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Lusutrombopag for thrombocytopenia in Chinese patients with chronic liver disease undergoing invasive procedures
Ding, Z., Wu, H., Zeng, Y., Kuang, M., Yang, W., Meng, Z., Chen, Y., Hao, C., Zou, S., Sun, H., et al
Hepatology International. 2023;17(1):180-189
Abstract
PURPOSE Probing efficacy and safety of lusutrombopag in Chinese chronic liver disease (CLD) and severe thrombocytopenia (PLT < 50 × 10(9)/L) patients undergoing elective invasive procedures. METHODS In this double-blind, parallel-group phase 3 study, 66 patients with CLD and severe thrombocytopenia were randomized 2:1 to lusutrombopag or placebo arm treatment regimens for seven days at 9 centers in China. Responders (PLT ≥ 50 × 10(9)/L that increased to ≥ 20 × 10(9)/L from the baseline and not received rescue therapy for bleeding) on Day 8 (the day after seven-day treatment) were assessed. PLT ≥ 50 × 10(9)/L on or after Day 8 and within 2 days before invasive procedure (alternative criteria for not requiring platelet transfusion) were also analyzed. Adverse events (AEs) were recorded. RESULTS The proportion of responders on Day 8 was evidently higher (p = 0.0011) in the lusutrombopag group (43.2%, 19/44) versus placebo (4.5%, 1/22). And 72.7% (32/44) patients receiving lusutrombopag met the alternative criteria for not requiring platelet transfusion, while 18.2% (4/22) in the placebo group. The median maximum PLT in lusutrombopag group increased to 80.5 × 10(9)/L, and median time to reach maximum was 14.5 days. Compared with placebo, the lusutrombopag group had a lower incidence of bleeding events (6.8% versus 13.6%), and only one patient had thrombotic-related AE. Overall, the incidence of treatment-emergent AEs was comparable between two groups. CONCLUSIONS Lusutrombopag was effective in raising PLT, diminishing platelet transfusion requirement, and documented a safety profile like the placebo in CLD and severe thrombocytopenia patients in a Chinese cohort undergoing elective invasive procedures. Chinese clinical trial registration number: CTR20192384.
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Avatrombopag ethnic sensitivity analysis in chronic liver disease and thrombocytopenia patients: individual-level pooled analysis
Lu J, Jamieson BD, Hui AM
Therapeutic advances in gastroenterology. 2022;15:17562848221105976
Abstract
INTRODUCTION Few data have been published on the ethnic sensitivity of effectiveness, pharmacokinetics (PK), and pharmacodynamics (PD) of avatrombopag for the management of thrombocytopenia in patients with chronic liver disease (CLD). METHODS An ethnic sensitivity analysis was performed based on the results from two phase III studies (ADAPT-1 and ADAPT-2), with a primary endpoint of the proportion of patients without the requirement of platelet transfusion or rescue treatment for bleeding after randomization to 7 days following a scheduled procedure, and three phase I studies in healthy subjects. Cochran-Mantel-Haenszel and Fisher's exact tests were used to compare the differences in effectiveness in different ethnicities and overall population. RESULTS In total, 435 patients (placebo, n = 158; avatrombopag, n = 277) were stratified into various ethnic groups: 121 East Asians, including the subgroup of 27 Chinese, and 259 Caucasians. The proportion of patients who did not receive a platelet transfusion and those with a platelet count ⩾50 × 10(9)/L in the avatrombopag 40 and 60 mg groups were higher than that of placebo for all ethnicities and in the overall population. Statistical significance was obtained in the overall population and for all ethnicities other than Chinese patients, a group with a very small sample size. No significant difference was observed in the proportion of responders in each ethnic group compared to overall population (p > 0.05). The incidence of adverse events in East Asians was similar to that in both Caucasians and the overall population. CONCLUSION Avatrombopag was effective and safe in the management of thrombocytopenia in Chinese patients with CLD. Ethnicity does not appear to influence the efficacy, safety, PK, or PD of avatrombopag.
