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Can we identify failure to control acute variceal bleeding? Virginia Hernández-Gea and Juan Carlos García-Pagan

Failure to control acute variceal bleeding is a strong predictor of mortality in patients with cirrhosis. Various criteria have been proposed to define failure to control bleeding for use as end points in randomized clinical trials. However, the clinical applicability and validation of these proposed criteria remain unresolved issues. Hernández-Gea, V. & García-Pagan, J. C. Nat. Rev. Gastroenterol. Hepatol. advance online publication 21 October 2014; doi:10.1038/nrgastro.2014.178

Variceal bleeding is one of the most severe complications of portal hypertension and is a major cause of death in patients with cirrhosis. Despite improvements in management and treatment of patients with acute variceal bleeding, about 10–15% of patients will die as a consequence of the bleeding episode. Thus, a strong need exists for clinical studies evaluating new therapeutic approaches to reduce mortality. However, using mortality as an end point in randomized clinical trials (RCTs) is usually unfeasible because it requires the inclusion of a very large number of patients to be able to demonstrate differences in efficacy. Failure to control bleeding is one of the strongest predictors of mortality in patients with cirrhosis and acute variceal bleeding and as such is considered one of the best surrogate markers for evaluating the efficacy of new treatments. Several efforts have therefore been made to identify the best criteria to define treatment failure. The so-called Baveno II/III,1 Baveno IV2 and Baveno V3 criteria—based on transfusion requirements, haemodynamic status and diverse manifestations of bleeding—have been proposed to adequately define treatment failure in clinical trials. However, some of these proposed criteria are difficult to apply in the clinical setting and attempts at clinical validation have led to contro­versial results. A multicentre study conducted by Thabut et al.4 aimed to prospectively validate the accuracy of the Baveno II/III and IV criteria and to retrospectively validate the Baveno V criteria in the identification of treatment failure in a

cohort of 249 patients with cirrhosis and acute variceal bleeding. The first difficulty of the study was to establish a gold-standard definition of failure that the results could be compared with. This issue was finally solved using the clinical judgment of three inde­ pendent senior clinicians who evaluated the patients’ clinical records. Agreement between evaluators, classifying the episode as success or treatment failure, was initially obtained in 80% of the cases and reached 100% after a consensus meeting. In total, 51 (20.5%) patients were classified by the clinicians as having treatment failure. However, by applying the Baveno II/III criteria, 131 (52.6%) patients were classified as presenting with treatment failure, which reduced to 117 (47.0%) when the Baveno IV c­riteria were used. Although the Baveno IV cri­ teria showed better discriminatory power than the Baveno II/III criteria, its specificity was still low and 33.7% of the patients were misclassified.

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…some points of potential selection bias … might have affected the results of the study…

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In an attempt to elucidate the reason underlying the low predictive positive value, the authors separately analysed the specificity of each Baveno IV criterion. In agreement with other studies, 5,6 the adjusted blood requirement index (ABRI;

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an index for estimating blood loss) was found to be the least specific parameter for identifying treatment failure even though different ABRI cut-off values were tested. On the basis of previous data questioning the value of ABRI, the authors evaluated the Baveno V criteria, which replaced ABRI with the presence or absence of hypovolemic shock.5 Surprisingly, applying the new proposed Baveno V criteria did not improve the results, and they were actually worsened. Indeed, if using the Baveno V criteria 63.1% of patients would have been classified as having treatment failure, which is more than three times higher than the estimate based on the clinicians’ judgement. In the study by Thabut and co-workers, mortality was 8.0% at day 5 and 15.3% at 6 weeks after an episode of variceal bleeding. The experts’ judgement on treatment failure, as well as the Baveno IV and V criteria, but not the Baveno II/III criteria, independently predicted survival. This finding confirms that treatment failure, if well defined (by experts and the Baveno IV and Baveno V criteria) is a good surrogate marker of mortality. Whereas 40.0% of patients classified by the experts as failing treatment later died, only 25.8% of patients identified as failing treatment when applying the Baveno  IV criteria died. This finding suggests that even the Baveno IV criteria is worse than the experts’ definition because the capacity to predict mortality is much better when treatment failure is defined by experts than by Baveno IV. Before discussing the possible connotations of these interesting findings, we would like to mention some points of potential selection bias that might have affected the results of the study. First, no clear explanation is given for the reason why only 249 of the 355 patients initially evaluated were included in the final analyses. Second, the number of patients with active bleeding at endoscopy (a well-known risk factor for treatment failure) was surprisingly high (68%) and was much higher than the level reported in other cohorts.5,7 These variables (as well as others that could have been unnoticed) might have also been responsible for the high rates of treatment failure reported in the study. Indeed, failure ADVANCE ONLINE PUBLICATION  |  1

NEWS & VIEWS rates reported in other studies using the Baveno IV (14–23%8,9) and Baveno V (18– 19%6,10) criteria were substantially lower than those recorded in this study.

