Phase II study of avatrombopag in thrombocytopenic patients with cirrhosis undergoing an elective procedure

Terrault, Norah A.; Hassanein, Tarek; Howell, Charles D.; Joshi, Shobha; Lake, John R.; Sher, Linda; Vargas, Hugo E.; McIntosh, Joe K.; Tang, Shande; Jenkins, Timothy M.

doi:10.1016/j.jhep.2014.07.007

Cited by 77 publications

(67 citation statements)

References 14 publications

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“…A Phase II study investigated avatrombopag administered 1 week before elective invasive procedures in 130 cirrhotic patients with thrombocytopenia (10 000‐58 000/μL) . Patients were randomized to placebo vs a first‐generation avatrombopag formulation (100 mg loading dose then 20, 40 or 80 mg/d on Days 2‐7; cohort A; n=67) or placebo vs a second‐generation formulation (80 mg loading dose then 10 mg/d on Days 2‐7 or 20 mg/d on Days 2‐4; cohort B; n=63).…”

Section: New Therapeutic Options For Thrombocytopenia In Cldmentioning

confidence: 99%

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Thrombocytopenia in chronic liver disease

Peck‐Radosavljevic

2016

Liver International

226

180

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Thrombocytopenia is a common haematological disorder in patients with chronic liver disease. It is multifactorial and severity of liver disease is the most influential factor. As a result of the increased risk of bleeding, thrombocytopenia may impact upon medical procedures, such as surgery or liver biopsy. The pathophysiology of thrombocytopenia in chronic liver disease has long been associated with the hypothesis of hypersplenism, where portal hypertension causes pooling and sequestration of all corpuscular elements of the blood, predominantly thrombocytes, in the enlarged and congested spleen. Other mechanisms of importance include bone marrow suppression by toxic substances, such as alcohol or viral infection, and immunological removal of platelets from the circulation. However, insufficient platelet recovery after relief of portal hypertension by shunt procedures or minor and transient recovery after splenic artery embolization have caused many to question the importance and relative contribution of this mechanism to thrombocytopenia. The discovery of the cytokine thrombopoietin has led to the elucidation of a central mechanism. Thrombopoietin is predominantly produced by the liver and is reduced when liver cell mass is severely damaged. This leads to reduced thrombopoiesis in the bone marrow and consequently to thrombocytopenia in the peripheral blood of patients with advanced-stage liver disease. Restoration of adequate thrombopoietin production post-liver transplantation leads to prompt restoration of platelet production. A number of new treatments that substitute thrombopoietin activity are available or in development.

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Section: New Therapeutic Options For Thrombocytopenia In Cldmentioning

confidence: 99%

“…120,121 A Phase II study investigated avatrombopag administered 1 week before elective invasive procedures in 130 cirrhotic patients with thrombocytopenia (10 000-58 000/μL). 122 Patients were randomized to placebo vs a first-generation avatrombopag formulation (…”

Section: Avatrombopagmentioning

confidence: 99%

Thrombocytopenia in chronic liver disease

Peck‐Radosavljevic

2016

Liver International

226

180

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“…However, two nonpeptide TPO agonists, avatrombopag and lusutrombopag, were recently approved for use in patients with advanced liver disease and thrombocytopenia who undergo elective procedures. Avatrombopag (Doptelet) was approved in the United States in May 2018 . In the global, multicenter, combined ADAPT‐1 and ADAPT‐2 phase III, randomized, double‐blind, placebo‐controlled clinical trials, avatrombopag given at 40 or 60 mg daily (based on initial platelet counts) for 5 days before an elective procedure increased the platelet count and reduced platelet transfusion requirements .…”

Section: Current Tpo Receptor Agonistsmentioning

confidence: 99%

“…Avatrombopag (Doptelet) was approved in the United States in May 2018. (40,41) In the global, multicenter, combined ADAPT-1 and ADAPT-2 phase III, randomized, double-blind, placebo-controlled clinical trials, avatrombopag given at 40 or 60 mg daily (based on initial platelet counts) for 5 days before an elective procedure increased the platelet count and reduced platelet transfusion requirements. (40) A total of 231 patients were included in the ADAPT-1 and 204 patients in the ADAPT-2 trials.…”

Section: Current Tpo Receptor Agonistsmentioning

confidence: 99%

Thrombocytopenia and Procedural Prophylaxis in the Era of Thrombopoietin Receptor Agonists

Caldwell

Flamm²

2019

Hepatol Commun

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Thrombocytopenia is common in patients with advanced liver disease. These patients frequently require invasive diagnostic or therapeutic procedures in the setting of thrombocytopenia. A common platelet goal before such procedures is ≥50,000/μL, but target levels vary by provider and the procedure. Platelet transfusion has disadvantages, including safety and cost. No other short‐term options for ameliorating thrombocytopenia before procedures were available until the thrombopoietin receptor agonists were recently approved. Avatrombopag and lusutrombopag can be used in certain patients with thrombocytopenia due to advanced liver disease undergoing elective invasive procedures; these new agents are highly effective in carefully selected patients, and real world data of safety and efficacy are awaited.

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“…The lower incidence of portal vein thrombosis (1.1%) in this study may reflect dose selection and the shorter duration of therapy resulting in a less exuberant platelet response. 34 Thrombotic complications may reflect a disruption of rebalanced hemostasis by a rapid and sustained increase in activated platelets. These initial studies of TPO R agonists demonstrate how small perturbations can overcome compensatory mechanisms and rapidly shift the balance toward thrombosis in an individual patient.…”

Section: Thrombopoietin Receptor Agonistsmentioning

confidence: 99%

Coagulopathy in liver disease: a balancing act

Kujovich

2015

Hematology

114

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Liver disease results in complex alterations of all 3 phases of hemostasis. It is now recognized that hemostasis is rebalanced in chronic liver disease. The fall in clotting factor levels is accompanied by a parallel fall in anticoagulant proteins. High von Willebrand factor levels counteract defects in primary hemostasis. Conventional coagulation tests do not fully reflect the derangement in hemostasis and do not accurately predict the risk of bleeding. Global coagulation assays (thrombin generation, thromboelastography) reflect the interaction between procoagulant factors, anticoagulant factors, platelets, and the fibrinolytic system and show promise for assessing bleeding risk and guiding therapy. These assays are not yet commercially approved or validated. Prevention of bleeding should not be aimed at correcting conventional coagulation tests. Thrombopoietin receptor agonists were shown to increase the platelet count in cirrhotic patients undergoing invasive procedures

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Phase II study of avatrombopag in thrombocytopenic patients with cirrhosis undergoing an elective procedure

Cited by 77 publications

References 14 publications

Thrombocytopenia in chronic liver disease

Thrombocytopenia in chronic liver disease

Thrombocytopenia and Procedural Prophylaxis in the Era of Thrombopoietin Receptor Agonists

Coagulopathy in liver disease: a balancing act

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