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Phase 2 Study of Avatrombopag in Japanese Patients with Chronic Liver Disease and Thrombocytopenia
Eguchi Y, Takahashi H, Mappa S, Santagostino E
Hepatology research : the official journal of the Japan Society of Hepatology. 2022
Abstract
AIM: Avatrombopag, a thrombopoietin receptor agonist, can reduce the need for platelet transfusions or rescue interventions for bleeding in patients with chronic liver disease (CLD) and thrombocytopenia undergoing scheduled procedures. A model analysis indicated that the effect of avatrombopag on platelet production was reduced in East Asian versus non-East Asian patients; however, the difference was deemed not clinically significant. Furthermore, a subgroup analysis of pooled Phase 3 trials showed similar avatrombopag efficacy across racial subgroups. The aim of this Phase 2 study was to corroborate the efficacy and safety of avatrombopag in Japanese patients with thrombocytopenia due to CLD. METHODS Japanese patients with CLD and thrombocytopenia were randomized to receive placebo or avatrombopag 20, 40, or 60 mg daily for 5 days. The primary endpoint was responder rate in platelet counts at Visit 4 (10-13 days after treatment initiation), defined as the proportion of patients with platelet count ≥50×10(9) /L and ≥20×10(9) /L increase from baseline. RESULTS Thirty-nine patients were randomized and completed the study (placebo, n=11; avatrombopag 20 mg, n=7; 40 mg, n=11; 60 mg, n=10). Avatrombopag treatment was associated with significant increases in responder rate at Visit 4 in the 40 mg (63.6%; P=0.004) and 60 mg (40%; P=0.024) groups versus placebo (9.1%). Avatrombopag was well tolerated and no new safety signals were detected. CONCLUSIONS Efficacy and safety results from this study were consistent with previous studies in patients with CLD and thrombocytopenia undergoing elective procedures, supporting treatment with avatrombopag in the Japanese population. ClinicalTrials.gov identifier: NCT02227693. This article is protected by copyright. All rights reserved.
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Systematic Review with Meta-Analysis: Efficacy and Safety of Lusutrombopag for Severe Thrombocytopenia in Patients with Chronic Liver Disease Undergoing Invasive Procedures
Orme, M. E., Bentley, R., Marcella, S., Peck-Radosavljevic, M., Perard, R., Wedemeyer, H., Yoshiji, H., Agarwal, K., Dusheiko, G.
Advances in Therapy. 2022;39(9):4169-4188
Abstract
INTRODUCTION Lusutrombopag is an oral thrombopoietin receptor agonist (TPO-RA). Clinical trials have shown lusutrombopag's efficacy in reducing need for preoperative platelet transfusion in patients with chronic liver disease (CLD) and severe thrombocytopenia. This analysis assessed efficacy and safety of lusutrombopag in patients with severe thrombocytopenia and CLD undergoing planned invasive procedures. METHODS An electronic database search (through 1 December 2020) identified three randomised, placebo-controlled, double-blind clinical trials comparing lusutrombopag with placebo in patients with CLD and platelet count below 50 × 10(9)/L scheduled to undergo a procedure with a perioperative bleeding risk. A random-effects meta-analysis examined treatment effect, with Cochrane Collaboration's tool assessing risk of bias. RESULTS The meta-analysis included 343 (lusutrombopag 3 mg, n = 173; placebo, n = 170) patients. More patients met the criteria for treatment response (platelet count at least 50 × 10(9)/L and increase of at least 20 × 10(9)/L from baseline anytime during the study) with lusutrombopag versus placebo (risk ratio [RR] 6.39; 95% confidence interval [CI] 3.69, 11.07; p < 0.0001). The primary efficacy outcome, proportion of patients requiring no platelet transfusion and no rescue therapy for bleeding for at least 7 days post procedure, was achieved by more patients treated with lusutrombopag versus placebo (RR 3.42; 95% CI 1.86, 6.26; p = 0.0001). The risk of any bleeding event was significantly lower with lusutrombopag compared to placebo (RR 0.55; 95% CI 0.32, 0.95; p = 0.03); conversely, thrombosis event rates were similar between lusutrombopag and placebo (RR 0.79; 95% CI 0.19, 3.24; p = 0.74). CONCLUSION This meta-analysis showed that treatment of severe thrombocytopenia with lusutrombopag in patients with CLD prior to a planned invasive procedure was efficacious and safe in increasing platelet counts, avoiding the need for platelet transfusions, and reducing risk of bleeding, thereby enhancing the certainty of evidence supporting the efficacy and safety of lusutrombopag.
