Immune thrombocytopenia (ITP) is an acquired autoimmune disorder characterized by a low platelet count due to increased platelet destruction and impaired platelet production (1). The prevalence of ITP generally ranges from 2 to 4 cases per 100,000 person-years, with two distinct peaks observed. The first peak occurs between the ages of 20 and 30, with a slight predominance of females, while the second peak is observed after the age of 60, exhibiting an equal sex distribution (2, 3). In adult patients, ITP typically manifests as a chronic acquired disorder. Compared to pediatric patients with ITP, adults are less likely to experience spontaneous remission, have a greater tendency toward hemorrhage, and require more intensive treatment (4).

For adults, the primary objective is to maintain a hemostatic platelet count while minimizing the toxicity of therapy (5). First-line treatment typically involves corticosteroids and intravenous immunoglobulins, whereas second-line treatment generally includes thrombopoietin receptor agonists (TPO-RA), immunosuppressants, rituximab, fostamatinib and splenectomy (6). TPO-RA has been demonstrated to induce megakaryocytic maturation and enhance platelet production, thereby increasing platelet levels and reducing hemorrhage (7). Currently, five types of TPO-RA have been approved for the treatment of adult ITP: avatrombopag, eltrombopag, romiplostim, hetrombopag, and recombinant human thrombopoietin (rhTPO).

Most studies aim to analyze the efficacy and safety of TPO-RA in ITP patients, however, there exists a limited number of investigations that have compared the respective efficacy and safety between different varieties of TPO-RA (8–10). The objective of this study was to analyze the differences in efficacy and safety between various TPO-RA. To this end, a meta-analysis of randomized clinical trials (RCTs) and a disproportionality analysis based on the FDA Adverse Events Reporting System (FAERS) database was conducted.

This study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis for Network Meta-Analysis (11). The protocol was registered on PROSPERO (CRD42024506242).

This study employed a network meta-analysis and disproportionality analysis based on the FAERS database to compare the efficacy and safety of four TPO-RA: romiplostim, avatrombopag, eltrombopag, and hetrombopag, as recommended by current guidelines for the treatment of ITP in adults. This network meta-analysis incorporates the most recent studies compared to previous meta-analyses and includes a larger patient population, providing higher statistical power than traditional pairwise meta-analyses. Additionally, it incorporates AEs data from real-world patients to further assess the safety of TPO-RA (2–7, 17–24).

This network meta-analysis demonstrated the overall efficacy and safety of romiplostim, avatrombopag, eltrombopag, and hetrombopag in the treatment of ITP, which is largely consistent with the findings of previous meta-analyses. ITP is an acquired autoimmune disease characterized by isolated thrombocytopenia, resulting from increased platelet destruction and decreased platelet production, both of which are mediated by immune disorders (25). The primary mechanism underlying ITP is the loss of immune tolerance to platelet autoantigens, leading to aberrant activation of both humoral and cellular immunity. These factors collectively contribute to accelerated platelet destruction and insufficient production of platelets by megakaryocytes (26). TPO-RA primarily increase platelet counts by binding to their receptor, the megakaryocyte progenitor cell receptor (MPL). MPL is a receptor tyrosine kinase that is highly expressed on the surface of megakaryocytes and platelet precursor cells. By binding to MPL, TPO-RA stimulates megakaryocyte proliferation and differentiation, thereby promoting platelet maturation and release (27). The results of this study differ from those of the network meta-analysis conducted by Liu (1), in which avatrombopag (87.5%) was found to be more effective than romiplostim (71.1%). This discrepancy in findings may be attributed to the inclusion of three recently published RCTs on avatrombopag in 2023 (7, 17, 18), which resulted in a shift in the ranking of avatrombopag and romiplostim in terms of efficacy. It has been demonstrated that neither avatrombopag nor romiplostim interacts with food or drugs. Eltrombopag represents the inaugural oral TPO-RA for the treatment of ITP. hetrombopag is a highly selective TPO-RA that has been developed through a series of modifications based on the structure of eltrombopag. This new agent exhibits greater activity and a reduced incidence of AE (28). However, they are susceptible to interactions with calcium-rich foods and antacids containing aluminum and magnesium, which can significantly reduce the concentration of the active ingredient and, consequently, its efficacy (29).

