cohorts (overall cohort, full adherence group, and suboptimal adherence group) were acceptable but lowest in the full adherence group (c-statistics: overall=0.734 vs. full adherence=0.709 vs. suboptimal adherence=0.752) (Supplemental Figure S6, http://links.lww.com/HEP/I286). This discrepancy was primarily because the calibrated MELD score overestimated the risk of 6-week mortality in the full adherence group. In other words, full adherence was independently associated with lower 6-week mortality across all the predicted risk categories. In contrast, the actual 6-week mortality in the suboptimal adherence group was higher than the risk predicted by the calibrated MELD. This effect was more pronounced when the predicted risk of 6-week mortality was low (where most patients resided). Similar findings were observed using calibrated CTP scores, where full adherence was associated with a lower actual risk of 6-week mortality when the predicted risk of mortality was low (Supplemental Figure S7, http://links.lww.com/HEP/I286). In contrast, suboptimal adherence was associated with a higher actual risk of 6-week mortality even when the predicted risk of mortality was low. (Supplemental Figure S7, http://links.lww.com/HEP/I286). When the predicted risk of 6-week mortality was high, the calibrated CTP model overestimated the actual 6-week mortality risk in patients with full adherence. This finding should be interpreted with caution because the proportion of patients with a high predicted mortality risk was small (Supplemental Figure S8, http://links.lww.com/HEP/I286).

FIGURE 4 (A) Observed 6-week mortality across various MELD scores between full and suboptimal adherence groups. Calibrated MELD score underestimated the risk of 6-week mortality in the overall cohort (B), particularly at the higher MELD scores. The 6-mortality was higher than the predicted risk in suboptimal adherence group (C) with a lower MELD score; the predicted risk of mortality was lower in suboptimal adherence group with a higher MELD score. In full adherence group (D), the 6-week mortality was consistently overestimated, indicating a lower observed mortality risk with full adherence of acute variceal bleeding quality indicator.

Sensitivity analysis

CTP-class

To minimize the confounding effect of the severity of liver disease, we performed a sensitivity analysis in 448 patients with CTP-class B and C. In the matched cohort (n=448), the full and suboptimal adherence groups had comparable baseline characteristics (Table 3). Full adherence was associated with a lower risk of mortality at 6 weeks (13.8% vs. 24.5%, p=0.005) and 1 year (26.9% vs. 38.7%, p=0.013), respectively.

TABLE 3 Comparison between baseline characteristics in patients with advanced cirrhosis (Child-Turcott-Pugh score beyond 7) with full and suboptimal adherence

