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Avatrombopag Before Procedures Reduces Need for Platelet Gastroenterology 2018;155:705–718 CLINICAL—LIVER Avatrombopag Before Procedures Reduces Need for Platelet Transfusion in Patients With Chronic Liver Disease and Thrombocytopenia Norah Terrault,1 Yi-Cheng Chen,2 Namiki Izumi,3 Zeid Kayali,4 Paul Mitrut,5 Won Young Tak,6 Lee F. Allen,7 and Tarek Hassanein8 1University of California San Francisco, San Francisco, California; 2Chang Gung Memorial Hospital and University, Taoyuan, Taiwan; 3Musashino Red Cross Hospital, Tokyo, Japan; 4Inland Empire Liver Foundation, Rialto, California; 5University of Medicine and Pharmacy of Craiova, Craiova, Romania; 6Kyungpool National University, Daegu, Korea; 7Dova Pharmaceuticals, Durham, North Carolina; and 8Southern California GI and Liver Centers, Coronado, California CLINICAL LIVER BACKGROUND & AIMS: Patients with thrombocytopenia and endpoint compared with 22.9% and 38.2% of patients chronic liver disease (CLD) may require platelet transfusions receiving placebo, respectively (P < .0001 for both). In the before scheduled procedures to decrease risk of bleeding. We ADAPT-2 study, 68.6% of patients who received 60 mg ava- performed 2 randomized, placebo-controlled, phase 3 trials in trombopag and 87.9% of patients who received 40 mg ava- patients with thrombocytopenia and CLD undergoing sched- trombopag met the primary endpoint compared with 34.9% uled procedures to evaluate the safety and efficacy of ava- and 33.3% of patients who received placebo, respectively (P < trombopag in increasing platelet counts in this patient .001 for both). Avatrombopag led to a measured increase in population. METHODS: In the ADAPT-1 and ADAPT-2 studies, platelet counts and increased the proportion of patients who adults with thrombocytopenia and CLD (n ¼ 231 and n ¼ 204, achieved the target platelet count 50 Â 109/L on procedure respectively) were in 1 of 2 cohorts according to their baseline day vs placebo. The incidence and severity of adverse events platelet count (below 40 Â 109/L or 40 to below 50 Â 109/L) were similar for the avatrombopag and placebo groups and and within each cohort were randomized (2:1) to receive 5 were consistent with those expected in the CLD population. daily doses of avatrombopag (60 mg if baseline platelet count CONCLUSIONS: In2phase3randomizedtrials,avatrombopag below 40 Â 109/L or 40 mg if 40 to below 50 Â 109/L) or was superior to placebo in reducing the need for platelet placebo. ADAPT-1 was conducted at 75 study sites in 20 transfusions or rescue procedures for bleeding in patients countries, from February 2014 through January 2017, and with thrombocytopenia and CLD undergoing a scheduled ADAPT-2 was conducted at 74 sites in 16 countries, from procedure. ClinicalTrials.gov nos.: NCT01972529 and December 2013 through January 2017. The primary endpoint NCT01976104. was the proportion of patients not requiring platelet trans- fusions or rescue procedures for bleeding up to 7 days after a scheduled procedure. RESULTS: In the ADAPT-1 study, 65.6% Keywords: Cirrhosis; Coagulation; Thrombopoietin Receptor of patients who received 60 mg avatrombopag and 88.1% of Agonist; Thrombosis. patients who received 40 mg avatrombopag met the primary 706 Terrault et al Gastroenterology Vol. 155, No. 3 Avatrombopag (previously known as E5501, YM477, and WHAT YOU NEED TO KNOW AKR501) is a novel, oral, small-molecule thrombopoietin BACKGROUND AND CONTEXT receptor agonist being developed to provide a predictable The efficacy of platelet transfusions to reduce bleeding increase in platelet counts as an alternative to platelet 30,31 risks in patients with thrombocytopenia and liver transfusions. Two identically designed, randomized, disease undergoing a scheduled procedure is variable placebo-controlled, phase 3 trials were conducted in pa- and may be associated with potentially fatal tients with thrombocytopenia and CLD undergoing sched- complications. uled procedures to evaluate the safety and efficacy of NEW FINDINGS avatrombopag in increasing platelet counts in this patient population (ADAPT-1 and ADAPT-2). Avatrombopag, a thrombopoietin receptor agonist, was well tolerated and superior to placebo in increasing The primary endpoint of these studies was the propor- platelet counts with significantly less patients requiring a tion of patients who did not require a platelet transfusion or platelet transfusion or rescue procedure for bleeding. rescue procedure for bleeding after randomization and up to 7 days after a scheduled procedure. LIMITATIONS CLINICAL LIVER The inability to demonstrate a difference in bleeding rates between treatment groups and the relatively small number Materials and Methods of patients in the subgroup analyses may be limitations of these studies. Study Design IMPACT ADAPT-1 and ADAPT-2 