In this cohort of patients with advanced liver disease, the MELDNa score underestimated mortality among patients with ascites when the score was less than 21. Even a small amount of ascites was associated with increased mortality risk, and addition of ascites to the MELDNa model substantially improved risk discrimination by three measures. The C-index is the most commonly used measure of a model’s ability to discriminate between those who develop the disease of interest and those who remain disease-free. Commonly, the addition of new predictor to an established risk model leads to only a marginal improvement.(15
) However, in our study the increase of more than 3% in the C-index represented a substantial and statistically significant improvement. The IDI suggested comparable improvement in discrimination and was also statistically significant. Finally, the model correctly reclassified a net of 15.8% of patients into the appropriate risk level. Thus our results support the need for additional studies to validate these findings and to better understand the use of ascites to improve risk assessment beyond what is predicted by the MELDNa score alone.
Ascites has historically been incorporated into risk models for patients with advanced liver disease, buts its value in the MELD era continues to be debated.(6
) An initial study using ascites and MELD suggested that ascites provided marginal prognostic value with increases in the C-index in the range of 0.01 to 0.03.(4
) Heuman et al. subsequently determined that persistent ascites was an independent predictor of mortality; specifically, ascites and low sodium and not MELD were the important factors when the MELD score was less than 21.(6
) Studies using other patient cohorts have further supported the independent effect of ascites on mortality.(7
) Our study provides affirmation of the prognostic value of ascites while further describing the interaction of ascites with MELD and MELDNa. Despite the prognostic improvement with the incorporation of Na to MELD, the presence of ascites in patients with MELDNa less than 21 signify a cohort whose risk appears to be underestimated by MELDNa alone.(11
Concern about the objectivity of quantifying ascites has cast doubt on inclusion of ascites in risk prediction models. Our study attempts to objectify the presence of ascites by relying on specific definitions of radiological evidence of ascites. By separating ascites assessment from the clinician thereby effectively blinding the radiologists from the clinical outcome, radiological ascites represents a relatively unbiased measure. Furthermore, given the frequent use and availability of radiological studies in patients with advanced liver disease, ascites can be easily assessed. In our cohort, increasing ascites did not confer additional risk above the group with small ascites. The lack of statistically significant volume-dependent mortality risk difference may represent the fact that the combination of serum sodium and the presence of any ascites, rather than the degree of ascites, captures the important effect of hemodynamic derangements. However, this retrospective study is unable to assess the impact of diuretic use and duration of use. In addition, variability in volume measurements between and within each individual radiologist could have led to the misclassification of ascites volume, which may underestimate the impact of increases in ascites volume on mortality.
Our study has several limitations. First, many earlier studies have assessed mortality within 90 or 180 days. Due to the small number of events within 90 and 180 days, we instead modeled one-year mortality, limiting direct comparison between studies. However, in unadjusted analyses censoring follow-up at both 90 and 180 days, our hazard ratios were similar. Additionally, we confirmed that the effect of ascites did not violate the proportional hazard assumption over the longer one-year period. Second, our dataset was restricted by creatinine. Restricting creatinine may reduce the discrimination of the model using the MELDNa score so that the addition of ascites appears to afford greater improvement in the C-index. However, in our sensitivity analysis including patients with elevated creatinine, the increase in the C-index after addition of ascites remained large. Furthermore, our data showed that ascites was only predictive among patients with MELDNa scores lower than 21; in contrast, patients with elevated creatinine are more likely to be associated with MELDNa scores greater than 21. This finding suggests that creatinine and ascites may contribute different prognostic information across the MELDNa spectrum, thereby explaining the prognostic value of ascites. Third, our safety-net population consists of patients with advanced liver disease of diverse etiologies and may receive variable levels of management for ascites. It is unclear how a model including ascites as well as MELDNa would perform among specific subgroups of patients. It is important that future studies validate these early findings, in particular, the interaction between ascites and MELDNa. Furthermore, more objective measures of the hemodynamic derangements in cirrhosis, such as plasma levels of aldosterone, renin, or norepinephrine, may importantly delineate the mortality risk.(17
In summary, incorporation of radiographic ascites significantly improves upon MELDNa for predicting one-year mortality. The presence of ascites may help identify patients at increased risk for short-term mortality not otherwise captured by MELDNa, in particular when scores are below 21. Future directions may include identifying simple and objective measurements of ascites or a surrogate for ascites that will capture the added mortality risk. In addition, the analysis should be extended to subgroups of liver disease such as those awaiting transplantation, undergoing pre-surgical evaluation, or being considered for treatment of hepatocellular carcinoma.(18
) Greater awareness of the mortality risk associated with ascites may impact available treatment options and therefore improve overall delivery of medical care.