Lusutrombopag, an oral small molecule agonist of the thrombopoietin receptor, achieves and maintains target platelet count in patients with chronic liver disease and thrombocytopenia undergoing invasive procedures, researchers report in a phase 3, placebo-controlled trial published in the May issue of Clinical Gastroenterology and Hepatology. The drug caused no significant safety concerns.
Thrombocytopenia, a deficiency of platelets that increases risk of bleeding, is a common complication of chronic liver diseases. Patients with liver disease and severe thrombocytopenia (platelet count <50,000/μL) have an increased risk of bleeding during surgical procedures and other complications. They often receive platelet transfusions to reduce their risk of hemorrhagic events during and/or immediately after invasive procedures. However, there are a number of limitations to this approach, so alternative treatments for thrombocytopenia are needed.
Lusutrombopag has been approved in Japan for treatment of thrombocytopenia in patients with chronic liver diseases scheduled to undergo invasive procedures. The drug activates the thrombopoietin receptor signal transduction pathway to induce platelet production. Lusutrombopag increased the proportion of patients with chronic liver diseases who did not require preoperative platelet transfusion in a phase 2 trial, compared with placebo.
Hisashi Hidaka et al performed a phase 3 study of lusutrombopag to determine its superiority over placebo in reducing the need for platelet transfusions in thrombocytopenic patients with chronic liver diseases undergoing invasive procedures. In the trial, 98 patients were randomly assigned to groups given once-daily lusutrombopag (3 mg, n=48) or placebo (n=48) for up to 7 days.
The proportions of patients who did not require preoperative platelet transfusion were 79.2% in the lusutrombopag group and 12.5% in the placebo group. (primary endpoint , see figure). A response (proportion of patients for whom the platelet count reached ≥50,000/μL with an increase of ≥20,000/μL from baseline) was observed in 77.1% of patients in the lusutrombopag group and 6.3% of patients in the placebo group.
In the lusutrombopag group without platelet transfusion, the median platelet count was 50,000/μL or more after 5 days, the mean time to reach the maximum platelet count was 13.4 days, and the number of days (adjusted mean) during which the platelet count was 50,000/μL or more was 21.09 days.
The most frequently reported adverse events were postoperative fever, procedural pain, procedural hypertension, and increased aspartate aminotransferase, reported in both groups.
There were fewer bleeding-related adverse events in the lusutrombopag group (7/48 patients) than that in the placebo group (3/48 patients). One patient in each group had a thrombotic event. Lusutrombopag was effective even in patients with antiplatelet antibodies.
The authors note that the trial excluded patients with splenectomy; any other causes of thrombocytopenia; history of liver transplantation; Child-Pugh class C liver disease, uncontrolled hepatic encephalopathy or ascites despite treatment; malignant tumors other than primary liver cancer; or a history of portal vein thrombosis. Invasive procedures after day 8, except transcatheter arterial chemoembolization, lipiodolization with anticancer drugs, and transcatheter arterial embolization without lipiodol infusion for marking, were also excluded.
Hidaka et al conclude that lusutrombopag could be an effective substitute for platelet transfusion in patients with chronic liver disease and thrombocytopenia who require invasive procedures.