What is the role of Avatrombopag (Avatrombopag) in treating thrombocytopenia?

Avatrombopag for Thrombocytopenia in Chronic Liver Disease

Avatrombopag is an FDA-approved oral thrombopoietin receptor agonist that effectively raises platelet counts in patients with chronic liver disease and thrombocytopenia (platelet count <50 × 10⁹/L) scheduled to undergo invasive procedures, significantly reducing the need for platelet transfusions without increasing bleeding or thrombotic complications. 1

Mechanism and Pharmacology

• Avatrombopag is a second-generation oral thrombopoietin receptor agonist that stimulates platelet production through TPO receptor activation 2, 3
• The drug has a half-life of 18-21 hours, supporting once-daily dosing 2
• Platelet count increases begin 3-5 days after administration, with maximum effects occurring 13-16 days after treatment initiation 2
• Peak concentration and exposure increase proportionally with dose 2

Clinical Efficacy: The ADAPT Trials

Two large phase III randomized controlled trials (ADAPT-1 and ADAPT-2) established avatrombopag's superiority over placebo:

Primary Endpoint Results

• In patients with baseline platelets <40 × 10⁹/L receiving 60 mg avatrombopag: 65.6% (ADAPT-1) and 68.6% (ADAPT-2) avoided platelet transfusions or rescue procedures versus 22.9% and 34.9% with placebo (P < 0.001 for both) 1, 4
• In patients with baseline platelets 40-50 × 10⁹/L receiving 40 mg avatrombopag: 88.1% (ADAPT-1) and 87.9% (ADAPT-2) avoided transfusions versus 38.2% and 33.3% with placebo (P < 0.001 for both) 1, 4

Platelet Response

• Avatrombopag achieved the combined primary endpoint with relative risk of 2.46 (95% CI, 1.77-3.41) for 40 mg dose and 2.36 (95% CI, 1.67-3.32) for 60 mg dose 1
• The drug successfully raised platelet counts to target levels (≥50 × 10⁹/L) on procedure day in the majority of treated patients 4

Safety Profile

Avatrombopag demonstrates an excellent safety profile with no increased risk of thrombosis or bleeding:

• No difference in thrombotic events compared to placebo (RR 0.28; 95% CI, 0.03-3.02) 1
• Bleeding rates were low in the entire cohort (3.5%; n=15 of 430) with no statistically significant differences between avatrombopag and placebo groups 1
• The 30-day thrombotic event risk is approximately 1% 1
• Most common adverse events are headache, fatigue, and gastrointestinal symptoms, comparable to placebo 3, 5
• No hepatotoxicity, dose-limiting toxicities, or serious adverse events leading to withdrawal in phase I studies 2

Dosing and Administration

Dose-specific regimen based on baseline platelet count:

• For platelets <40 × 10⁹/L: 60 mg once daily for 5 consecutive days 1, 4
• For platelets 40-50 × 10⁹/L: 40 mg once daily for 5 consecutive days 1, 4
• Treatment requires completion of a 5-7 day course prior to the scheduled procedure 1, 6
• Unlike eltrombopag, avatrombopag does not require food restrictions 5

Clinical Context and Guideline Recommendations

Procedure Types Studied

• The majority of procedures in clinical trials were low-risk (61-66%), predominantly diagnostic and therapeutic endoscopies (52% were EGD procedures) 1
• Studies included both medical and surgical procedures but focused primarily on low-risk interventions 1

Advantages Over Platelet Transfusion

According to EASL 2022 guidelines, thrombopoietin receptor agonists offer several benefits: 1

• Improved clinical management by avoiding procedure cancellations due to low platelet counts
• Avoidance of prophylactic platelet transfusions, which have unpredictable efficacy in cirrhosis
• Prevention of transfusion-related complications including refractoriness to future platelet transfusions
• Increased platelet availability for other clinical purposes

Evidence Quality Considerations

• The certainty of evidence was rated down for indirectness because surrogate outcomes (transfusion avoidance) were used instead of clinically significant bleeding as the primary endpoint 1
• No studies compared TPO receptor agonists to a restrictive strategy (no intervention) in patients with thrombocytopenia 1
• None of the original studies demonstrated differences in procedure-associated bleeding rates, though bleeding was numerically lower in some analyses 1

Important Clinical Pitfalls

Key considerations to avoid misuse:

• Do not use avatrombopag as routine prophylaxis for all procedures—baseline bleeding risk for common procedures is generally low even with thrombocytopenia 1, 7
• Platelet counts alone do not reliably predict bleeding risk in cirrhosis; progressive decompensation (Child-Turcotte-Pugh score) is a more important marker 1
• Prophylactic platelet transfusions have not demonstrated significant reduction in procedural bleeding and may paradoxically increase bleeding risk by raising portal pressure 7, 6
• The drug requires 5-7 days of treatment before procedures, so it cannot be used for urgent interventions 1, 6
• Consider that most bleeding in cirrhosis is attributable to portal hypertension rather than low platelet counts themselves 6

Additional FDA-Approved Indication

• Avatrombopag is also approved for chronic immune thrombocytopenia (ITP) in adults who are refractory or have unsatisfactory response to other treatments, with high durable response rates and potential corticosteroid-sparing effects 3, 5