were identically designed, global, multicenter, randomized, double-blind, placebo-controlled Avatrombopag may be an alternative therapy to platelet phase 3 studies that assessed the efficacy and safety of ava- transfusions for patients with thrombocytopenia and trombopag in adults with thrombocytopenia and CLD under- liver disease undergoing scheduled procedures as a A means to minimize bleeding and improve clinical going a scheduled procedure (Figure 1 ). ADAPT-1 was management. conducted at 75 study sites across 20 countries between February 2014 and January 2017; ADAPT-2 was conducted at 74 sites in 16 countries from December 2013 through January hrombocytopenia is common in patients with 2017. Study sites were located in Argentina, Australia, Austria, T chronic liver disease (CLD), affecting up to 84% of Belgium, Brazil, Canada, Chile, China, Czech Republic, France, – patients1 6 and worsens with the degree of cirrhosis.7,8 Germany, Hungary, Israel, Italy, Japan, Mexico, Republic of Ko- Severe thrombocytopenia is associated with poor clinical rea, Romania, Russia, Poland, Portugal, Spain, Taiwan, Thailand, outcomes,5,9 including both an increased risk of the United Kingdom, and the United States. Studies were con- bleeding8,10,11 and mortality.5,9 For patients with CLD and ducted under the World Medical Association Declaration of severe thrombocytopenia (platelet count < 50 Â 109/L) Helsinki and Good Clinical Practice guidelines, protocols were undergoing scheduled procedures, platelet transfusions are approved by local institutional review boards or independent administered prophylactically to mitigate the risk of ethics committees, and written informed consent was obtained bleeding.2,12 The risk of bleeding during or after invasive from all patients before screening. Both trials were registered procedures in patients with CLD varies with the patient’s at Clinicaltrials.gov (NCT01972529, NCT01976104). platelet count, coagulopathy status, and type of procedure, although there is no universal consensus regarding the use Patient Population of prophylactic platelet transfusions. An increased risk of Eligible patients were adults (18 years of age) with CLD bleeding with invasive procedures in these patients has (Model for End-Stage Liver Disease [MELD] score 24) and 3,4,8 been reported, and some clinical guidelines recommend thrombocytopenia with a mean baseline platelet count of 13–18 prophylactic platelet transfusions. < 50 Â 109/L. Platelet counts were measured during the Once the decision has been made to use platelets, it is screening period and at baseline at least 1 day apart, and the important to appreciate that the efficacy of platelet trans- mean value used to determine eligibility and assignment to fusions in increasing platelet counts is variable19,20 and may either the low (<40 Â 109/L) or high (40 to <50 Â 109/L) be associated with serious complications, including trans- baseline platelet count cohort; neither platelet count was fusion reactions; the transmission of infectious agents, permitted to be > 60 Â 109/L. Per the study inclusion criteria, which can be fatal in rare cases; and the development of all patients were scheduled to undergo a procedure with an refractoriness to subsequent platelet transfusion.12,21–23 associated risk of bleeding that would require a platelet Although 2 thrombopoietin-receptor agonists, eltrombopag and romiplostim, are approved to increase platelet counts in Abbreviations used in this paper: 24–28 AE, adverse event; AESI, adverse event adults with chronic immune thrombocytopenia, no of special interest; CLD, chronic liver disease; MELD, Model for End-Stage product is approved for the treatment of thrombocytopenia Liver Disease; TEAE, treatment-emergent adverse event. associated with CLD in patients undergoing scheduled Most current article procedures. Eltrombopag was studied in this patient popu- © 2018 by the AGA Institute. Published by Elsevier Inc. This is an open lation, but the trial was terminated early because of safety access article under the CC BY-NC-ND license (http://creativecommons. org/licenses/by-nc-nd/4.0/). concerns, that is, an increased incidence of thromboembolic 0016-5085 29 events with eltrombopag. https://doi.org/10.1053/j.gastro.2018.05.025 September 2018 Avatrombopag Before Procedures in CLD 707 CLINICAL LIVER Figure 1. Overview of the phase 3 studies ADAPT-1 and ADAPT-2 (A) Study design. aVisit 3 occurred on day 4 (±1 day) during the treatment period. (B) Patient disposition. PLT, platelet count; R, ratio. transfusion, unless there was a clinically significant increase in dental procedures, renal biopsy, biliary interventions, neph- platelet counts from baseline. Permitted procedures were rostomy tube placement, radiofrequency ablation, laparoscopic classified by the
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