Regarding safety, our systematic review indicated that there was no significant difference in the incidence rate of AEs among patients in the four drug and placebo groups. This study is in accordance with the results of the traditional meta-analysis conducted by Shen (30). Even if there is no statistically significant difference in safety, their use still needs to be cautious. Regarding the most common thrombotic AE associated with ITP, no significant difference was observed compared to placebo. The SUCRA analysis indicates that among the four drugs, avatrombopag (23.8%) has the best safety profile, followed by eltrombopag (42.5%), romiplostim (53.1%), and hetrombopag (59.5%). The FAERS database was utilized to analyze the occurrence of AEs, particularly focusing on hemorrhagic and thrombotic events of greatest clinical concern. Among the four drugs, romiplostim reported the highest number of adverse events (55.09%), while avatrombopag reported the lowest (3.46%). However, it would be misleading to conclude that romiplostim has a high incidence of AEs and poor safety. This perception may be attributed to its earlier market entry, which occurred 10 years prior to the launch of avatrombopag in 2018 (31, 32). A review of AE reports indicates that avatrombopag has a lower incidence of hemorrhagic and thrombotic events since its launch, with a relatively limited number of AEs occurring concurrently. The most frequently reported AE associated with both romiplostim and avatrombopag is deep vein thrombosis. The occurrence of deep vein thrombosis is related to several factors, including a history of venous thromboembolism, coronary artery disease, atrial fibrillation, and other conditions. Nevertheless, the guidelines do not prohibit the use of TPO-RA in this population, and therefore, the use of TPO-RA is not considered to increase the risk of deep vein thrombosis in patients. The most frequently reported AE associated with eltrombopag is hemorrhage, which is often a result of the drug’s ineffectiveness. As a medication for the treatment of thrombocytopenia, eltrombopag increases platelet counts by stimulating platelet production in the bone marrow, with the majority of the drug being metabolized by the liver (33). The initial dosage is calculated according to the patient’s weight. The platelet count is monitored on an individual basis in order to ascertain the optimal maintenance dose. The effects of treatment may take several weeks or even months to manifest (34). Concurrently, concomitant administration of proton pump inhibitors (35), H2 receptor antagonists (36), anticoagulants (37) and liver enzyme inducers will result in a reduction in the efficacy of the drug. A review of the reported hemorrhage events associated with eltrombopag suggests that the drug’s efficacy may be compromised by factors such as dosage, the use of concomitant medications, and other variables that fall outside the standard treatment parameters.

The results of this study indicate that among TPO-RA, romiplostim exhibits superior efficacy, followed by avatrombopag. Additionally, avatrombopag demonstrates a favorable safety profile within the TPO-RA category. Findings from the FAERS database analysis further support the conclusion that avatrombopag offers a favorable safety profile among TPO-RA. As an oral formulation, avatrombopag is more convenient to use than romiplostim, which requires injection. Furthermore, it is less likely to interact with food and other medications. Based on these findings, avatrombopag presents distinct advantages in the second-line treatment of ITP in adults, providing new evidence for the clinical use of TPO-RA in this context.

This study has several limitations. First, the number of studies included in the systematic review is limited, and various types of interventions are employed, which restricts the interpretation of the research results. Second, each trial utilizes different definitions of response criteria. Additionally, the dose and duration of treatment were not standardized in this study. Most of the included RCTs adjusted drug dosages based on individual patient conditions, which may lead to variability in platelet outcomes. Furthermore, discrepancies exist in the definitions of AEs, potentially introducing heterogeneity into the analysis. Finally, the FAERS database, as a global spontaneous AE reporting system, has inherent biases. Moreover, due to the lack of information on healthy patients, the incidence of drug-related AEs cannot be accurately calculated. Hetrombopag, as a newly launched drug in China, is not recorded in the FAERS database and therefore lacks this data.

The data derived from the systematic review and network meta-analysis suggest that among TPO-RA, romiplostim exhibits robust efficacy, whereas avatrombopag distinguishes itself with favorable safety profiles. When integrating evidence from both the network meta-analysis and the FAERS database, avatrombopag emerges with specific advantages as a second-line treatment option for ITP in adults among TPO-RA. Nevertheless, further controlled head-to-head RCTs are imperative to augment the evidence base for the clinical management of ITP.