Soft and hard endpoints in acute variceal bleeding
Authors: Juan G. Abraldes, Puneeta Tandon
Journal: Hepatology (2014)

Potential conflict on interest: Nothing to report. See Article on Page 1024 and Page 1033 Portal hypertension (PH) is widely recognized as an area with high‐quality trials.1 This success is, in large part, attributable to the field's continued efforts to standardize trial design by agreeing on homogeneous definitions of study endpoints.2 At successive Baveno consensus meetings over the last 30 years, the most difficult area to achieve consensus on has been the definitions of key endpoints in acute variceal bleeding (AVB). Although mortality has always been accepted as an important endpoint, death in AVB is largely driven by the severity of the underlying cirrhosis.3 Therefore, it was felt that an intermediate endpoint ("treatment failure") was needed to evaluate the efficacy of hemostatic therapies. This concept was very relevant at a time when the efficacy of hemostatic therapies was much lower (∼60%) than it is today (∼85%), but it was highly controversial, requiring two major revisions (Table 1) and a continuous reassessment to make these criteria evidence based. Criteria proposed at the Baveno II conference4 were brought up for revision in Baveno III,5 but it was not until Baveno IV6 that the criteria were redefined in depth. This was driven, in large part, by a landmark article by Cales et al. showing the many difficulties in applying Baveno II/III criteria.7 A subsequent retrospective assessment of the Baveno IV criteria showed again that these were an inaccurate surrogate of actual therapeutic failure,8 which prompted a new revision at the Baveno V meeting.9 The common characteristic of these definitions is that they were used as a composite endpoint to evaluate efficacy. This composite included different criteria of failure to control bleeding, rebleeding, or death within 5 days of the index bleed. Importantly, the aim of developing these criteria was to homogenize trial design and not to guide clinical practice. Table 1 - Baveno Criteria for Defining Treatment Failure in Acute Variceal Bleeding Baveno II/III criteria The definition of failure to control bleeding was divided into two time frames. 1. Within 6 hours, any of the following factors: a. transfusion of 4 units of blood or more and inability to achieve an increase in systolic blood pressure of 20 mmHg or to 70 mmHg or more and/or b. pulse reduction to less than 100/min or a reduction of 20/min from baseline pulse rate 2. After 6 hours, any of the following factors: a. the occurrence of hematemesis b. reduction in blood pressure of more than 20 mmHg from the 6‐hour point and/or c. increase of pulse rate of more than 20/min from the 6‐hour point on two consecutive readings 1 hour apart d. transfusion of 2 units of blood or more (over and above the previous transfusions) required to increase the Ht to above 27% or Hb to above 9 g/dL Baveno IV criteria 1. The time frame for the acute bleeding episode should be 120 hours (5 days). 2. Failure signifies need to change therapy: one criterion defines failure, whichever occurs first: a. Fresh hematemesis R2 h after start of specific drug treatment or therapeutic endoscopy. In the minority of patients who have a nasogastric tube in place, aspiration of greater than 100 mL of fresh blood represents failure. b. 3‐g drop in Hb (z9% drop in Ht) if no transfusion is administered c. Death d. ABRI (see below) ≥0.75 at any time point (the threshold of ABRI defining failure requires validation) ABRI = blood units transfused/(final Ht − initial Ht + 0.01). Ht is measured at lease every 6 hours for the first 2 days and every 12 hours for days 3‐5. The transfusion target should be an Ht of 24% or a Hb of 8 mg/dL. Baveno V criteria 1. The time frame for the acute bleeding episode should be 120 hours (5 days). 2. Failure is defined as death or the need to change therapy defined by one of the following criteria: a. Fresh hematemesis or nasogastric aspiration of 100 mL of fresh blood ≥2 hours after the start of a specific drug treatment or therapeutic endoscopy b. Development of hypovolemic shock c. 3‐g drop in Hb (9% drop of Ht) within any 24‐hour period if no transfusion is administered. This time frame needs to be further validated. d. The potential value of an index of blood transfusion requires prospective validation. Among the components of the composite endpoint, two have been especially problematic: the use of heart rate and the use of a transfusion index. Heart rate was eliminated from the criteria in Baveno IV, but a new, highly controversial transfusion index was introduced, the adjusted blood requirement index (ABRI; Table 1). A negative ABRI or values ≥0.75 were considered indicative of treatment failure. Among other problems, the time frame to measure the initial and final hematocrits (Hts) was not defined, and the volume of fluid administered between the two measurements was not taken into account. In both Baveno IV and V, it was emphasized that the criteria required prospective validation. Although these kinds of validation studies are difficult to design and cumbersome to conduct, this issue of Hepatology includes two articles prospectively assessing the accuracy of the Baveno criteria to represent true treatment failure. In the first of these studies,10 Thabut et al. included 249 patients with cirrhosis and variceal bleeding (VB) in a prospective multicenter observational study aimed at validating Baveno IV and II/III criteria for treatment failure. The ABRI transfusion index was evaluated at standardized time points. Patients were treated according to the current standard (antibiotics, vasoactive drugs [mainly octreotide], and endoscopic therapy). The gold standard to evaluate 5‐day treatment failure was the clinical judgment of three experts based on a summary of the patient's chart. The experts had 80% agreement in their first vote and reached consensus in 100% of the patients after a consensus meeting. The gold standard classified 21% of the patients as treatment failures, whereas Baveno II/III, IV, and V criteria classified 53%, 47%, and 63% as failures, respectively. The most accurate criteria for the diagnosis of treatment failure were Baveno IV criteria (66% of correctly classified patients, as compared to 57% with Baveno II/III and 52% with Baveno V). Because Baveno IV criteria is a composite, the investigators analyzed the performance of each individual component. Hematemesis and a hemoglobin (Hb) drop of 3 points were very specific criteria (99% and 93%, respectively), but had low sensitivity (27% and 