	Unmatched cohort (n=610)	1:1 PSM-matched cohorta (n=448)	
Baseline characteristics	Full adherence (n=341), n (%)	Suboptimal adherence (n=269), n (%)	p	Full adherence (n=224), n (%)	Suboptimal adherence (n=224), n (%)	p	
Ageb	61 (11)	60 (13)	0.47	61 (11)	61 (13)	0.865	
Maleb	267 (78.3)	207 (77.0)	0.696	171 (76)	173 (77)	0.911	
Raceb	—	—	—	—	—	—	
 Chinese	203 (59.5)	165 (61.4)	0.804	136 (60.7)	137 (61.1)	0.737	
 Malay	67 (19.6)	53 (19.7)	—	44 (19.6)	44 (19.6)	—	
 Indian	46 (13.5)	34 (12.6)	—	32 (14.3)	27 (12.1)	—	
 Others	25 (7.3)	17 (6.3)		12 (5.4)	16 (7.1)	—	
Etiologyb	—	—	—	—	—	—	
 Viral	120 (35.2)	92 (34.2)	0.864	78 (34.8)	77 (34.4)	1	
 Nonviral	221 (64.8)	177 (65.8)		146 (65.2)	147 (65.6)		
Liver-related complicationsb	
 Prior variceal bleeding	68 (19.9)	51 (19.0)	0.837	42 (18.8)	42 (18.8)	1	
 Ascites	123 (36.1)	124 (46.1)	0.013	84 (37.5)	95 (42.4)	0.335	
 HE	131 (38.4)	103 (37.9)	0.764	88 (39.3)	83 (37.)	0.776	
 HCC	85 (24.9)	80 (29.7)	0.199	67 (29.9)	60 (26.8)	0.529	
 Portal vein thrombosis	68 (19.9)	51 (19.0)	0.837	48 (21.4)	45 (20.1)	0.816	
CTP scoreb	8 (7–8)	8 (7–9)	0.012	8 (7–8)	8 (7–9)	0.282	
CTP class	—	—	—	—	—	—	
 A	0	0	0.134	0	0	1	
 B	306 (89.7)	230 (85.5)	—	197 (87.9)	198 (88.4)	—	
 C	35 (10.3)	39 (14.5)	—	27 (12.1)	26 (11.6)	—	
MELD scoreb	14.8 (6.1)	15.9 (7.4)	0.042	15.0 (6.3)	15.3 (7.1)	0.558	
Laboratory resultsb	
 Bilirubin (mmol/L)	32 (15–56)	32 (16–61)	1	33 (16–59)	28 (16–58)	0.57	
 Albumin (g/L)	29 (26–34)	30 (26–35)	0.222	29 (25–33)	30 (26–35)	0.076	
 Alanine aminotransferase (U/L)	32 (23–53)	34 (22–65)	0.746	32 (23–51)	32 (22–57)	0.926	
 INR (mean; SD)	1.3 (1.2–1.5)	1.3 (1.2–1.6)	0.434	1.3 (1.2–1.6)	1.3 (1.1–1.6)	0.38	
 Hemoglobin	8.4 (6.7–10.5)	8.2 (6.6–10.4)	0.502	8.2 (6.4–10.3)	8.4 (6.7–10.4)	0.382	
 Platelet (×109/L)	120 (86–165)	119 (85–172)	0.959	118 (86–161)	126 (89–175)	0.37	
 Creatinine (mmol/L)	80 (63–109)	84 (67–125)	0.415	80 (62–110)	85 (67–123)	0.356	
Severity of bleedingb	
 Hypotension	71 (20.8)	54 (20.1)	0.841	49 (21.)	46 (20.5)	0.817	
 Hematemesis	245 (71.8)	136 (50.6)	<0.0001	136 (60.7)	132 (58.9)	0.773	
 Active bleeding during endoscopy	59 (17.3)	53 (19.7)	0.462	38 (17.0)	45 (20.1)	0.466	
Clinical outcomes	
Infection	86 (25.2)	83 (30.9)	0.145	60 (26.8)	60 (26.8)	1	
ACLF	6 (1.9)	8 (3.2)	0.418	3 (1.5)	6 (2.9)	0.503	
Early rebleeding	24 (7.0)	28 (10.4)	0.147	18 (8.0)	23 (11.2)	0.336	
Mortality, 6 weeks	36 (10.8)	67 (25.7)	<0.001	30 (13.8)	53 (24.5)	0.005	
Mortality, 1 year	84 (25.8)	102 (39.7)	<0.001	57 (26.9)	82 (38.7)	0.013	
a Matched for age, MELD score, cirrhosis etiology (viral vs. nonviral), PVT, HCC, prior variceal bleeding, prior HE, hematemesis, and serum albumin using the nearest neighbor algorithm with maximal calliper of 0.1 in 1:1 ratio.

b Categorical variables reported in number (%), continuous variables reported in mean±SD or median (interquartile range).

Abbreviations: ACLF, acute-on-chronic liver failure; CTP, Child-Turcotte-Pugh; PSM, propensity score matching.

HCC versus non-HCC

To minimize the confounding effect of HCC on clinical outcomes, we performed sensitivity analysis by excluding patients with HCC (n=748). In the matched cohort consisting of 514 patients with balanced baseline characteristics (Table 4), full adherence was associated with a lower risk of infection (18.3% vs. 30.4%, p=0.001), lower risk of early rebleeding (4.3% vs. 9.7%, p=0.016), lower risk of mortality at 6 weeks (5.5% vs. 15.8%, p<0.001), and lower risk of mortality at 1 year (15.2% vs. 26.1%, p=0.003) (Table 4).

