For patients with severe thrombocytopenia and chronic liver diseases, including hepatocellular carcinoma, treatment with lusutrombopag prior to invasive procedures significantly decreased the need for platelet transfusions without increasing the need for rescue treatment for bleeding or the rate of thromboembolic events.
In a post hoc analysis of data from 270 patients in two manufacturer-sponsored, multicenter, randomized, double-blind, placebo-controlled, phase 3 trials, significantly more lusutrombopag recipients met the primary efficacy endpoint, including patients with hepatocellular carcinoma (68.0% vs. 8.9% in the placebo group; P < .0001) and those without it (77.0% vs. 21.6%; P < .0001). Rates of treatment-emergent adverse events were similar between the lusutrombopag and placebo groups, and patients with hepatocellular carcinoma were not at increased risk for thrombosis, Naim Alkhouri, MD, of Texas Liver Institute in San Antonio, and associates wrote in.
Platelet transfusion is the treatment mainstay for patients with thrombocytopenia related to cirrhosis who are undergoing invasive procedures, but its effects are short-lived, and at least one in five transfusions fails. Thrombopoietin agonists such as lusutrombopag are efficacious and approved in this setting, but they can be prothrombotic, particularly in patients with hepatocellular carcinoma, who already are at heightened risk for portal vein thrombosis.
Dr. Alkhouri and associates performed an integrated analysis of the PLUS 1 trial (Japan, October 2013–May 2014) and the L-PLUS 2 (global, June 2015–April 2017). Participants were adults with Child-Pugh Class A or B chronic liver disease and baseline platelet counts under 50 x 109 per L who were scheduled for invasive procedures. Of the 270 patients, 95 had hepatocellular carcinoma. Patients were randomly assigned on a one-to-one basis to receive either lusutrombopag (3 mg) or placebo daily for up to 7 days before procedures. The primary endpoint was the percentage of patients in the per-protocol population who did not need a platelet transfusion before the invasive procedure or rescue therapy within 7 days afterward.
The treatment and placebo arms were similar except that patients with hepatocellular carcinoma were about 10 years older on average. In patients with hepatocellular carcinoma, 60.5% more lusutrombopag recipients than placebo recipients met the primary endpoint, and rates of bleeding-related adverse events were 9.1% and 15.7%, respectively. In patients with other chronic liver diseases, 52.6% more lusutrombopag recipients met the primary endpoint. Rates of bleeding-related adverse events were 5% and 10.6%.
“Approximately 88% of patients with hepatocellular carcinoma underwent a liver-related procedure, compared with approximately 10% of patients without hepatocellular carcinoma,” the investigators wrote. “This is significant because ablations or transcatheter arterial chemoembolizations can be associated with serious bleeding complications. It is clinically important that, given the greater number of liver-related procedures, the incidence of bleeding-related adverse events was lower in patients treated with lusutrombopag than placebo.”
Imaging after the procedures confirmed low rates of thromboses in both groups and subgroups. Four patients developed portal vein thromboses, including two lusutrombopag recipients (one of whom had hepatocellular carcinoma) and two placebo recipients without hepatocellular carcinoma.
These trials excluded patients undergoing major surgical procedures and those with decompensated cirrhosis; portal vein thrombosis; hematopoietic tumors; aplastic anemia; myelodysplastic syndrome; myelofibrosis; liver transplantation; splenectomy; and thrombocytopenia that was congenital, autoimmune, or drug induced. “A limitation of this study was the high rate of protocol violations related to platelet transfusions,” the researchers noted. “A number of patients [42 in all] were excluded from the per-protocol population owing to receipt of unnecessary platelet transfusions, or because they did not receive a needed platelet transfusion.”Shionogi makes lusutrombopag and sponsored the study. Dr. Alkhouri reported an advisory relationship with Shionogi and Dova Pharma. Two coinvestigators reported being employed by Shionogi. Three coinvestigators also disclosed ties to Shionogi and to several other pharmaceutical companies.
SOURCE: Alkhouri N et al. Clin Gastroenterol Hepatol. 2020 Mar 20.