Comparison of outcomes between variceal and non-variceal gastrointestinal bleeding in patients with cirrhosis: Insights from a Nationwide Inpatient Sample

Introduction

Upper gastrointestinal bleeding (UGIB), broadly classified into variceal UGIB (VUGIB) and non-VUGIB (NVUGIB), results in significant mortality as high as 10-15% [1,2]. VUGIB occurs in patients with decompensated cirrhosis, but NVUGIB is not uncommon, and 30-40% of cirrhotic patients can have NVUGIB [3,4]. Despite advances in the management of UGIB, it remains a strong predictor of overall mortality [5]. UGIB in cirrhotic patients yields higher mortality trends compared to patients who do not have cirrhosis [6,7]. Frailty due to accompanying comorbidities and disturbances in coagulation pathways due to reduced hepatic synthetic function and thrombophilia are mechanisms that lead to greater mortality from UGIB in cirrhotic patients [8-10].

Apart from mortality, UGIB overall is also responsible for greater health resource utilization, including healthcare costs and length of stay (LOS) in patients with cirrhosis [11]. Despite the aforementioned unfavorable outcomes, no study has compared the outcomes of VUGIB and NVUGIB in the cirrhosis population based on a large sample size. Therefore, the present study was undertaken to assess the difference in mortality due to VUGIB and NVUGIB in cirrhotic patients. In addition, we reported the impact of diverse patient characteristics and comorbidities on mortality.

Materials and methods

Results

Patient characteristics

Fig. 1 shows the flow diagram for study inclusion. The total number of patients in the studied NIS cohort was 107,001,355, of whom 2,166,194 (2.02%) had a diagnosis of cirrhosis (Table 1). The causes of cirrhosis included alcohol (42.38%), toxins/poisoning (0.12%), nonalcoholic steatohepatitis (12.35%), passive congestion (0.30%), autoimmune hepatitis (2.14%), biliary cirrhosis (2.93%), chronic viral hepatitis (28.36%), and others (11.42%). Among patients with cirrhosis, 92,439 had NVUGIB, 17,620 were admitted with a primary diagnosis of VUGIB, and 3584 had hepatic encephalopathy. There were no differences between the match variables before and after propensity score matching. Patients with NVUGIB were more likely to be older and female, more likely to be insured by Medicare, less likely to have Medicaid or private insurance, and had no to very little difference in median annual income compared with VUGIB patients. NVUGIB was found more in the White and Black population, while Hispanic and Asian patients with cirrhosis had a higher comparative prevalence of VUGIB. Among VUGIB, 37.21% had diabetes mellitus, and 24.78% had chronic kidney disease. Patients with VUGIB also had higher CCI scores.

Table 1 Baseline characteristics of patients

Figure 1 Study selection process

n, number; NVUGIB, non-variceal upper gastrointestinal bleeding; VUGIB, variceal upper gastrointestinal bleeding

Inpatient mortality

Overall, inpatient mortality due to any cause in cirrhotic patients was 5.83% (Table 2). Mortality was 3.79% for NVUGIB and 5.42% for patients with VUGIB (unadjusted). Even after adjusting for confounders, VUGIB patients had higher odds of inpatient mortality compared to NVUGIB (adjusted odds ratio [aOR] 1.42, 95% confidence interval [CI] 1.19-1.69; P<0.001).

Table 2 Outcomes in hospitalized patients

Independent predictors of mortality

Independent predictors of mortality were assessed for VUGIB. The final model (multivariate regression model) is presented in Table 3. The variables that independently increased mortality in VUGIB patients were ascites, hyponatremia, spontaneous bacterial peritonitis, hepatic encephalopathy, hepatorenal syndrome, age, and admission to medium or large-sized hospitals. The variables resulting in lower mortality odds from VUGIB in cirrhosis were diabetes mellitus and female sex.

Table 3 Independent predictors of mortality

Treatment modalities

Upper endoscopy

An in-hospital diagnostic endoscopic examination was performed more in NVUGIB than in VUGIB patients (58.54% vs. 26.24% of admissions), while VUGIB required more endoscopic therapy (35.32% vs. 17.20% of admissions). Similar results were reproduced on confounder-adjusted odds analysis (Table 4). In addition, early (within 24 h) upper endoscopy (whether diagnostic or with therapy) was performed more in VUGIB (50.96% vs. 49.04%, P<0.001). The discharge endoscopic diagnoses for NVUGIB were esophagitis (10.8%), esophageal ulcer (3.6%), gastritis (12.8%), gastric ulcer (21.2%), duodenitis (2.5%), duodenal ulcer (14.8%), angiodysplasia (12.7%), Dieulafoy’s lesion (4.2%), and others (17.4%).

