Metabolic dysfunction-associated steatohepatitis (MASH) is the most common type of chronic liver disease worldwide with an estimated global prevalence of 30%.1 Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses chronic liver disease on a wide spectrum of severity ranging from subclinical mild steatosis to necroinflammation and rapidly developing fibrosis seen in MASH, the most advanced form of MASLD which may ultimately progress to cirrhosis.2 MASH is now the second most common indication for liver transplantation (LT) worldwide.1 A meta-analysis by Dufour et al estimated the prevalence of MASLD in the United States to range from 11.2-37.2%, with 15.9-68.3% of those having biopsy-proven MASH.3 Shetty et al4 reported a 170% increase in LT due to MASH-related cirrhosis between 2004-2013. An analysis of the U.S. Census Bureau’s data between 2000 and 2014 predicted LT for MASH cirrhosis to further increase by 55.4% by 2030, correlating with rising obesity trends.5 MASH has also been identified as the fastest growing cause of liver cancer (+39%) and liver cancer-related deaths (+38%).6

Metabolic disorders such as obesity, insulin resistance, diabetes mellitus, hypercholesterolemia, and hypertension (along with Asian and Hispanic ethnicity and genetics) are risk factors for developing MASLD and also contribute to the rate of disease progression to MASH and MASH-related cirrhosis.3 Type 2 diabetes mellitus (T2DM) is the most important metabolic risk factor and clinical predictor of adverse outcomes and progression of disease in MASLD. Globally, up to 55% of patients with T2DM have MASLD and 37% have MASH.7 Insulin resistance is believed to be a factor in the progression of steatosis to MASH and fibrosis through sinusoidal collagen deposition, activation of hepatic stellate cells, and ductular proliferation causing portal fibrosis.8

Metabolic disorders are risk factors for the development of coronary artery disease (CAD) in addition to MASH. Patients with MASH are at a higher risk of morbidity and mortality from cardiovascular (CV) events. A meta-analysis by Targher et al9 of 34,043 adults found that patients with MASLD (36.3% of participants) had an increased rate of fatal and nonfatal CV events compared to those without MASLD (odds ratio 2.58; 95% CI, 1.78–3.75). Consequently, many patients being evaluated for LT with other risk factors for CAD (e.g. hyperlipidemia, hypertension, diabetes mellitus, tobacco use, and age greater than 60 years) require further cardiac evaluation; if left heart catheterization with coronary artery stenting is performed, patients will ultimately require dual antiplatelet therapy (DAPT) prior to undergoing LT.10,11 CV events are the leading cause of morbidity and mortality post-LT, but successful coronary revascularization prior to LT has been shown to reduce 30-day myocardial infarction (MI) rates and mortality at 1-year post-LT, highlighting the importance of intentional CV evaluation and intervention prior to LT.10

As part of LT evaluation, patients with cirrhosis undergo evaluation and screening for CAD. Those at high risk of CAD and CV-related complications (e.g. age >60, history of diabetes, impaired systolic function, etc.) must have a heart team evaluation, typically involving invasive testing with coronary angiography.12 Percutaneous coronary intervention (PCI) has historically not been used in patients with decompensated cirrhosis and prominent CAD. Thus, data on the safety of PCI in cirrhosis is limited. An analysis of hospitalized patients found that those with MASH cirrhosis received PCI nearly twice as frequently and were are at an increased risk of mortality following the procedure than their non-MASH equivalents; however, when cardiac risk factors were accounted for, this risk was no longer statistically significant.13 In contrast, a small retrospective study of 16 patients with cirrhosis (most with significant thrombocytopenia) undergoing PCI had no death or acute MI within 30 days, and 9 of 16 patients were listed for LT, suggesting that PCI in cirrhosis is safe and feasible.14

Cirrhosis is associated with an increased risk of both bleeding and clotting due to a disequilibrium of pro- and anti-coagulant components. The liver is the primary source of proteins and coagulation factors. Development and progression of cirrhosis leads to synthetic dysfunction with resulting coagulopathy from lack of natural anticoagulants and Vitamin K-dependent clotting factors. Portal hypertension also precipitates thrombocytopenia via splenic vein congestion, hypersplenism, splenic sequestration, and shunting of blood into the peripheral circulation, inducing a consumptive coagulopathy.15 Clinically significant portal hypertension (CSPH), defined as a hepatic vein portal gradient greater than 10 mmHg, heralds the development of gastroesophageal varices, which also independently increase the risk of gastrointestinal (GI) bleeding.16 Esophageal variceal hemorrhage (VH) has been associated with a significantly increased risk of mortality in cirrhosis, up to 20% at 6 weeks.17,18 Thus, it has been assumed that patients with cirrhosis receiving DAPT are at an extensively higher risk of GI bleeding with an associated increased risk of bleeding-related mortality compared to the average population.

Data regarding the safety of DAPT in cirrhosis is also limited. Use of DAPT in cirrhosis following acute MI was shown to reduce the risk of recurrent MI at 1 year as compared to patients without cirrhosis; DAPT was associated with a significant increase in GI bleeding, but there was no difference in major bleeding events. The higher GI bleeding rate was speculated to have been driven by old events since the variceal hemorrhage rate was exceptionally low (2.8%).19 Spence et al 20 reported nearly a five-fold increase in risk of GI bleeding with use of DAPT following angioplasty for CAD in patients with cirrhosis and thrombocytopenia (but without varices); however, there was no difference in mortality. Krill et al21 also reported that CAD treated with stenting and DAPT led to much higher rates of GI bleeding, but with no difference in mortality. These studies suggest that DAPT can be used in patients with cirrhosis and CAD for short periods of time with a known increased risk of GI bleeding but with no impact on mortality. Thus, CAD evaluation and intervention should not be avoided in cirrhotics undergoing LT evaluation. Our aim is to investigate the risk of and outcomes related to GI bleeding in cirrhotics undergoing LT evaluation who received DAPT.