TABLE 4 Comparison between baseline characteristics and clinical outcomes in patients with full and suboptimal adherence after excluding patients with HCC

	Unmatched cohort (n=748)	1:1 Propensity-matched cohorta (n=514)	
Baseline characteristics	Full adherence (n=428), n (%)	Suboptimal adherence (n=320), n (%)	p	Full adherence (n=257), n (%)	Suboptimal adherence (n=257), n (%)	p	
Ageb	61 (12)	60 (14)	0.356	62 (12)	60 (14)	0.155	
Maleb	300 (70)	200 (69)	0.753	177 (68.9)	174 (67.7)	0.85	
Raceb	—	—	—	—	—	—	
 Chinese	253 (59.1)	194 (60.6)	0.256	150 (58.4)	153 (60.3)	0.885	
 Malay	82 (19.2)	73 (22.8)	—	65 (25.3)	61 (23.7)	—	
 Indian	61 (14.3)	37 (11.6)	—	28 (10.9)	29 (11.3)	—	
 Others	32 (7.5)	16 (5.0)	—	14 (5.4)	14 (5.4)		
Etiologyb	—	—	—	—	—	—	
 Viral	15 (3.5)	21 (6.6)	0.059	12 (4.7)	12 (4.7)	1	
 Nonviral	413 (96.5)	299 (93.4)	—	245 (95.3)	245 (95.3)	—	
Liver-related complicationsb	
 Prior variceal bleeding	78 (18.2)	55 (17.2)	0.772	52 (20.2)	43 (16.7)	0.363	
 Ascites	99 (23.1)	94 (29.4)	0.065	73 (28.4)	73 (28.4)	1	
 HE	102 (23.8)	77 (24.1)	0.741	68 (26.5)	66 (25.7)	0.979	
 HCC	0	0	—	0	0	—	
 Portal Vein Thrombosis	35 (8.2)	19 (5.9)	0.304	28 (10.9)	18 (7.0)	0.745	
CTP scoreb	7 (6–8)	7 (6–8)	0.213	7 (1.2)	7 (1.4)	0.085	
CTP class	—	—	—	—	—	—	
 A	172 (40.2)	131 (40.9)	0.166	99 (38.5)	110 (42.8)	0.142	
 B	235 (54.9)	163 (50.9)	—	146 (56.8)	127 (49.4)	—	
 C	21 (4.9)	26 (8.1)	—	12 (4.7)	20 (7.8)	—	
MELD scoreb	13 (5.6)	14 (7.0)	0.239	13.3 (5.8)	13.5 (6.2)	0.63	
Laboratory resultsb	
 Bilirubin (mmol/L)	22 (13–38)	22 (12–40)	0.518	21 (13–35)	22 (13–40)	0.442	
 Albumin (g/L)	29 (26–33)	30 (26–34)	0.166	30 (26–34)	30 (25–34)	0.807	
 Alanine aminotransferase (U/L)	31 (22–47)	31 (21–49)	0.823	31 (22–47)	32 (22–50)	0.575	
 INR (mean; SD)	1.3 (1.2–1.5)	1.3 (1.1–1.5)	0.127	1.3 (1.1–1.4)	1.3 (1.1–1.5)	0.327	
 Hemoglobin	8.4 (6.6–10.2)	8.2 (6.7–10.1)	0.911	8.4 (6.7–10.3)	8.2 (6.9–10.1)	0.968	
 Platelet (×109/L)	120 (89–166)	122 (85–172)	0.914	120 (88–169)	123 (86–172)	0.799	
 Creatinine (mmol/L)	77 (60–103)	77 (62–109)	0.629	76 (63–99)	77 (62–105)	0.828	
Severity of bleedingb	
 Hypotension	82 (19.2)	71 (22.2)	0.355	45 (17.5)	63 (24.5)	0.066	
 Hematemesis	311 (77.3)	160 (50.0)	<0.0001	160 (962.3)	160 (62.3)	1	
 Active bleeding during endoscopy	77 (18.0)	58 (18.1)	1	37 (14.4)	52 (20.2)	0.102	
Clinical outcomes	
Infection	91 (21.3)	97 (30.3)	0.005	47 (18.3)	78 (30.4)	0.002	
ACLF	6 (1.6)	2 (0.7)	0.477	1 (0.5)	1 (0.4)	1.000	
Early rebleeding	24 (5.6)	26 (8.1)	0.185	11 (4.3)	25 (9.7)	0.023	
Mortality, 6 weeks	18 (4.3)	53 (16.8)	<0.001	14 (5.5)	40 (15.8)	<0.001	
Mortality, 1 year	55 (13.3)	81 (26.0)	<0.001	38 (15.2)	65 (26.1)	0.003	
a Matched for baseline ascites, hematemesis, and cirrhosis etiology (viral vs. nonviral) using nearest neighbor matching algorithm, maximal calliper of 0.1 in 1:1 ratio.