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The efficacy and safety of thrombopoietin receptor agonists in patients with chronic liver disease undergoing elective procedures: a systematic review and meta-analysis
Lindquist I, Olson SR, Li A, Al-Samkari H, Jou JH, McCarty OJT, Shatzel JJ
Platelets. 2021;:1-7
Abstract
Thrombopoietin receptor agonists (TPO-RAs) can mitigate preprocedural thrombocytopenia in patients with chronic liver disease (CLD) however their effects on procedural outcomes is unclear. In this meta-analysis, we aimed to better define the efficacy, thrombotic risk and bleeding mitigation associated with the use of preoperative TPO-RAs in patients with CLD. We performed a systematic review and meta-analysis of randomized placebo-controlled clinical trials to assess the use of preprocedural TPO-RAs in patients with CLD, searching MEDLINE, EMBASE and the Cochrane library database. Six publications comprising eight randomized trials (1229 patients; 717 received TPO-RAs, 512 received placebo) and three unique TPO-RAs were retrieved. The majority of the included procedures were endoscopic. TPO-RAs were significantly more likely to result in a preoperative platelet count greater than 50 x 10(9)/L (72.1% vs 15.6%, RR 4.8, 95% CI 3.6-6.4 p < .00001. NNT 1.8) and reduced the incidence of platelet transfusions (22.5% vs 67.8%, RR 0.33, 95% CI 0.3-0.4 p < .00001. NNT 2.2). Total periprocedural bleeding was decreased in patients who received TPO-RAs (11.6% vs 15.6%, RR 0.64, 95% CI 0.5-0.9 p = .01. NNT 24.7) and there was no increase in the rate of thrombosis (2.2% vs 1.8% RR 1.25, 95% CI 0.6-2.9 p = .60. NNH 211.1). In patients with CLD the use of preprocedural TPO-RAs resulted in significant increased platelet counts, and decreased the incidence of platelet transfusions as compared to placebo. TPO use likewise decreased the incidence of total periprocedural bleeding without increasing the rate of thrombosis.
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Potential therapeutics for antiphospholipid antibody associated thrombocytopenia: A systematic review and meta-analysis
Abe, N., Oku, K., Amengual, O., Fujieda, Y., Kato, M., Bohgaki, T., Yasuda, S., Mori, R., Morishita, E., Suzuki-Inoue, K., et al
Modern Rheumatology. 2020;30(1):116-124
Abstract
Objectives: Thrombocytopenia is frequently observed in antiphospholipid antibody (aPL) carriers. Due to the paradoxical risks of thrombosis and hemorrhage, the management of aPL-associated thrombocytopenia (APAT) is often deductive. We aimed to investigate the efficacy and safety of therapeutic approaches for APAT through a systematic review. Methods: Four therapeutic approaches for APAT, including antiplatelet agents, glucocorticoids, splenectomy and thrombopoietin receptor agonists, were selected. Clinical trials evaluating therapeutic outcomes including the remission, complications, mortality and relapse, were searched in MEDLINE, EMBASE and CENTRAL from the inception dates to 28 November 2016. A meta-analysis was performed to calculate risk ratios (RRs) and 95% confidence intervals (CIs) using random-effects models. Results: Out of 1407 papers, eight controlled clinical trials were included. In patients with APAT, the remission rates were higher in patients on glucocorticoids (RR 8.33 [95% CI 3.07-22.6]) or splenectomy (RR 8.37 [95% CI 1.61-43.7]) than in patients without those treatments. There was no significant association between glucocorticoids and thrombosis (RR 1.57 [95% CI, 0.17-14.9]) or between splenectomy and hemorrhage (RR 0.17 [95% CI 0.02-1.28]). The extracted data of mortality and relapse rate were not available for synthesis. Conclusion: Glucocorticoids or splenectomy seemed suitable therapeutic approaches for APAT.