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…it remains a real challenge to find realistic and precise criteria to define treatment failure

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Although Thabut and co-worker’s study agrees with previous studies discouraging the use of ABRI in the diagnosis of treatment failure, it is in disagreement with other data prospectively validating the Baveno V criteria.6 Ahn et al.6 reported failure rates using Baveno II/III and IV criteria similar to those reported by Thabut and colleagues, but showed a very good correlation between diagnosing treatment failure using their gold-standard definition (based on endoscopic signs) and the Baveno V criteria. The findings from both these studies have generated controversy and the reliability of the Baveno V criteria requires confirmation before its use can be recommended for future RCTs. According to the study by Thabut et al., all the Baveno criteria overestimate the likelihood of a patient failing treatment. This overestimation of failure might lead to misclassification of patients, which would limit the reliability of the results of RCTs aimed at demonstrating the utility or i­nefficacy of new strategies to control bleeding.

Identifying failure to control bleeding in patients with cirrhosis seems to be a very challenging and unresolved task, as after almost 30 years, five Baveno meetings and many hours of enthusiastic discussions, it remains a real challenge to find realistic and precise criteria to define treatment failure. A blind evaluation of patients’ clinical records by expert clinicians, as used in the study by Thabut and co-workers, might be a good way to evaluate failure; however, this strategy is costly and time consuming. We should not forget that the Baveno criteria emerged as an attempt to prevent the potential bias of physicians in the classification of patients as being successfully treated or not. Should we forget the use of the strongest end point—survival? Clearly, achieving the huge sample size needed to demonstrate superiority of new treatments is unrealistic if all patients with variceal bleeding, with an expected mortality of ~15%, are considered. A more realistic option could be to identify patients with a high risk of mortality to test new treatments using the end point of survival. Anyhow, the noteworthy findings of this paper indicate that more efforts are needed to find robust criteria to define failure in treating patients with cirrhosis and variceal bleeding and reopen the matter to debate. Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Institut de IDIBAPS and CIBERehd, Villaroel 170, 08036 Barcelona, Spain (V.H.‑G., J.C.G.‑P.). Correspondence to: J.C.G.‑P. [email protected]

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Competing interests The authors declare no competing interests. 1.

de Franchis, R. Updating consensus in portal hypertension: report of the Baveno III Consensus Workshop on definitions, methodology and therapeutic strategies in portal hypertension. J. Hepatol. 33, 846–852 (2000). 2. de Franchis, R. Evolving consensus in portal hypertension. Report of the Baveno IV consensus workshop on methodology of diagnosis and therapy in portal hypertension. J. Hepatol. 43, 167–176 (2005). 3. de Franchis, R. et al. Revising consensus in portal hypertension: report of the Baveno V consensus workshop on methodology of diagnosis and therapy in portal hypertension. J. Hepatol. 53, 762–768 (2010). 4. Thabut, D. et al. A multicenter prospective validation of the Baveno IV and Baveno II/III criteria in cirrhotic patients with variceal bleeding. Hepatology http://dx.doi.org/ 10.1002/hep.27407. 5. Thabut, D. et al. Diagnostic performance of Baveno IV criteria in cirrhotic patients with upper gastrointestinal bleeding: analysis of the F7 liver‑1288 study population. J. Hepatol. 53, 1029–1034 (2010). 6. Ahn, S. Y. et al. Prospective validation of Baveno V definitions and criteria for failure to control bleeding in portal hypertension. Hepatology http://dx.doi.org/10.1002/hep.27441. 7. Villanueva, C. et al. Transfusion strategies for acute upper gastrointestinal bleeding. N. Engl. J. Med. 368, 11–21 (2013). 8. Bosch, J. et al. Recombinant factor VIIa for variceal bleeding in patients with advanced cirrhosis: A randomized, controlled trial. Hepatology 47, 1604–1614 (2008). 9. Seo, Y. S. et al. Lack of difference among terlipressin, somatostatin, and octreotide in the control of acute gastroesophageal variceal hemorrhage. Hepatology 60, 954–963 (2014). 10. Ripoll, C. et al. Rebleeding prophylaxis improves outcomes in patients with hepatocellular carcinoma. A multicenter case-control study. Hepatology 58, 2079–2088 (2013).

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Liver: Can we identify failure to control acute variceal bleeding?

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