b Categorical variables reported in number (%), continuous variables reported in mean ± SD or median (interquartile range).

Abbreviations: ACLF, acute-on-chronic liver failure; CTP, Child-Turcotte-Pugh.

E-value for unmeasured confounder

Conditional on measured covariates, the E-values for the point estimate and upper CI for 6-week mortality were 4.85 and 2.72, respectively (Supplemental Figure S9, http://links.lww.com/HEP/I286). This indicates that the observed OR for 6-week mortality could only be explained by another unmeasured confounder that was associated with both adherence to AVB QI and 6-week mortality with a risk ratio of >4.85.

DISCUSSION

In this Singapore nationwide AVB audit, we identified a critical gap in delivering the care bundle of full adherence to patients with AVB. Through a propensity-matched cohort nested within this nationwide AVB audit, we found that full adherence to the AVB QI was associated with lower mortality at 6 weeks. Our findings have important clinical implications because AVB is a devastating complication in patients with cirrhosis. While various guidelines have incorporated evidence-based recommendations to improve the outcomes of patients with AVB, real-world adherence to these guidelines has never been assessed at a national level.10,11 Furthermore, the survival benefit of adhering to these QIs has not been demonstrated to date, as most studies were single-center studies with limited sample sizes. Identifying the gaps in clinical practice is paramount, as it represents the first critical step to improving care delivery in AVB.

Suboptimal adherence to the AVB QI can lead to poorer outcomes in patients with AVB. Strikingly, suboptimal adherence was associated with a higher mortality risk among patients with AVB with a low risk of death (Supplemental Figures 6, 7, http://links.lww.com/HEP/I286). The predicted risk of mortality among the high-risk group (defined by the calibrated MELD score) was lower than that of the Reverter cohort,25 which may reflect the improvement in critical care over the past decade. Given that full adherence is associated with a lower risk of mortality, this should be a target for quality improvement.18 A dedicated care bundle for AVB should be implemented to maximize adherence and minimize heterogeneity in clinical practice. Despite full adherence to all QIs, patients with AVB with CTP class C remained at a high risk of early rebleeding and death following AVB episodes. Our findings reaffirm the current recommendation that definitive treatment, such as pre-emptive TIPSS or liver transplantation, must be considered in high-risk patients.2,7

A meta-analysis of randomized and observational studies has shown that prophylactic antibiotics improve clinical outcomes in patients with AVB.39 However, real-world adherence to prophylactic antibiotics during AVB varied greatly, with the recent large administrative studies showing suboptimal uptake of prophylactic antibiotics (11.5%–60%).3,13,14 In contrast to an administrative database study,13 we found that high adherence to prophylactic antibiotics can be achieved in real-world settings. We hypothesized that this was related to 3 main reasons. First, earlier studies included patients from older period which pre-dates the introduction of AASLD AVB QI.3,40 Second, the management of AVB can varied between institutions, as shown in recent meta-analysis by Tapper et al.13 Lastly, large administrative databases may be prone to miscoding with regard to the diagnosis of cirrhosis and QIs. We believe our findings are accurate, as all patients were individually reviewed by investigators.