16%). ABRI had a balanced sensitivity and specificity (63% and 69%, respectively). The Hb drop criteria and ABRI were the main sources of discrepancy between the Baveno IV and expert criteria. Because the use of ABRI has raised the most controversy in consensus discussions, the value of Baveno IV criteria with or without ABRI was evaluated. Baveno IV with or without ABRI had a comparable performance overall, but sensitivity substantially dropped by removing ABRI (from 82% to 47%). The definition of treatment failure that best predicted 6‐week mortality was the gold standard (the chart review by the experts). Failure defined according to Baveno IV had predictive value, but was not as good as the gold standard in predicting 6‐week mortality. The Baveno II/III definition of failure did not predict mortality. In the second study,11 Anh et al. aimed to validate the Baveno V criteria of treatment failure in 246 patients with cirrhosis and PH‐related hemorrhage (94% variceal in origin). Although this was a prospective study, the recruitment started before Baveno V criteria were defined. Patients were treated according to the current standard of care. The gold standard to define treatment failure was a repeat endoscopy showing active bleeding or fresh blood in the stomach. The second‐look endoscopy was performed before day 5 if Baveno V criteria were verified at any point during the first 5 days, or if rebleeding was suspected on clinical grounds (by ongoing melena for 48 hours). If rebleeding was not suspected, endoscopy was attempted on day 5. Twenty‐six of the one hundred ninety‐seven patients who reached 5 days without treatment failure refused endoscopy and were considered successes. The rate of treatment failure was 23% with the gold standard and 19%, 43%, and 50% with Baveno V, IV, and II/III criteria, respectively. Baveno V criteria had excellent performance characteristics, with a sensitivity of 83% and specificity of 98%. Ninety‐five percent of the patients were correctly classified against the gold standard. The performance of the Baveno IV criteria was also good, with a sensitivity and specificity of 85% and 71%. Following the suggestion of the Baveno consensus, the investigators assessed whether ABRI (taken at two different time points) added to the Baveno V criteria, with negative results. The study was limited to 5 days and did not provide data on the association between treatment failure and 6‐week mortality. These two very important studies will have a major impact on how endpoints will be redefined at the Baveno VI conference, to be held in 2015. The conclusions from both studies are, however, discrepant. Thabut et al. recommend using Baveno IV criteria without the ABRI index to define treatment failure in new trials, acknowledging that the use of experts to reassess every event would be impractical. We are not convinced that their data support this recommendation, given that Baveno IV criteria without ABRI captured less than half of the treatment failures (sensitivity was 47%). Baveno IV with ABRI had a much better sensitivity (82%), but classified more than twice as many patients as failures (47%), as compared to the gold standard (21%). The conclusions drawn about the Baveno V criteria are also met with significant limitations. First, the analysis of these criteria was performed retrospectively owing to the fact that the study was completed before Baveno V criteria were released, requiring cautious interpretation of these results. Second, the investigators chose to include ABRI in the assessment of the Baveno V criteria, which, in our view, is not consistent with what was agreed on at the latest consensus conference.9 Notably, ABRI criterion accounted for 67% of treatment failures with Baveno V. Before the upcoming consensus meeting, and particularly in light of the good performance of the Baveno V criteria in the study by Ahn et al., it will be valuable for Thabut et al. to reevaluate their Baveno V criteria without the addition of ABRI. Indeed, Ahn et al. concluded that the Baveno V criteria were excellent to define treatment failure, better than Baveno IV and II/III criteria. Their rather spectacular results must also, however, be tempered with caution, given that they could be conditioned by the way the gold standard was applied. Indeed, during the first 5 days after the bleeding episode (the highest‐risk period), the gold standard (endoscopy) was only applied if Baveno V criteria were met (47 cases) or the patients had ongoing melena for 48 hours (2 cases). This potential for verification bias12 brings into question the robustness and future reproducibility of the results. A final consideration is whether 5‐day treatment failure should be used as the primary endpoint in new trials for VB. Treatment failure is strongly associated with increased 6‐week mortality (the consensus definition of bleeding‐related mortality). However, a decrease in 5‐day treatment failure with drugs or endoscopic therapy has not been consistently associated with improved survival,13 which suggests that treatment failure and mortality might have a common determinant (likely the severity of liver dysfunction) that is not targeted by hemostatic treatments. Indeed, a recent U.S. Food and Drug Administration panel15 questioned the clinical relevance of treatment failure as a primary endpoint to assess the efficacy of drugs for VB, mainly on the basis that improving treatment failure was not associated with a survival benefit. This suggests that the approval of new treatments might face serious difficulties unless trials are designed with mortality as the principal endpoint. With a current mortality rate of 15%‐20% with standard therapy (that has not substantially decreased in the last decade), there is certainly room for improvement with new treatments. Preemptive transjugular intrahepatic portosystemic shunt in high‐risk patients has recently shown that this is possible,16 though this needs confirmation. Given that liver function is the major determinant of mortality, new treatments would likely have to include strategies for protecting or improving liver function during acute bleeding. In summary, these two articles provide an excellent insight on the challenges with using the current criteria to identify treatment failure in AVB. This will set the evidence‐based framework for redefining the key endpoints for the design of future trials at the Baveno VI consensus conference. In our view, mortality should become the primary endpoint in future trials, with treatment failure playing a secondary role. Author names in bold designate shared co‐first authorship.