Thrombopoietin receptor agonists use and risk of thrombotic events in patients with immune thrombocytopenic purpura: A systematic review and meta‑analysis of randomized controlled trials

Abstract

Thrombopoietin receptor agonists (TPO-RAs) have a role in second-line immune thrombocytopenic purpura (ITP) treatment, binding to and activating thrombopoietin receptors on megakaryocyte membranes in the bone marrow. This promotes megakaryocyte maturation and increases platelet production. Despite a 2-6% incidence of thrombotic events during TPO-RA treatment, it remains uncertain whether TPO-RAs elevate thrombosis rates. A comprehensive search of electronic databases was conducted using the relevant search criteria. To assess the risk of bias, the included studies were assessed using the revised Cochrane Risk of Bias Assessment Tool 2.0, and a meta-analysis was performed using RevMan 5.4.1. A total of 1,698 patients with ITP were included from randomized controlled trials (RCTs). There were 26 thromboembolic events in the TPO-RAs group and 4 in the control group. However, there was no significant difference in the incidence of thrombotic events between the two groups [odds ratio (OR)=1.76, 95% confidence interval (CI): 0.78-4.00, P=0.18], even if the duration of treatment was >12 weeks (OR=2.46, 95% CI: 0.81-7.43, P=0.11). Subgroup analysis showed that none of the four drugs significantly increased the incidence of thrombotic events (romiplostim: OR=0.92, 95% CI: 0.14-6.13, P=0.93; eltrombopag: OR=2.32, 95% CI: 0.64-8.47, P=0.20; avatrombopag: OR=4.15, 95% CI: 0.20-85.23, P=0.36; and hetrombopag: OR=0.76, 95% CI: 0.03-18.76, P=0.87). There was also no significant difference in the results of the double-blinded placebo-controlled RCTs (OR=1.21, 95% CI: 0.41-3.58, P=0.73). Compared to patients with ITP who did not receive TPO-RA treatment, those receiving TPO-RA treatment did not exhibit a significantly increased risk of thrombotic events.

Keywords: immune thrombocytopenia; meta-analysis; thrombopoietin receptor agonists; thrombosis.

Figure 1

Flowchart of study inclusion. CNKI, China National Knowledge Infrastructure; ITP, immune thrombocytopenia; RCT, randomized controlled trial.

Figure 2

Risk of bias assessment using the ROB 2.0 tool. A provides a summary for all studies and B is the evaluation of each individual study (+, low risk of bias; ?, unclear risk of bias).

Figure 3

Thrombosis events on total TPO-RAs. TPO-RA, thrombopoietin receptor agonist; M-H, Mantel-Haentzel; df, degrees of freedom.

Figure 4

Subgroup analysis of thrombosis events on TPO-RAs. TPO-RA, thrombopoietin receptor agonist; M-H, Mantel-Haentzel; df, degrees of freedom.

Figure 5

Thrombosis events on TPO-RAs with a treatment time of >12 weeks. TPO-RA, thrombopoietin receptor agonist; M-H, Mantel-Haentzel; df, degrees of freedom.

Figure 6

Thrombosis events on TPO-RAs in double-blinded, placebo-controlled randomized controlled trials. TPO-RA, thrombopoietin receptor agonist; M-H, Mantel-Haentzel; df, degrees of freedom.