In contrast to another study,13 we found that full adherence to the AVB QI was associated with a lower risk of 6-week mortality and early rebleeding, even in patients with AVB with HCC. Importantly, real-world adherence to the AVB QI was not influenced by the presence of HCC. In contrast to our findings, Lee et al,41 reported a higher risk of early rebleeding in patients with AVB with HCC; however, the proportion of patients receiving prophylactic antibiotics was also substantially lower than that in our nationwide cohort (33.7% vs. 92.8%). It is arguable that the stage of HCC may influence these outcomes; however, these data were not captured in the current study.

As the standard of care for managing AVB has improved over the years, it is paramount to better define the benchmark for AVB care and outcomes. Our nationwide study provides updated and representative data on the key outcomes of AVB (5-day rebleeding and 6-week mortality) in a real-world setting, thus setting the benchmark for future quality improvement projects and studies in AVB. The strength of our study lies in the representativeness of our cohort, which included a sizable cohort of patients with AVB from all public hospitals in Singapore to demonstrate the benefit of full adherence. To the best of our knowledge, this is the largest audit to date using a nonadministrative database to evaluate adherence to QIs in the setting of AVB.

The main limitation of this study was its retrospective nature. Information on post-discharge care and admitting disciplines were not captured in our study. Despite the propensity score matching analysis, it was inevitable that residual bias from unmeasured confounding bias may still exist in the absence of randomization. However, the sensitivity analysis using the E-value indicates that the observed OR of 0.37 for 6-week mortality could only be explained by an unmeasured confounder that was associated with both adherence to AVB QI and 6-week mortality by a risk ratio of >4.85. Given that this risk ratio was much greater than any observed and known outcome predictors, such as age (OR=1.03), MELD (OR=1.11), CTP class (Class B: OR=1.22, Class C=2.39), HCC (OR=2.3), PVT (OR=2.8), and active bleeding during endoscopy (OR=1.9) reported in our study (Supplemental Table S2, http://links.lww.com/HEP/I286), it seems implausible that an unmeasured confounder exists that can overcome the effect of full adherence observed in the current study.

Arguably, a randomized trial would not have been ethical if these QIs were the current “standard of care” in the management of AVB. As a multicenter study, our study was subject to heterogeneity across different centers. Nevertheless, our study enhances the external validity and generalizability of our findings as it reflects real-world practice. The reasons behind the nonadherence of QIs were not collected in our study, which would be a relevant extension of our study, given the significant impact of full adherence on AVB outcomes. The findings have been disseminated to the respective centers for reflection, thus allowing each participating center to identify key areas for improvement.

In conclusion, full adherence to QIs was associated with a lower risk of 6-week mortality; however, full adherence to the AVB QI remained suboptimal. Full adherence to the AVB QI should be the target for future quality improvement projects.

Supplementary Material

SUPPLEMENTARY MATERIAL

AUTHOR CONTRIBUTIONS

Yu Jun Wong and Jason Chang: study conception:; Margaret Teng, Guan Sen Kew, Garrett Kang, Alyssa Sim, Jonathan Kuang, Htay Myat Thet, Sarah Low, Xuhui Teoh, Jing Liang Ho, Marianne Anastasia De Roza, Pooi Ling Loo, Kai Lim, and Jason Chang: data acquisition; Yu Jun Wong and Juan G Abraldes: manuscript draft; Yu Jun Wong: critical review of the manuscript; all authors: final review.

ACKNOWLEDGMENTS

The authors thank the Gastroenterology Society of Singapore for endorsing and supporting this audit.

FUNDING INFORMATION

Yu Jun Wong is supported by the Nurturing Clinician Scientist Scheme (NCSS) award from the SingHealth Duke-NUS Academic Medical Center.

CONFLICTS OF INTEREST

Yu Jun Wong is on the speakers’ bureau for AbbVie and Gilead. Juan G. Abraldes consults for 89Bio, Advanz, Astra Zeneca, Boehringer Ingelheim, Boston Pharmaceuticals, and Novo Nordisk. He received grants from Cook and Gilead. The remaining authors have no conflicts to report.

Abbreviations: ACLF, acute-on-chronic liver failure; AVB, acute variceal bleeding; CTP, Child-Turcotte-Pugh; GESS, Gastroenterological Society of Singapore; QI, quality indicator.

Juan G. Abraldes and Jason Chang are co-last authors.

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.hepjournal.com.
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