Prognostic value of the De Ritis ratio for 1-year major adverse cardiovascular events in elderly patients with acute decompensated heart failure

This was a single-center, prospective, longitudinal observational cohort study conducted at Tam Duc Cardiology Hospital, Ho Chi Minh City, Vietnam, from December 2020 to August 2023. The study enrolled consecutive patients aged ≥65 years who were hospitalized with ADHF. ADHF was diagnosed based on the 2021 European Society of Cardiology guidelines for the diagnosis and treatment of acute and chronic HF, requiring the presence of at least one symptom and one physical sign of HF, along with elevated NT-proBNP levels (≥300 pg/mL) and echocardiographic evidence of cardiac dysfunction [2]. Exclusion criteria included (1) acute coronary syndrome at admission; (2) elevated aminotransferase levels due to other causes unrelated to HF, such as acute or chronic hepatitis B virus, chronic hepatitis C virus, cirrhosis, acute cholecystitis, or acute pancreatitis; (3) severe renal failure requiring peritoneal dialysis or hemodialysis; (4) acute myocarditis; and (5) active severe systemic infection at admission.

Demographic, clinical, laboratory, and echocardiographic data were collected at baseline. All patients underwent standard investigations, including blood tests, chest radiography, electrocardiography, and transthoracic echocardiography. Biochemical tests, including AST and ALT, were performed from the initial blood sample obtained at hospital admission. Analyses were conducted in the hospital’s laboratory using the Beckman Coulter AU680 analyzer (Beckman Coulter, Japan). Blood samples were processed within 2-3 h of collection, ensuring a storage time of no more than 6 h according to ISO 15189:2012 standards to maintain sample integrity and result accuracy. The reference ranges for AST and ALT in our laboratory were <50 U/L. The De Ritis ratio was defined as the ratio of AST to ALT activity, both measured from the same blood sample obtained at admission. Based on the distribution of De Ritis ratio value in the study population, patients were classified into 3 tertiles: <1.18 (first tertile), 1.18-1.49 (second tertile), and ≥1.49 (third tertile). This classification was applied for comparing clinical characteristics and outcome analyses. Anemia was defined as a hemoglobin concentration of less than 13 g/dL for men or less than 12 g/dL for women [14]. Hypertension was defined as previous history of hypertension, or if the patient was on antihypertensive medication [15]. Diabetes mellitus was diagnosed when fasting blood glucose was ≥126 mg/dL, or HbA1c was ≥6.5%, or if the patient was on antidiabetic medications [16]. Renal function was assessed by calculating the estimated glomerular filtration rate according to the Kidney Disease: Improving Global Outcomes (KDIGO) 2012 guidelines [17].

After discharge, patients were scheduled for follow-up visits at 1 week, 1 month, 3 months, 6 months, and 1 year. Follow-up was conducted via outpatient visits or standardized telephone interviews by 2 trained research physicians. Information collected included survival status, date and cause of death (if applicable), rehospitalizations for HF, nonfatal MI, and stroke. Data were cross-referenced with the hospital’s electronic medical records and official death certificates when available. All discrepancies were resolved by direct contact or document verification. Complete 1-year follow-up data were obtained for all enrolled patients. The primary outcome was the incidence of MACEs within 1 year from the time of index hospital admission, defined as a composite of allcause mortality, nonfatal MI, stroke, and rehospitalization for HF.

All statistical analyses were performed using IBM SPSS Statistics version 25.0 (IBM Corp.). The normality of continuous variables was assessed using the Kolmogorov-Smirnov test. Continuous variables were summarized as median (Me) and interquartile range (IQR), while categorical variables were expressed as frequencies and percentages. Comparisons of baseline demographic, clinical, laboratory, and echocardiographic characteristics across tertiles of the De Ritis ratio were conducted using the chi-squared test or Fisher’s exact test for categorical variables. Pairwise comparisons of proportions were performed using Z-tests with Bonferroni adjustment to correct for multiple comparisons. Continuous variables were compared using the Kruskal-Wallis test, and when appropriate, pairwise comparisons were conducted using Mann-Whitney U tests with Bonferroni-adjusted significance levels. Due to positive skewness, NT-proBNP levels were log-transformed prior to regression analysis. The association between clinical variables and 1-year MACEs was assessed using univariate and multivariate Cox proportional hazards regression models. Variables with clinical relevance or a P-value <0.2 in univariate analysis were included in the multivariate model. Results were presented as hazard ratios (HRs) with corresponding 95% confidence intervals (CIs). Kaplan-Meier survival analysis was performed to estimate event-free survival rates, and differences between tertile groups were assessed using the log-rank test. The prognostic performance of the De Ritis ratio in predicting MACEs was evaluated by constructing a receiver operating characteristic (ROC) curve, with calculation of the area under the curve (AUC), optimal cutoff value, sensitivity, specificity, positive predictive value, and negative predictive value. A two-tailed P-value <0.05 was considered statistically significant.

