Safety and Efficacy of Thrombopoietin Receptor Agonists in Patients with Previously Treated Chronic Immune Thrombocytopenia: A Systematic Review and Meta-Analysis

Background: The current American Society of Hematology guideline recommends the use of thrombopoietin receptor agonists, eltrombopag or romiplostim as one of the second-line therapies for chronic immune thrombocytopenia (ITP). The efficacy and safety of those drugs have been tested in several clinical trials. However, the safety profile was not consistent throughout trials and is not yet well understood. We herein conducted a meta-analysis of randomized control trials to compare the safety and efficacy of thrombopoietin receptor agonists; eltrombopag and romiplostim versus placebo in patients with previously treated chronic ITP. Our primary outcome was drug-related adverse events greater than CTCAE grade 3.

Methods: We performed a literature search in MEDLINE, EMBASE, Cochrane library, and the American Society of Hematology website up to September, 2015 by two independent authors according to PRISMA guideline. We included only randomized clinical trials comparing eltrombopag or romiplostim versus placebo. Random-effects model was used to estimate pooled odds ratio (OR) with 95% confidence interval (CI).

Results: A total of eight trials involving 834 participants were included in the analysis. There was no significant difference of grade 3 or higher adverse events between placebo and treatment group (OR=1.01, 95% CI=0.57-1.78). Thromboembolism (OR=0.59, 95% CI=0.20-1.73), elevated ALT (OR=0.68, 95% CI=0.26-1.74), headache (OR=1.26, 95% CI=0.90-1.78), nausea (OR=0.82, 95% CI=0.43-1.55), or fatigue (OR=1.13, 95% CI=0.65-1.91) did not show a significant difference between groups, either. Clinical response, which is defined as platelets ≥50,000/μL at least once on treatment was significantly better in treatment group than in placebo group (OR=0.10, 95% CI=0.07-0.15). Bleeding symptoms (WHO Grades 1-4) were significantly more frequent in the placebo group (OR=1.60, 95% CI=1.14-2.24) during treatment.

Conclusions: Although several studies have suggested clinically significant treatment-related adverse events, such as thromboembolism, this meta-analysis showed that thrombopoietin receptor agonists are safe, well-tolerated, and effective in patients with previously treated chronic ITP.