Table 4 In-hospital procedures

Radiology interventions

Transjugular intrahepatic portosystemic shunt (TIPS) was performed more in VUGIB (aOR 6.18, 95%CI 3.32-11.49; P<0.001). The indication for TIPS was refractory ascites in NVUGIB patients. However, radiography-guided embolization was required more in NVUGIB (0.42% vs. 0.17%). After adjusting for confounders, the NVUGIB group was 59% more likely to have undergone radiologic-guided embolization than the VUGIB group (aOR 0.41, 95%CI 0.17-0.95; P=0.03).

Discussion

We showed that in-hospital mortality in patients with cirrhosis and NVUGIB is 3.79%. This finding is in line with a prior study showing that cirrhotic patients are at higher risk of NVUGIB than the general population [15]. However, it differs from the in-hospital mortality of 2.1% reported by Abougergi et al [16]. A previous study by Tandon et al compared mortality from VUGIB with NVUGIB and yielded results contradictory to ours, as they found no difference in mortality [17]. That study was performed outside of the United States and had a very small sample size. Our study had a large sample size, which reduces the likelihood of beta error in estimates obtained, and the population studied is nationally representative of the inpatient population in the United States. Another plausible explanation is that the mortality trend is specific to the healthcare system in the United States, but studies in different regions across the globe are not available.

Historically, predictors independently associated with the mortality from VUGIB described in the literature include age, higher Child-Pugh class and model for end-stage liver disease (MELD) score, low hemoglobin, systolic blood pressure, rebleeding, higher serum bilirubin, impaired renal function, and active bleeding seen on endoscopy [18-21]. Our study found that certain systematic and biologic factors, such as age, self-pay status, admission to larger hospitals, admission over the weekend, ascites, hepatic encephalopathy, spontaneous bacterial peritonitis, hyponatremia and hepatorenal syndrome also predict mortality from VUGIB independently. Age, ascites, hepatic encephalopathy, and hyponatremia represent scoring components for calculating Child-Pugh class and MELD scores [22,23]. Larger hospitals usually act as referral and tertiary care centers for patients with higher comorbidity and higher frailty. Previous studies have resulted in contradictory findings regarding the impact of the day of admission on mortality in VUGIB and NVUGIB. For NVUGIB specifically, most studies found no effect based on the day of admission [24-26]. Ananthakrishnan et al and Abougergi et al reported that weekend admission was not associated with greater odds of mortality for VUGIB. Both studies used a smaller subset of the same dataset that we used and employed the same definition of weekend admission as we did. Ananthakrishnan et al captured 7240 weekend admissions with VUGIB, while there were 3251 patients with VUGIB in the Abougergi et al study. In our study, we were able to use a larger sample size (n=17,620 VUGIB) and demonstrated that weekend admission is independently associated with mortality for VUGIB when compared to NVUGIB. Female sex was associated with lower odds of mortality in VUGIB: a finding in line with prior studies where female sex was associated with better survival outcomes in VUGIB and overall cirrhosis [27,28]. Studies pointing towards more immune suppression following hemorrhage and trauma in males can offer a potential explanation for sex-related differences in mortality trends observed in VUGIB [29].

There was a greater likelihood of hemorrhagic shock, vasopressor requirement, intubation and ICU stay in patients with VUGIB. Hemorrhagic shock is an established phenomenon in patients with VUGIB, usually treated with PBRC transfusion and administration of crystalloids. Prophylactic endotracheal intubation is commonly practiced for airway protection in critically ill patients with UGIB prior to upper endoscopy, despite the limited evidence suggesting a clear outcome benefit [30]. Studies directly comparing endotracheal intubation rates and effects on outcomes are lacking, but we showed that the rate of endotracheal intubation was higher in VUGIB than in NVUGIB (11.74% vs. 4.52%). Hepatic encephalopathy commonly complicates VUGIB and governs the increased rate of endotracheal intubation in the peri-endoscopy period.

We also demonstrated that a greater proportion of patients required endoscopic therapy in the VUGIB group, while endoscopy without therapy (i.e., diagnostic endoscopy) was performed more in NVUGIB patients. Varices are formed because of blockage in the blood flow in the liver with resultant high backpressure, causing the formation of varices with an increased tendency to rupture and bleed [30]. The endoscopic treatment of choice for VUGIB is band ligation. Minor cases of NVUGIB may not need endoscopic therapy and improve with supportive measures. Recurrent bleeding despite endoscopic therapy or failure to achieve hemostasis requires rescue radiologic or surgical intervention to control bleeding. Radiography-guided embolization of the bleeding vessel was performed more in NVUGIB, while TIPS was the most commonly used radiologic procedure in the VUGIB population.

Using a nationally representative sample, we also demonstrated that PRBC transfusion was more common in VUGIB than NVUGIB. There is very limited literature directly comparing blood transfusion requirements between the 2 groups. We also showed that the PRBC transfusion requirement within the first 24 h was also greater in VUGIB. Variceal bleeding correlates with a high hepatic venous pressure gradient (>20 mmHg) [31]; thus, a restricted threshold should be adopted for transfusion while balancing the need to avoid complications from hemorrhagic shock. However, no difference was found in the time from patient presentation to when the first PRBC transfusion was given. This suggests that emergency room providers efficiently prioritize the blood transfusion needs of patients with UGIB, depending on their hemodynamic status, and intervene promptly.