In our elderly ADHF cohort, higher admission De Ritis ratio was associated with a graded increase in several 1-year components: all-cause death (8.5%, 21.6%, 34.2%), HF rehospitalization (18.3%, 30.7%, 46.8%), and MI (1.2%, 3.4%, 7.6%) across the first to third tertiles, respectively. Stroke exhibited a nonmonotonic pattern (0%, 12.5%, 5.1%). These findings support a link between greater cardio-hepatic stress and both mortality and morbidity, particularly recurrent decompensation (rehospitalization). Notably, inhospital mortality was numerically lower in the third versus second tertile (5.1% vs 10.2%), but this difference was not statistically significant (P = 0.094) and involved small event counts; it is therefore most likely explained by random variation and case-mix effects rather than a true protective association. Overall, the clearest and most consistent gradient in our study was seen for HF rehospitalization and total MACE burden, suggesting that the De Ritis ratio reflects overall disease severity through a combination of hepatic congestion, systemic hypoperfusion, and extrahepatic AST release, rather than being linked to a single outcome.

The prognostic role of the De Ritis ratio in HF has been evaluated in several prior studies. Maeda et al. [10], in a cohort of 774 elderly patients (mean age 80.2 ± 7.8 years, 43% female) hospitalized for ADHF, demonstrated that a De Ritis ratio ≥1.7 was an independent predictor of 1-year mortality, with an AUC of 0.60 (95% CI: 0.56-0.65). In comparison, the AUC in our study was 0.76 (95% CI: 0.70-0.82) in predicting MACEs, indicating better discriminative ability in predicting adverse outcomes in elderly Vietnamese patients with ADHF. In a cohort of 3,212 patients with HF with preserved ejection fraction, Cao et al. reported that a De Ritis ratio >1.0 was associated with a 30% increased risk of MACEs over a median follow-up of 3.3 years [12], reinforcing the prognostic value of this biomarker in different HF phenotypes. Additionally, the ESC-HF-LT Registry, a large prospective, multicenter cohort of 9,134 HF patients, identified liver dysfunction as an independent predictor of 1-year all-cause mortality in patients with mildly reduced LVEF, with an adjusted odds ratio of 2.37 (95% CI: 1.28-4.38, P = 0.0059) [23]. This finding highlights the clinical importance of incorporating hepatic parameters, including the De Ritis ratio, into risk assessment models for HF patients.

A recent comprehensive review by Ndrepepa [24] summarized accumulating evidence regarding the prognostic implications of the De Ritis ratio in cardiovascular diseases. Elevated De Ritis ratio has been independently associated with increased risk of cardiovascular mortality in multiple cohorts, including patients with hypertension [25], CAD [26], and acute MI [27]. In CAD populations, Ndrepepa et al. [26] reported that in 5,020 patients with stable CAD undergoing percutaneous coronary intervention, all-cause mortality rates at 3 years were 5.0%, 7.5%, and 14.5% across De Ritis ratio tertiles, with an adjusted HR of 1.09 (95% CI: 1.06-1.12, P < 0.001) per unit increase, and similar trends for cardiovascular death. In a pooled analysis of high-risk diabetic patients, Ferrannini et al. [28] reported that each unit increase in the log De Ritis ratio was associated with a 2-fold increase in the risk of HF hospitalization and cardiovascular death. These findings confirm the prognostic value of the De Ritis ratio in various cardiovascular settings.

The prognostic value of the De Ritis ratio remained significant after adjusting for NT-proBNP and LVEF, 2 of the most widely accepted prognostic markers in HF. This is of particular interest, given that access to NT-proBNP testing remains limited in many low- and middle-income countries. The De Ritis ratio, derived from routine liver function panels, offers a low-cost, widely available alternative or adjunct to established biomarkers, particularly in resource-constrained settings such as Vietnam.

In the multivariable Cox regression analysis, several clinical and laboratory variables were identified as independent predictors of 1-year MACEs in our study. Type 2 diabetes mellitus (HR: 1.48), chronic lung disease (HR: 1.70), and previous CVA (HR: 1.50) were independently associated with adverse outcomes, consistent with previous studies [29, 30]. Elevated log-transformed NT-proBNP (HR: 3.76) and LVEF ≤ 40% (HR: 1.56) remained important prognostic indicators, reaffirming their established value in acute HF [31]. Notably, an elevated De Ritis ratio >1.30 retained its independent predictive value (HR: 2.36, P < 0.001) after adjustment for these variables, underscoring its potential as a complementary biomarker reflecting systemic congestion, multiorgan dysfunction, and disease severity.

This study has several limitations. First, it was conducted at a single specialized cardiovascular center, which may limit the generalizability of its findings to other patient populations or healthcare settings. Second, we analyzed only the baseline De Ritis ratio at hospital admission; serial measurements may have provided a more accurate assessment of dynamic hepatic or systemic congestion during hospitalization and follow-up. Third, although patients with known chronic liver disease were excluded, the influence of unrecognized hepatic dysfunction or alcohol use cannot be fully ruled out. Fourth, despite adjustment for major clinical covariates, residual confounding from unmeasured factors—such as nutritional status, sarcopenia, or frailty—may have affected the results. Fifth, the study was not powered to perform cause-specific analyses of individual MACE components; thus, subgroup findings, particularly for inhospital mortality and stroke, should be interpreted cautiously. Finally, although we identified an optimal cutoff value of 1.30 for predicting adverse events, this threshold requires external validation in larger, multicenter cohorts before it can be adopted in routine clinical practice.