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• W2910011746 abstract "We appreciate the opportunity to respond to Dr Weinberg’s comments and to provide additional data to aid clinicians in determining the clinical scenarios where avatrombopag should be considered. Dr Weinberg suggests the reason for the portal vein thrombosis (PVT) events in the prior ELEVATE trials was due to the duration of therapy, but the post hoc analysis of those events suggested it was related to level of platelet elevation, with those patients with levels >200 × 109/L (occurring in 25% of eltrombopag-treated patients) at higher risk of PVT.1Afdhal N.H. et al.N Engl J Med. 2012; 367: 716-724Crossref PubMed Scopus (226) Google Scholar This finding was applied to the ADAPT study dosing design. Importantly, based on comprehensive pharmacokinetic/pharmacodynamic modeling, 2 titrated doses of avatrombopag were administered according to patients’ baseline platelet counts to achieve the target platelet count of ≥50 × 109/L and minimize the risk of PVT occurring with platelet counts ≥200 × 109/L in previous studies. The ADAPT studies showed a predictable doubling of the platelet count with the avatrombopag doses used, and only 3 patients (1.1%) had platelet counts of ≥200 × 109/L.2Terrault N. et al.Gastroenterology. 2018; 155: 705-718Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar Thus, both the specific thrombopoietin receptor agonist used and the dose are likely more relevant than the duration of therapy in minimizing PVT risk. The controversy among clinicians regarding what platelet count is safe for performing invasive procedures is well-recognized and long standing. The categorization of low-, moderate-, and high-risk procedures in the ADAPT studies was to ensure a spectrum of invasive procedures was represented in the 2 study groups. However, the risk of bleeding in persons with cirrhosis is not only related the procedure performed and the platelet count, but also to factors such as severity of coagulopathy, presence of kidney dysfunction, invasiveness of the procedure, and the skills of the proceduralist. Given the multiplicity of factors, the intent of the ADAPT trials was not to define the specific platelet count for which preprocedure correction was needed, but to evaluate an alternative to platelet transfusion in clinical setting where they were already being used. Dr Weinberg proposes an alternative study design that included low-risk procedures that proceduralists would a priori not use platelet transfusion, and prohibited the use of platelet transfusion in the control arm. Although potentially interesting information for the field, this does not address the primary study aim, which was to identify clinical scenarios in which avatrombopag would be a safe and effective alternative to platelet transfusions. Thus, the appropriate inclusion criterion in the ADAPT studies was “subjects scheduled to undergo a procedure and who, in the opinion of the investigator, otherwise required a platelet transfusion to address a risk of bleeding associated with the procedure.” Moreover, a study design that requires or prohibits the use of platelets can be challenging to enroll and might be considered unethical by many. To this point, despite the requirement that clinical investigators enroll only patients with planned transfusion of platelets, 17.7% of those in the placebo treatment group with platelet counts <50 × 109/L did not receive a platelet transfusion. The rates of bleeding requiring treatment were low in the ADAPT trial but, as previously highlighted, the rates of bleeding in the context of invasive procedures may be influenced by factors other than platelet count and, for this reason, a comparison of bleeding rates across different trials of thrombopoietin-agonists should be undertaken with great caution. In the ADAPT trials, only 7.2% of avatrombopag-treated patients (20/277) and 9.5% of placebo-treated patients (15/158) had a bleeding event on or after procedure day. Of those patients, 7 of the 20 avatrombopag-treated patients and 10 of the 15 of placebo-treated patients received a rescue procedure, the majority of which were platelet transfusions; only 3 avatrombopag-treated patients and 4 placebo-treated patients received a rescue procedure other than a platelet transfusion. Dr Weinberg suggests the cost of avatrombopag is high; rather than comparing it with treatment for hepatitis C, the more appropriate comparison is the cost of platelet transfusion, including the management of transfusion-related complications, facility costs, and clinician and patient preferences. In a recent analysis evaluating the various costs, the overall cost of a platelet transfusion was shown to vary between $5258 and $13,117 in the United States.3Barnett C.L. et al.J Med Econ. 2018; 21: 827-834Crossref PubMed Scopus (19) Google Scholar More than cost, physicians need to importantly factor in the risks associated with the use of platelet transfusions particularly in this patient population. For example, for wait-listed patients with a need for combined liver–kidney transplantation, the repeated use of prophylactic platelet transfusions may contribute to sensitization and reduced access to transplant. Clinicians ultimately need to weigh the risk and benefits of any therapy, and the ADAPT trials provide important safety and efficacy data on a new treatment option for managing thrombocytopenia in patients with cirrhosis undergoing invasive procedures. What Did We Learn From the ADAPT Trials?GastroenterologyVol. 156Issue 3PreviewI read with interest the recent publication of the pair of phase III trials for the use of avatrombopag before invasive procedures in patients with chronic liver disease and severe thrombocytopenia.1 Given the increase in portal vein thrombosis that occurred in trials in a similar group of patients receiving the once-promising eltrombopag, the investigators were bold in this endeavor.2 Learning from the 2012 ELEVATE trial, the ADAPT trials were more conservative in design, treating patients with the thrombopoietin-receptor agonist for 5 days (compared with 14 days) to mitigate the potential for portal vein thrombosis. Full-Text PDF" @default.
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• W2910011746 doi "https://doi.org/10.1053/j.gastro.2019.01.024" @default.
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