The available literature hints at mixed trends for the difference in LOS between the 2 groups of UGIB. Tandon et al directly compared the LOS between the 2 groups and found no significant difference between them (median LOS, VUGIB: 4.9, NVUGIB: 5.0, P=0.34); however, the results were probably skewed due to the smaller sample size. In our study, the mean LOS for VUGIB ranged from 4.68-4.98, while the NVUGIB range was 4.42-4.56. Prior high-quality evidence suggests that early endoscopy reduces the LOS in UGIB [32]. We found in our dataset that early endoscopy (within 24 h) was performed more in VUGIB (50.96% vs. 49.04, P<0.001), whereas mean LOS was significantly greater by 0.30 days in VUGIB, even though the difference may not be clinically relevant. Total hospital costs and charges were greater in VUGIB as a result of greater resource utilization, be it LOS or requiring comparatively more endoscopic therapy.

This trend is also supported by a prior study comparing the costs between the 2 groups [11]. In the contemporary healthcare delivery system, there is a great deal of focus on cost-effectiveness and viability of systems, as the center of Medicare and Medicaid Services has established a target to cover half of Medicare payments in unconventional and substitute payment models involving value-based purchasing. Prevention of bleeding represents an ideal way of achieving better cost-effectiveness. We showed that VUGIB results in higher resource utilization compared to NVUGIB. Each episode of VUGIB prevented will decrease in-hospital mortality by 42%, LOS by 0.30 days, total hospitalization costs by $1467-2632, and the total hospitalization charges by $5634-10,998 compared to NVUGIB in patients with cirrhosis. These numbers are based on observational findings from a retrospective cohort study, and prospective studies in the future will help directly test and confirm these findings in real-life practice.

There are various limitations to our study. First, the exposure is not completely randomized, given the retrospective nature of our study. We employed propensity matching and multivariate regression models to control for confounders. Even though the results obtained from both methods were similar, which reduces the likelihood of confounding, residual confounding can still exist. Moreover, we controlled for diverse patient and hospital-level characteristics, which further minimizes the risk. Second, an administrative database was used to acquire the data. Claims-based databases such as NIS are inherently vulnerable to missing codes or erroneously entered data [33]. Moreover, UGIB itself is prone to coding inaccuracies, as shown by Joos et al [34]. Nonetheless, the frequency of missing data among the variables we used was less than 2.5%, with a few exceptions, and the multiple imputations method was used to explicate the missing data. Third, the unavailability of laboratory values in the database made it impossible to use UGIB-specific severity scales and MELD score; instead, the CCI, a generalized validated prognostic scale, was used, as in previous studies [26]. Similarly, the overlapping diagnosis of AKI and hepatorenal syndrome in cirrhosis poses challenges in assessment. Even though reflective of clinical practice in the United States, care should be taken during analyzing AKI results in the study, as low baseline creatinine in cirrhotic patients can lead to misdiagnosis of AKI. Finally, we reported the overall inpatient mortality of patients hospitalized with a principal diagnosis of either VUGIB or NVUGIB, as the cause of death could not be determined from the database. We believe further well-designed cohort studies are required to overcome the limitations in this study.

Regardless of these limitations, our study has numerous strengths. To our knowledge, this is the first study that compares the mortality of VUGIB, its predictors and other outcomes, with those of NVUGIB at the national level. Moreover, the NIS database eliminates the commonly encountered limitation of single-center studies by allowing the use of a large sample size, as it is the largest publicly available all-payer database consisting of the inpatient population. Propensity matching is a powerful tool for the analysis of administrative databases and helps control confounding by indication [35]. It relies on a wide range of empirically-derived covariates that serve as surrogates for unmeasured confounding variables while matching cases with controls [36]. Utilizing nationally representative data, our study eliminated biases related to practice patterns in single- or multi-center studies. Similarly, the distinctive variables in the database granted us the opportunity to explore variables such as household income estimates, hospitalization cost and hospital factors, which are not generally possible in single-center studies.

In conclusion, cirrhotic patients with VUGIB have 5 times the inpatient mortality compared with NVUGIB patients. In addition to the already known prognostic indicators, we report that self-pay status, admission to larger hospitals, ascites, spontaneous bacterial peritonitis, and hyponatremia are independent predictors of mortality and should alert treating physicians to a poorer prognosis. VUGIB patients also had a higher likelihood of morbidity measured by hemorrhagic shock, vasopressor requirement, intubation and ICU stay, as well as higher resource utilization as indicated by PRBC transfusion, hospital LOS, adjusted total hospitalization charges and costs, and higher rates of upper endoscopy therapy involving both acuity and complexity of intervention during the procedure. Further research is warranted to test interventions to reduce the morbidity and mortality gap between these 2 subgroups.