Chronic immune thrombocytopenia (ITP) is a chronic autoimmune disorder characterized by a low platelet count (<100 × 10⁹/L), leading to an increased risk of bleeding and significantly impaired health-related quality of life (1–4). Beyond the immediate clinical risks of hemorrhage, the burden of ITP includes debilitating fatigue, activity restrictions, and anxiety. These factors impose a substantial economic strain on healthcare systems due to the costs associated with long-term monitoring, hospitalization, and the management of bleeding events (5–9).

The primary goals of ITP management are to increase platelet counts to a safe level, minimize the risk of clinically significant bleeding, and maintain patient quality of life (10). While corticosteroids and intravenous immunoglobulin (IVIg) remain standard first-line therapies, their long-term utility is often restricted by significant adverse effects and high relapse rates upon tapering (10–12). Consequently, a substantial proportion of patients require second-line therapies. In recent years, thrombopoietin receptor agonists (TPO-RAs) have become a standard of care for second-line treatment (11, 13). By stimulating platelet production, TPO-RAs effectively maintain safe platelet counts and reduce bleeding events in patients with chronic ITP (14–16).

Despite their clinical benefits, the high acquisition costs of TPO-RAs present challenges for healthcare resource allocation. While several pharmacoeconomic analyses of TPO-RAs have been conducted (17–20), the available evidence remains fragmented in terms of settings and comparators. Consequently, an economic evaluation that simultaneously compares the three oral TPO-RAs currently relevant to clinical practice in China—including the domestically developed hetrombopag—remains lacking. This uncertainty presents a challenge for policymakers and clinicians in making informed formulary and treatment decisions.

Therefore, the objective of this study was to evaluate the cost-effectiveness of three TPO-RAs—eltrombopag, hetrombopag, and avatrombopag—as second-line treatments for adult patients with chronic ITP from the perspective of the Chinese healthcare system.

This study provides the first comparative cost-utility analysis of three oral TPO-RAs—eltrombopag, hetrombopag, and avatrombopag—specifically within the Chinese healthcare system. Our results indicate that hetrombopag is currently the most economically efficient strategy for the second-line treatment of adult ITP. It demonstrated dominance over eltrombopag by providing greater health benefits at a lower cost. Furthermore, compared with avatrombopag, hetrombopag offered a substantial iNMB. Although avatrombopag yielded the highest aggregate QALYs, its incremental cost per QALY significantly exceeded the Chinese WTP threshold, making it economically less favorable under current pricing.

Our findings diverge from international pharmacoeconomic evaluations. A recent UK-based study by Cooper et al. reported that avatrombopag offered superior health outcomes and was cost-effective compared with eltrombopag (18). In contrast, our analysis in China suggests that despite the clinical efficacy advantages of avatrombopag, it is not cost-effective at current local price levels. This disparity underscores the critical role of local acquisition costs in determining value and highlights that conclusions from Western markets cannot be directly extrapolated to the Chinese setting.

To further address economic disparities across Chinese provinces, we evaluated the impact of alternative WTP thresholds. As illustrated in the Cost-Effectiveness Acceptability Curve (Figure 5), hetrombopag maintains the highest probability of being cost-effective across a wide range of WTP values. This is further corroborated by our scenario analysis using a stricter threshold equivalent to the per capita GDP, which confirmed that lowering the threshold solidifies the preference for hetrombopag, as the high incremental cost per QALY of avatrombopag becomes even less acceptable (Supplementary Table S5).

Beyond the specific context of China, this study may offer certain implications for other middle-income countries. First, the hybrid decision tree-Markov model structure developed here could potentially serve as a methodological framework adaptable to other healthcare settings, subject to careful recalibration of local cost and utility inputs. Second, while drug prices differ globally, the economic trade-off discussed in our analysis—weighing the higher acquisition costs of novel agents against the administration burden of lower-cost alternatives—might offer a relevant perspective for policymakers in other resource-limited settings when optimizing their formularies.

