1. Patient characteristics
A total of 943 HBV-related cirrhosis and acute gastrointestinal bleeding were included in the final analysis, of which 593 and 350 patients were randomly enrolled into the derivation and validation cohorts, respectively. Table 1 compares demographic, clinical, and laboratory characteristics between the two cohorts of patients. The two cohorts were not entirely matched: in the derivation cohort, the prevalence of hepatocellular carcinoma (HCC), the percentage of males and QTc interval prolongation were significantly lower than those among the patients in the validation cohort (Table 3).
2. Lipid profiles correlate with liver disease severity
Lipid profiles include triglyceride, cholesterol, HDL-C and low-density lipoprotein cholesterol (LDL-C). In the derivation and validation cohorts, the association of individual lipid fractions with prognostic models (Child-Pugh, MELD, and ALBI) was assessed by Pearson correlation, as shown in Table 3. HDL-C was found to have strongest correlation with liver function score.
3. Derivation cohort: predictors of 6-week mortality
On ROC analysis, HDL-C showed excellent diagnostic accuracy for 6-week mortality, with an AUROC of 0.841 (95% CI 0.809-0.870). The best cut-off value of HDL-C was 0.57mmol/L, with a sensitivity of 71.7% and specificity of 84.4%.
We performed univariate and multivariate analyses to assess the independent predictors of 6-week mortality. Variables included in the univariate analysis are shown in Table 4. The variables significantly associated with 6-week mortality in the univariate analysis were as follows: ascites, hepatic encephalopathy, HCC, heart rate, hemoglobin (HGB), total leukocyte count (WBC), alanine aminotransferase (ALT), serum sodium (Na), total bilirubin (TBIL), albumin (ALB), QTc interval prolongation, cholesterol, HDL-C, LDL-C, prothrombin time (PT), international normalized ratio (INR), fibrinogen (FIB), Child-Pugh, MELD, and ALBI (Table 4). Multivariate logistic regression analyses showed that HDL-C, Na, HCC, and QTc interval prolongation were independently associated with 6-week death. Based on the multivariate regression coefficients, we calculated a new prognostic model for HBV-related cirrhotic patients with acute GIB named N-CGIB according to the following formula: 12.654 - 0.095 × Na + 1.041 × QTc prolongation (yes=1, no=0) – 3.846 × HDL (mmol/L) + 0.856×HCC (yes=1, no=0). The N-CGIB model showed an excellent discrimination for 6-week death prediction, with an AUROC of 0.880 (95% CI 0.832-0.928). Hosmer and Lemeshow analysis confirmed goodness-of-fit for the model (P=0.904).
The developed model showed an excellent predictive accuracy, with AUROCs significantly better than that of Child-Pugh, MELD, ALBI, and Augustin scores (Table 5, Fig. 1A). Comparison with D’Amico score shows that N-CGIB is a more accurate predictor than the D’Amico score for outcome, although the differences failed to reach statistical significance for mortality. (Table 5, Fig. 1A)
4. Mortality in external validation cohort
HDL-C was an excellent predictor of 6-week mortality (AUROC 0.838, 95% CI 0.763-0.912) in the validation cohort.
Hosmer and Lemeshow analysis confirmed the goodness-of-fit of the N-CGIB model (P=0.531). The diagnostic accuracy of the N-CGIB model (AUROC 0.882; 95% CI 0.822-0.942) was similar to D’Amico model (AUROC 0.832; 95% CI 0.789-0.870), significantly better than that of the other models, including Child–Pugh (AUROC 0.794; 95% CI 0.748-0.835), ALBI (AUROC 0.803; 95% CI 0.758-0.844), MELD (AUROC 0.793, 95% CI 0.705-0.881), and Augustin model (AUROC 0.788; 95% CI 0.741-0.829) (Table 5, Fig 1B). 5. Survival
In the derivation cohort, 60 of the 593 (10.1%) patients died during study observation, with early death rate (12 of 60, 20%) occurring within the first five days. In the test set, 40 of the 350 (11.4%) patients died during study observation, with early death rate (11 of 40, 27.5%) occurring within the first five days.
Mortality increased with increasing N-CGIB score. The final selected cutoff value accurately discriminated patients in 3 subgroups with distinct prognosis: a low-risk group (N-CGIB score below -3), whose in-hospital mortality was 1.7%; an intermediate-risk group (N-CGIB score range from -3 to -1), with a 10.6% mortality; and a high-risk group (N-CGIB score more than -1) associated with a 55.6% or greater predicted risk. Comparable results were found in the validation set with a significant decrease in 6-week probability of survival: 98%, 89.8%, and 41.9%, respectively. (Fig. 2A.2B)
On Kaplan-Meier analysis, baseline HDL-C values ≤ 0.57mmol/L were associated with markedly lower 6-week survival in the derivation cohorts (Fig. 3A), and validation cohorts (Fig. 3B).