By William Elliott, MD, FACP, and James Chan, PharmD, PhD

Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.

Drs. Elliott and Chan report no financial relationships relevant to this field of study.

The FDA has approved the first drug to treat low blood platelet counts in adults with chronic liver disease who are scheduled to undergo a medical or dental procedure. The FDA issued a fast-track designation and priority review for avatrombopag, a thrombopoietin receptor agonist. It is marketed as Doptelet.

INDICATIONS

Doptelet is prescribed for adults with thrombocytopenia and chronic liver disease who are scheduled to undergo a medical procedure.1

DOSAGE

Patients take avatrombopag orally with food once daily for five consecutive days starting 10-13 days prior to a scheduled procedure.1 Patients should undergo the procedure within five to eight days after the last dose. The recommended dose is 60 mg (three tablets) for patients with a baseline platelet count of < 40 × 109/L and 40 mg (two tablets) if platelet count is 40 × 109/L to < 50 × 109/L. Avatrombopag is available as 20 mg tablets, too.

POTENTIAL ADVANTAGES

Avatrombopag may decrease or eliminate the need for platelet transfusion or rescue procedures for bleeding in patients who are candidates for platelet transfusion due to low platelet counts. Doptelet is the first drug approved for this indication.

POTENTIAL DISADVANTAGES

There is potential to increase clotting risk in patients with known risk for thromboembolism (e.g., genetic prothrombotic conditions, antithrombin deficiency).1 The efficacy has not been established in patients ≥ 65 years of age.1

COMMENTS

Avatrombopag binds to the thrombopoietin receptor, but does not compete with endogenous thrombopoietin, which leads to an added stimulus on platelet production.1 The peak effect is observed 10-13 days after the start of the five-day course. Platelet counts gradually return near baseline after 35 days.

Safety and efficacy were evaluated in two randomized, placebo-controlled trials in subjects with chronic liver disease and thrombocytopenia (baseline count, < 50 × 109/L) scheduled to undergo a procedure with low, moderate, or high bleeding risk, which would require a platelet transfusion.1,2 Subjects were stratified by baseline platelet count: low (< 40 × 109/L) or high (≥ 40 × 109/L to < 50 × 109/L). Those with low counts were randomized to 60 mg or placebo for five days. Those with high counts received 40 mg or placebo for five days.

In trial 1, the authors randomized 90 subjects to avatrombopag in the low count group and 59 in the high count group, with corresponding placebo subjects of 48 and 34, respectively. For trial 2, the number of subjects in the avatrombopag groups were 70 in the low platelet count group and 58 in the high platelet count group, with 43 and 33, respectively, in the placebo groups. Mean baseline platelet counts were 31 to 33 × 109/L in the low count groups and 44 × 109/L to 45 × 109/L in the high count groups. The most common liver diseases were chronic viral hepatitis (57%) and hepatocellular carcinoma (27%).2 Sixty-one percent of subjects underwent low bleeding risk procedures. Twenty-two percent underwent high bleeding risk procedures. The major efficacy endpoint was the proportion of subjects who did not require a platelet transfusion or any rescue procedure for bleeding after randomization and up to seven days following an elective procedure (defined as responders). The secondary endpoint was achieving a platelet count of > 50 × 109/L.

In the low count group, the frequency of responders was 66% in trial 1 and 69% in trial 2, compared to 23% and 35%, respectively, for the placebo groups. For the high count group, response rates were 88% in both trials for avatrombopag, and 38% and 33% for placebo groups, respectively. In the low count group, 67-69% achieved a count > 50 × 109/L compared to 3-7% for the placebo groups. The most frequently reported adverse reactions (vs. placebo) were pyrexia (10% vs. 9%) and abdominal pain (7% vs. 6%).1

CLINICAL IMPLICATIONS

Thrombocytopenia is a complication of chronic liver disease, with the level of thrombocytopenia corresponding to the severity of liver disease.3 Severe thrombocytopenia (< 50 × 109/L) complicates invasive procedures for diagnosis or therapy in these patients. However, a recent case series study suggested that bleeding after invasive procedures is rare and not predicted by platelet counts in cirrhotic patients.4 Strategies to boost platelet counts include platelet infusion or use of a thrombopoietin receptor agonist.5,6 Platelet transfusion is limited by transfusion reactions, short duration of action, and platelet refractoriness.7 The thrombopoietin receptor agonist eltrombopag has been associated with portal vein thrombosis.8 Romiplostim has not been approved for this indication, and there are no published comparative studies with avatrombopag. Avatrombopag is the only approved drug that is an alternative to platelet infusion. The wholesale acquisition cost for a five-day course is $9,000 for the 40 mg daily dose and $13,500 for the 60 mg daily dose.

REFERENCES

  1. Doptelet Prescribing Information. Dova Pharmaceuticals, Inc., May 2018. Available at: https://bit.ly/2NvmkiX. Accessed July 5, 2018.
  2. Terrault N, Chen YC, Izumi N, et al. Avatrombopag before procedures reduces need for platelet transfusion in patients with chronic liver disease and thrombocytopenia. Gastroenterology 2018 May 17. pii: S0016-5085(18)34545-1. doi: 10.1053/j.gastro.2018.05.025. [Epub ahead of print].
  3. Maan R, de Knegt RJ, Veldt BJ. Management of thrombocytopenia in chronic liver disease: Focus on pharmacotherapeutic strategies. Drugs 2015;75:1981-1992.
  4. Napolitano G, Iacobellis A, Merla A, et al. Bleeding after invasive procedures is rare and unpredicted by platelet counts in cirrhotic patients with thrombocytopenia. Eur J Intern Med 2017;38:79-82.
  5. Qureshi K, Patel S, Meillier A. The use of thrombopoietin receptor agonists for correction of thrombocytopenia prior to elective procedures in chronic liver diseases: Review of current evidence. Int J Hepatol 2016;2016:1802932. Epub 2016 Oct 9.
  6. Afdhal N, McHutchison J, Brown R, et al. Thrombocytopenia associated with chronic liver disease. J Hepatol 2008;48:1000-1007.
  7. Estcourt LJ, Malouf R, Doree C, et al. Prophylactic platelet transfusions prior to surgery for people with a low platelet count. Cochrane Database Syst Rev 2017;2017(9). pii: CD012779. doi: 10.1002/14651858.CD012779. Epub 2017 Sep 2.
  8. Afdhal NH, Giannini EG, Tayyab G, et al. Eltrombopag before procedures in patients with cirrhosis and thrombocytopenia. N Engl J Med 2012;367:716-724.