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Avatrombopag, an Alternate Treatment Option to Reduce Platelet Transfusions in Patients with Thrombocytopenia and Chronic Liver Disease-Integrated Analyses of 2 Phase 3 Studies
Poordad F, Terrault NA, Alkhouri N, Tian W, Allen LF, Rabinovitz M
International journal of hepatology. 2020;2020:5421632
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Editor's Choice
Abstract
Aims: Thrombocytopenia complicates the management of patients with chronic liver disease (CLD) undergoing invasive procedures with a bleeding risk. Until recently, prophylactic platelet transfusion was the only treatment option, but has significant safety and efficacy limitations. Phase 3 data demonstrated the superiority of avatrombopag to placebo in reducing platelet transfusions for bleeding, supporting its recent approval. Methods: Integrated analyses of pooled data (N = 435) from two randomized, double-blind, placebo-controlled, phase 3 studies assessed the original efficacy endpoints. Additional analyses included subgroup analyses, alternate Baseline platelet count definitions, and another efficacy endpoint. Results: Avatrombopag was superior to placebo in increasing patients not requiring a platelet transfusion or rescue procedure, those achieving a platelet count ≥50 x 10(9)/L on Procedure Day, and the change in platelet counts from Baseline. The avatrombopag treatment effect was consistently positive across clinically important disease and Baseline clinical characteristic subgroups, and using alternate Baseline platelet count cohort definitions. Similarly, more avatrombopag-treated patients achieved ≥50 x 10(9)/L platelets with an increase of ≥20 x 10(9)/L from Baseline. The incidence and severity of adverse events were similar between avatrombopag and placebo. Further, safety data demonstrated a low risk for thromboembolic events and hepatotoxicity. Conclusion: These integrated analyses confirmed the superiority of avatrombopag to placebo in reducing platelet transfusions or rescue procedures for bleeding in patients with thrombocytopenia and CLD scheduled to undergo an invasive procedure, and its tolerable safety profile. Importantly, these data warrant reconsideration of clinical decision making regarding the need to treat thrombocytopenia in patients with CLD. This trial was registered with NCT01972529 and NCT01976104.
PICO Summary
Population
Adults with thrombocytopenia associated with chronic liver disease (n=435).
Intervention
Low Baseline Platelet Count Cohort (<40 × 109/L) 60 mg avatrombopag (n=160) or placebo (n=91).
Comparison
High Baseline Platelet Count Cohort (40 to <50 × 109/L) five daily doses of 40 mg avatrombopag (n=117) or placebo (n=67).
Outcome
Avatrombopag was superior to placebo in increasing patients not requiring a platelet transfusion or rescue procedure. The avatrombopag treatment effect was consistently positive across clinically important disease and Baseline clinical characteristic subgroups, and using alternate Baseline platelet count cohort definitions. Similarly, more avatrombopag-treated patients achieved >/=50 x 10(9)/L platelets with an increase of >/=20 x 10(9)/L from Baseline. The incidence and severity of adverse events were similar between avatrombopag and placebo. Further, safety data demonstrated a low risk for thromboembolic events and hepatotoxicity.
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Efficacy and safety of thrombopoietin receptor agonists in children with chronic immune thrombocytopenic purpura: meta-analysis
Tumaini Massaro J, Chen Y, Ke Z
Platelets. 2019;:1-8
Abstract
Immune thrombocytopenic purpura (ITP) is an autoimmune disorder presenting with low platelet count <100 x 10(9)/L. The condition affects both adults and children. Thrombopoietin receptor agonists (TPO-RAs) are second-line of therapy that includes Romiplostim and Eltrombopag, which stimulate the production of normally functioning platelets. Although the biological effect of these drugs is well established, there has not been a meta-analysis in children. To estimate the efficacy and safety of Romiplostim and Eltrombopag, we performed a systematic review and meta-analysis in children with chronic ITP. Systematic literature search was conducted in the following database: PubMed, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL). Review Manager 5.3 for Windows was used to analyze the data. Five randomized controlled trials with total of 261 pediatric patients from 1-17 years of age were included. The efficacy and safety analysis showed TPO-RA groups were superior over placebo, and there was no difference in adverse event occurrence between TPO-RA (Romiplostim and Eltrombopag) and placebo groups. The efficacy and safety of Eltrombopag did not differ significantly from those of Romiplostim. Both drugs were effective in treatment of children with chronic ITP. Our findings extend the currently available data on ITP treatment and is helpful for pediatric health providers and for the design of future clinical trials.
