Thrombopoietin-receptor agonists in perioperative treatment of patients with chronic liver disease

Table 1 Efficacy and safety results from clinical trials studying the effect of perioperative use of thrombopoietin-receptor agonists in patients with thrombocytopenia

Ref.	Dosing	Efficacy results	AEs
Romiplostim
Basu et al[38], 2012	65 patients with CLD and thrombocytopenia randomized 1:1:1 to 500 μg romiplostim: 75 mg eltrombopag: 7 units of platelet transfusion	Improved platelet count > 180 × 109/L in all groups	Nausea, vomiting, dry mouth, headache, insomnia, irritability, local skin rash, shortness of breath, myalgia, arthralgia, erythema
Moussa et al[3], 2013	35 male patients with thrombocytopenia and CLD secondary to hepatitis C infection, dosed 2 μg/kg romiplostim weekly	Improved platelet count ≥ 70 × 109/L	No serious AEs reported
Marshall et al[39], 2015	18 patients with various etiologies of thrombocytopenia, including CLD, undergoing wide range of procedures	Improved platelet counts in all patients; all patients could receive surgery without delay or cancellation	No venous thromboembolic events
Al-Samkari et al[9], 2018	48 patients with various etiologies of thrombocytopenia, including CLD, undergoing 51 procedures, dosed 3 μg/kg romiplostim weekly (range 1-10 μg/kg/wk)	Improved platelet counts achieved in all patients after 1, 2 or 3 doses	Bleeding and thromboembolic events within acceptable limits
Eltrombopag
ELEVATE (Eltrombopag); Afdhal et al[11], 2012	292 patients with CLD administered	Platelet transfusion not required in 72% of patients in the eltrombopag group and 19% of patients in the placebo group	Early study termination due to six portal vein thrombotic events in the eltrombopag group; headache, pyrexia, abdominal pain, diarrhea, nausea, etc.
	75 mg/d or placebo for 14 d
Avatrombopag
ADAPT-1; Terrault et al[14], 2018	231 patients with CLD and thrombocytopenia divided into low (<40 × 109/L) and high (40 to < 50 × 109/L) baseline platelet count cohorts	Platelet transfusion, or rescue procedure for bleeding not required in 65.6% of avatrombopag-treated patients and 22.9% of placebo-treated patients in the low platelet count cohort and 88.1% of avatrombopag-treated patients and 38.2% of placebo-treated patients in the high platelet count cohort	Mild to moderate in severity in all treatment groups; most common TEAEs: abdominal pain, dyspepsia, nausea, pyrexia, dizziness, and headache; no thromboembolic TEAEs
	Both cohorts were randomized 2:1 to receive avatrombopag or placebo; the low baseline cohort was treated with 60 mg and the high baseline cohort was treated with 40 mg avatrombopag, or placebo
ADAPT-2; Terrault et al[14], 2018	204 patients with CLD and thrombocytopenia; same dosing as ADAPT-1	Platelet transfusion, or rescue procedure for bleeding not required in 68.6% of avatrombopag-treated patients and 34.9% of placebo-treated patients in the low platelet count cohort and 87.9% of avatrombopag-treated patients and 33.3% of placebo-treated patients in the high platelet count cohort	Same as ADAPT-1; three thromboembolic TEAEs reported
Lusutrombopag
L-PLUS-1; Hidaka et al[18], 2018	97 patients with thrombocytopenia and CLD randomized to receive 3 mg of lusutrombopag or placebo once daily for up to 7 d	Platelet transfusion, or rescue procedure for bleeding not required in 79.2% of lusutrombopag-treated patients and 12.5% of placebo-treated patients	Most common TEAEs: Nausea, pyrexia, headache, pain, and portal vein thrombosis; most common SAE with lusutrombopag was portal vein thrombosis
L-PLUS-2; Peck-Radosavljevic et al[17], 2019	215 patients; same dosing as L-PLUS-1	Platelet transfusion, or rescue procedure for bleeding not required in 64.8% of lusutrombopag-treated patients and 29% of placebo-treated patients	Most TEAEs were mild or moderate in severity; four asymptomatic thrombotic events, two each in the lusutrombopag and placebo groups, respectively; none attributed to lusutrombopag

AE: Adverse event; CLD: Chronic liver disease; SAE: Serious adverse event; TEAE: Treatment-emergent adverse event.

Table 2 Key safety and tolerability information for thrombopoietin-receptor agonists approved for use[4-7]

Drug	Indication	Boxed warning	AEs	Use in special populations
Romiplostim	Treatment of thrombocytopenia in patients with chronic ITP who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy	None	Thrombotic and thromboembolic events; bone marrow fibrosis; most common AEs: Arthralgia, dizziness, insomnia, myalgia, pain in extremity, abdominal pain, shoulder pain, dyspepsia, and paresthesia, headache	Not to be used in pregnancy and during lactation; safety and effectiveness in pediatric patients has not been established; use in geriatric patients with dose adjustment
Eltrombopag	Treatment of thrombocytopenia in adult and pediatric patients 1 yr and older with chronic ITP who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy; treatment of thrombocytopenia in patients with chronic hepatitis C to allow the initiation and maintenance of interferon-based therapy; treatment of patients with severe aplastic anemia who have had an insufficient response to immunosuppressive therapy	Risk for hepatic decompensation in patients with chronic hepatitis C; risk of hepatotoxicity	Thrombotic and thromboembolic events; hepatoxicity; monitor liver function before and during therapy; increased risk of death and progression of MDS to AML; common AEs in patients with ITP: Nausea, diarrhea, upper respiratory tract infection, vomiting, increased ALT, myalgia and urinary tract infection	Not to be used in pregnancy and during lactation; safety and effectiveness in pediatric patients 1 yr and older with chronic ITP has been established; use in geriatric patients has not been studied in clinical trials; reduced initial dose recommended for patients of East Asian ancestry with ITP
Avatrombopag	Treatment of thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo a procedure	None	Thrombotic and thromboembolic complications: Monitoring platelet counts essential; common AEs: Pyrexia, abdominal pain, nausea, headache, fatigue, and edema peripheral	Not to be used in pregnancy and during lactation; safety and effectiveness in pediatric patients has not been established; use in geriatric patients has not been studied in clinical trials
Lusutrombopag	Treatment of thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo a procedure	None	Thrombotic and thromboembolic complications: Monitoring platelet counts essential; most common AE: headache	Not to be used in lactating patients; use in geriatric patients has not been studied in clinical trials; safety and effectiveness in pediatric patients has not been established

AE: Adverse event; AML: Acute myeloid lymphoma; ITP: Immune thrombocytopenia; MDS: Myelodysplastic syndrome.