Global disparities in mortality and liver transplantation in hospitalised patients with cirrhosis: a prospective cohort study for the CLEARED Consortium

Summary

Background

Cirrhosis, the end result of liver injury, has high mortality globally. The effect of country-level income on mortality from cirrhosis is unclear. We aimed to assess predictors of death in inpatients with cirrhosis using a global consortium focusing on cirrhosis-related and access-related variables.

Methods

In this prospective observational cohort study, the CLEARED Consortium followed up inpatients with cirrhosis at 90 tertiary care hospitals in 25 countries across six continents. Consecutive patients older than 18 years who were admitted non-electively, without COVID-19 or advanced hepatocellular carcinoma, were enrolled. We ensured equitable participation by limiting enrolment to a maximum of 50 patients per site. Data were collected from patients and their medical records, and included demographic characteristics; country; disease severity (MELD-Na score); cirrhosis cause; medications used; reasons for admission; transplantation listing; cirrhosis-related history in the past 6 months; and clinical course and management while hospitalised and for 30 days post discharge. Primary outcomes were death and receipt of liver transplant during index hospitalisation or within 30 days post discharge. Sites were surveyed regarding availability of and access to diagnostic and treatment services. Outcomes were compared by country income level of participating sites, defined according to World Bank income classifications (high-income countries [HICs], upper-middle-income countries [UMICs], and low-income or lower-middle-income countries [LICs or LMICs]). Multivariable models controlling for demographic variables, disease cause, and disease severity were used to analyse the odds of each outcome associated with variables of interest.

Findings

Patients were recruited between Nov 5, 2021, and Aug 31, 2022. Complete inpatient data were obtained for 3884 patients (mean age 55·9 years [SD 13·3]; 2493 (64·2%) men and 1391 (35·8%) women; 1413 [36·4%] from HICs, 1757 [45·2%] from UMICs, and 714 [18·4%] from LICs or LMICs), with 410 lost to follow-up within 30 days after hospital discharge. The number of patients who died while hospitalised was 110 (7·8%) of 1413 in HICs, 182 (10·4%) of 1757 in UMICs, and 158 (22·1%) of 714 in LICs and LMICs (p<0·0001), and within 30 days post discharge these values were 179 (14·4%) of 1244 in HICs, 267 (17·2%) of 1556 in UMICs, and 204 (30·3%) of 674 in LICs and LMICs (p<0·0001). Compared with patients from HICs, increased risk of death during hospitalisation was found for patients from UMICs (adjusted odds ratio [aOR] 2·14 [95% CI 1·61–2·84]) and from LICs or LMICs (2·54 [1·82–3·54]), in addition to increased risk of death within 30 days post discharge (1·95 [1·44–2·65] in UMICs and 1·84 [1·24–2·72] in LICs or LMICs). Receipt of a liver transplant was recorded in 59 (4·2%) of 1413 patients from HICs, 28 (1·6%) of 1757 from UMICs (aOR 0·41 [95% CI 0·24–0·69] vs HICs), and 14 (2·0%) of 714 from LICs and LMICs (0·21 [0·10–0·41] vs HICs) during index hospitalisation (p<0·0001), and in 105 (9·2%) of 1137 patients from HICs, 55 (4·0%) of 1372 from UMICs (0·58 [0·39–0·85] vs HICs), and 16 (3·1%) of 509 from LICs or LMICs (0·21 [0·11–0·40] vs HICs) by 30 days post discharge (p<0·0001). Site survey results showed that access to important medications (rifaximin, albumin, and terlipressin) and interventions (emergency endoscopy, liver transplantation, intensive care, and palliative care) varied geographically.

Interpretation

Inpatients with cirrhosis in LICs, LMICs, or UMICs have significantly higher mortality than inpatients in HICs independent of medical risk factors, and this might be due to disparities in access to essential diagnostic and treatment services. These results should encourage researchers and policy makers to consider access to services and medications when evaluating cirrhosis-related outcomes.

Funding

National Institutes of Health and US Department of Veterans Affairs.

Introduction

Chronic liver disease and cirrhosis are important causes of morbidity and mortality worldwide,¹ and this burden is projected to grow with time.² Chronic liver disease accounts for 2 million (4%) deaths annually and is the 11th leading cause of death worldwide.¹ Cirrhosis progresses from a compensated to a decompensated stage, with complications such as ascites, variceal bleeding, hepatic encephalopathy, acute kidney injury, and increased infection risk. The proximate cause of death in most patients is organ failure.³ Inpatients with cirrhosis require resource-intensive management strategies that vary worldwide in affordability and access. In the USA in 2016, the cost of treating liver disease was US$32·5 billion, with almost 70% of this amount used for inpatient or emergency department care; however, it is unclear whether this substantial expenditure in high-income countries (HICs) is associated with better outcomes than those in lower-income countries.⁴ Most cirrhosis studies are from HICs or are regional5, 6, 7 and have not considered the availability and affordability of diagnostic and treatment modalities or cultural or social factors. Disparities in liver disease diagnosis, management, and outcomes among underserved populations have been identified in the USA.⁸ Global, prospectively collected data are sparse and are needed to inform approaches to improving patient outcomes. We initiated the Chronic Liver Disease Evolution and Registry for Events and Decompensation (CLEARED) Consortium with the aim of determining predictors of death in hospitalised patients with cirrhosis across all populated continents using prospectively collected data.