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Non-invasive response prediction in prophylactic carvedilol therapy for cirrhotic patients with esophageal varices

Hwi Young Kim (hwiyoung@ewha.ac.kr)

Department of Medicine

Non-selective beta-blockers (NSBBs) are the mainstay of primary prophylaxis of esophageal variceal bleeding in patients with liver cirrhosis. Reducing the hepatic venous pressure gradient (HVPG) by NSBBs has been shown to be associated with a decreased risk of variceal hemorrhage. However, it is difficult to routinely measure HVPG in cirrhotic patients who receive prophylactic NSBBs. Although elastographic assessments of portal hypertension using new technologies have yielded promising data recently, non-invasively predicting changes in HVPG during NSBB therapy represents an unmet clinical need. Hence, the aim of this study was to investigate whether non-invasive markers such as LS and SS measurements using ARFI elastography can predict hemodynamic response to NSBBs as primary prophylaxis in cirrhotic patients with high-risk esophageal varices.

In this prospective cohort study, 106 cirrhotic patients with high-risk esophageal varices in the derivation cohort received carvedilol prophylaxis, and completed paired measurements of hepatic venous pressure gradient, liver stiffness (LS), and spleen stiffness (SS) at the beginning and end of dose titration. LS and SS were measured using acoustic radiation force impulse imaging. A prediction model for hemodynamic response was derived, and subject to an external validation in the validation cohort (63 patients).


Fig 1. Flowcharts for patient selection. (A) Derivation cohort. (B) Validation cohort.

Hemodynamic response occurred in 59 patients (55.7%) in the derivation cohort, and in 33 patients (52.4%) in the validation cohort, respectively. Multivariate logistic regression analysis identified that ΔSS was the only significant predictor of hemodynamic response (odds ratio 0.039; 95% confidence interval 0.008–0.135; P<0.0001). The response prediction model (ModelΔSS = 0.0490–2.8345×ΔSS; score = (exp[ModelDSS])/(1 + exp[ModelΔSS]) showed good predictive performance (area under the receiver-operating characteristic curve [AUC] = 0.803) using 0.530 as the threshold value. The predictive performance of the ModelΔSS in the validation set improved using the same threshold value (AUC = 0.848).


Fig.2 A spleen stiffness-based new model for non-invasive prediction of portal pressure response to beta-blocker therapy


In summary, our new model based on dynamic changes in SS exhibited good performance in predicting hemodynamic response to NSBB prophylaxis in patients with high-risk esophageal varices. Paired SS measurements using ARFI elastography may be a promising non-invasive tool for predicting hemodynamic response to carvedilol therapy as primary prophylaxis in patients with cirrhosis and high-risk esophageal varices. Replacement of HVPG measurement with ARFI-measured SS for the prediction of NSBB responses requires further investigation in different clinical settings, including different etiologies, treatment settings, types, and doses of NSBBs.

* Related Article
Hwi Young Kim,Young Ho So, Won Kim, Dong-Won Ahn, Yong Jin Jung, Hyunsik Woo, Donghee Kim, Moon Young Kim, Soon Koo Baik, Non-invasive response prediction in prophylactic carvedilol therapy for cirrhotic patients with esophageal varices, Journal of Hepatology. 2019 Mar;70(3):412-422

* Reference
applicability, reliability and accuracy for clinically significant portal hypertension. J Hepatol 2015;62:1068–1075.

Reiberger T, Ulbrich G, Ferlitsch A, et al. Carvedilol for primary prophylaxis of variceal bleeding in cirrhotic patients with haemodynamic non-response to propranolol. Gut 2013;62:1634–1641.

Kim HY, Jin EH, Kim W, et al. The role of spleen stiffness in determining the severity and bleeding risk of esophageal varices in cirrhotic patients. Medicine (Baltimore) 2015;94 e1031.

Mandorfer, M., Hernández-Gea, V., Reiberger, T. et al. Hepatic Venous Pressure Gradient Response in Non-Selective Beta-Blocker Treatment—Is It Worth Measuring? Curr Hepatology Rep (2019) 18: 174

원본  : 연구처  2020 Newsletter for Science & Engineering