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Lusutrombopag for the Treatment of Thrombocytopenia in Patients With Chronic Liver Disease Undergoing Invasive Procedures (L-PLUS 2)
Peck-Radosavljevic, M., Simon, K., Iacobellis, A., Hassanein, T., Kayali, Z., Tran, A., Makara, M., Ben Ari, Z., Braun, M., Mitrut, P., et al
Hepatology (Baltimore, Md.). 2019;70(4):1336-1348
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Abstract
Thrombocytopenia may be associated with increased bleeding risk impacting timing and outcome of invasive procedures in patients with chronic liver disease (CLD). Lusutrombopag, a small-molecule, thrombopoietin (TPO) receptor agonist, was evaluated as a treatment to raise platelet counts (PCs) in patients with thrombocytopenia and CLD undergoing invasive procedures. L-PLUS 2 was a global, phase 3, randomized, double-blind, placebo-controlled study. Adults with CLD and baseline PCs < 50 × 10(9) /L were randomized to receive once-daily lusutrombopag 3 mg or placebo ≤ 7 days before an invasive procedure scheduled 2-7 days after the last dose. The primary endpoint was avoidance of preprocedure platelet transfusion and avoidance of rescue therapy for bleeding. A key secondary endpoint was number of days PCs were ≥ 50 × 10(9) /L throughout the study. Safety analysis was performed on patients who received at least one dose of study drug. This study occurred between June 15, 2015, and April 19, 2017, with a total of 215 randomized patients (lusutrombopag, 108; placebo, 107); 64.8% (70/108) of patients in the lusutrombopag group versus 29.0% (31/107) in the placebo group met the primary endpoint (P < 0.0001; difference of proportion 95% confidence interval [CI], 36.7 [24.9, 48.5]). The median duration of PCs ≥ 50 × 10(9) /L was 19.2 days with lusutrombopag (without platelet transfusion) compared with 0.0 in the placebo group (with platelet transfusion) (P = 0.0001). Most adverse events were mild or moderate in severity, and rates were similar in the lusutrombopag and placebo groups (47.7% and 48.6%, respectively). Conclusion: Lusutrombopag was superior to placebo for reducing the need for platelet transfusions and achieved durable PC response in patients with thrombocytopenia and CLD undergoing invasive procedures, with a safety profile similar to placebo.
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Avatrombopag Increases Platelet Count but Not Platelet Activation in Patients with Thrombocytopenia due to Liver Disease
Michelson AD, Smolensky Koganov E, Forde EE, Carmichael SL, Frelinger AL 3rd
Journal of Thrombosis and Haemostasis. 2018;16((12):):2515-2519.
Abstract
BACKGROUND The thrombopoietin receptor agonist (TPO-RA) avatrombopag has recently been FDA-approved for the treatment of thrombocytopenia in patients with chronic liver disease (CLD) scheduled for a procedure. The TPO receptor c-mpl is expressed on the platelet surface and TPO lowers the threshold for platelet activation. TPO-RAs may therefore also lead to platelet activation. OBJECTIVES To evaluate the effects of avatrombopag on platelet activation. PATIENTS/METHODS CLD patients with thrombocytopenia participated in a randomized, double-blind, placebo-controlled, parallel-group study. No patient received a platelet transfusion within 10 days of study blood draws. Platelet activation was evaluated by whole blood flow cytometry (which, unlike other methods, is accurate in thrombocytopenic samples). RESULTS Avatrombopag, but not placebo, increased platelet counts. As measured by platelet surface P-selectin and activated GPIIb-IIIa: 1) Circulating activated platelets were not increased in avatrombopag-treated patients compared with placebo-treated patients. 2) Platelet reactivity to low and high concentrations of ADP and thrombin receptor activating peptide was not increased in avatrombopag-treated patients compared with placebo-treated patients. CONCLUSIONS In this randomized, double-blind, placebo-controlled, parallel-group study of CLD patients with thrombocytopenia, avatrombopag increased platelet counts but did not increase platelet activation in vivo or platelet reactivity in vitro. This article is protected by copyright. All rights reserved.
