Thrombocytopenia in chronic liver disease: Physiopathology and new therapeutic strategies before invasive procedures

Table 1 ADAPT 1-2 key characteristics

Key characteristic	ADAPT 1-2
Key inclusion criteria	Chronic liver disease (MELD score ≤ 24) and thrombocytopenia (platelet counts < 50000/μL). Age ≥ 18 yr
Key exclusion criteria	ADAPT-1/2: History of thrombosis or hematologic disorders. Significant cardiovascular disease. Portal or splenic mesenteric system thrombosis at screening; portal vein blood flow < 10 cm/s at screening. Platelet transfusion within 7 d of screening. Use of heparin, warfarin, FANS, aspirin, verapamil, or antiplatelet therapy with ticlopidine or glycoprotein IIb/IIIa antagonists, or erythropoietin-stimulating agents within 7 d of screening. Advanced hepatocellular carcinoma (BCLC C or D)
Dosing	Low baseline platelet count cohort (≤ 40000/μL): 60 mg avatrombopag or placebo once daily with a meal on days 1-5. High baseline platelet count cohort (40000-50000/μL): 40 mg avatrombopag or placebo once daily with a meal on days 1-5
Type of study	ADAPT-1/2: Global, multicenter, randomized, double-blind, placebo- controlled, phase 3 studies
Patients number	ADAPT-1: 231; ADAPT-2: 204
Endpoints	Efficacy assessment: (1) Primary: Proportion of patients not requiring a platelet transfusion or rescue procedure for bleeding bleeding in the 7 d after the procedures; and (2) Secondary: Proportion of patients achieving the target platelet count of 50000/μL on procedure day; the change in platelet count from baseline to procedure day. Safety assessment: The incidence of adverse events adverse drug reactions, treatment-emergent adverse events

MELD: Model for end-stage liver disease.

Table 2 Lusutrombopag for the Treatment of Thrombocytopenia in Patients with Chronic Liver Disease Undergoing Invasive Procedures trial 1-2 key characteristics

Key characteristic	L-PLUS 1-2
Key inclusion criteria	Chronic liver disease (Child Pugh A or B) and thrombocytopenia (platelet counts < 50000/μL). Age ≥ 18 yr (≥ 20 yr in L-PLUS 2)
Key exclusion criteria	L-PLUS 1: (1) Hematopoietic tumors; aplastic anemia, myelodysplastic syndrome, myelofibrosis, congenital, immune, or drug-induced thrombocytopenia; (2) Splenectomy, any other causes of thrombocytopenia; (3) History of portal vein thrombosis; (4) Active malignant tumor other than primary hepatic cancer; (5) Therapies that could influence platelet count (L-PLUS 1); (6) Chronic liver disease with Child-Pugh C; (7) Portal vein tumor embolism; and (8) Past or present thrombosis or prothrombotic condition. L-PLUS 2: (1) Hematopoietic tumors; aplastic anemia, myelodysplastic syndrome, myelofibrosis, congenital, immune, or drug-induced thrombocytopenia; (2) Portal vein thrombosis within 28 d prior to randomization or a history of portal vein thrombosis; absence of hepatopetal blood flow in the main trunk of the portal vein as demonstrated by doppler ultrasonography within 28 d prior to randomization; (3) Chronic liver disease with Child-Pugh C; (4) Portal vein tumor embolism; and (5) Past or present thrombosis or prothrombotic condition, history of splenectomy
Dosing	3 mg lusutrombopag or placebo once daily for up to 7 d
Type of study	L-PLUS 1: Double-blind, parallel-group, phase 3 study; L-PLUS 2: Global, phase 3, randomized, double-blind, placebo-controlled study
Patients number	L-PLUS 1: 96; L-PLUS 2: 215
Endpoints	Efficacy assessment: (1) Primary: Proportion of patients who required no platelet transfusions before the primary invasive procedure and no rescue therapy for bleeding; and (2) Secondary: Rate of response (defined as proportion of patients who achieved platelet count of more than 50000/μL with an increase of ≥ 20000/μL from baseline at any time during the study); the duration of sustained platelet count increase; time courses of changes in platelet count. Safety assessment: The incidence of adverse effects, adverse drug reactions, treatment-emergent adverse effects, bleeding-related adverse effects, and thrombotic events

L-PLUS: Lusutrombopag for the Treatment of Thrombocytopenia in Patients with Chronic Liver Disease Undergoing Invasive Procedures trial.