Beyond direct acquisition costs, the convenience of administration and its impact on adherence warrant consideration. Our model assumed 100% adherence, which may overestimate real-world effectiveness for regimens with complex dosing requirements. Eltrombopag requires strict dietary restrictions, necessitating administration on an empty stomach (at least 2 h before or 4 h after consuming polyvalent cations). Hetrombopag shares similar but slightly less stringent requirements (administration on an empty stomach with food permitted 2 h post-dose). In contrast, avatrombopag can be taken with food, offering a distinct convenience advantage that may translate to better adherence. In real-world practice, the strict fasting requirements for eltrombopag and hetrombopag may impose a higher administration burden. This could potentially lead to non-adherence and subsequent sub-therapeutic drug levels, which could compromise clinical effectiveness compared to the controlled trial setting. However, the substantial cost differential observed in our base case suggests that even if the “no fasting” benefit of avatrombopag resulted in slightly superior real-world effectiveness, it is unlikely to offset the economic advantage of hetrombopag. This is supported by our sensitivity analysis, where hetrombopag remained cost-effective even when relative efficacy parameters varied in a direction favorable to avatrombopag.

The exclusion of splenectomy from our model’s treatment pathway reflects specific clinical practices in China. Although international guidelines recommend splenectomy as a definitive option for refractory ITP (28, 29), its utilization in China has significantly declined. Cultural aversion to organ removal and concerns regarding surgical risks often render splenectomy a last-resort option rather than a standard second-line therapy. Consequently, TPO-RAs in China are not merely a “bridge” to surgery but often serve as lifelong maintenance therapy. This practice pattern underscores the importance of the lifetime horizon used in our model. In a system where patients may remain on pharmacological treatment for decades, the cumulative acquisition cost becomes the dominant driver of total healthcare expenditure, further solidifying the advantage of the lowest-cost efficacious agent, hetrombopag.

Several limitations of this study should be acknowledged. First, relative efficacy parameters were derived from an NMA (22) rather than head-to-head randomized controlled trials, introducing inherent uncertainty into the comparative estimates. Second, we assumed equivalent safety profiles across the three TPO-RAs, as recent systematic reviews indicated no statistically significant differences in overall adverse event rates (22). Third, the use of a standardized subsequent treatment regimen (rituximab + rhTPO) simplifies the heterogeneity of clinical practice across different regions in China, although this regimen aligns with current Chinese clinical guidelines (13). To address this uncertainty, we performed a scenario analysis varying the costs and efficacy of subsequent treatment by ±30% (Supplementary Table S5), which confirmed that the economic superiority of hetrombopag remained robust. Fourth, due to the lack of local data, utility values were derived from UK patients. Although cultural differences in health perception may introduce bias, sensitivity analyses indicated that variations in utility values were not key drivers of the model and did not alter the study’s conclusions. Fifth, the long-term extrapolation of response durability was based on eltrombopag data, assuming a class effect for the shape of the survival curve. Notably, our estimated mean duration of response for eltrombopag differs from prior estimates by Lee et al. (17), as our analysis incorporated the final results from the EXTEND study (16) rather than the interim data (30) used in previous models. This approach, while robust for eltrombopag, may not perfectly reflect the long-term trajectory of newer agents such as hetrombopag and avatrombopag. Finally, we did not explicitly quantify the utility decrement associated with the dietary restrictions of eltrombopag and hetrombopag, which may slightly favor these agents over avatrombopag in the utility analysis.

From the perspective of the Chinese healthcare system, hetrombopag represents the preferred strategy for the second-line treatment of adult chronic ITP, offering the optimal balance between cost and health outcomes. It dominates eltrombopag and provides a superior net monetary benefit compared with avatrombopag under current pricing conditions. These findings support the prioritization of hetrombopag in formulary decision-making and resource allocation, particularly in resource-constrained settings.