Pulmonary arterial hypertension (PAH, group 1) is a rare, progressive, and fatal disease. Recent registry data have indicated a PAH incidence and prevalence of 5.8 and 47.6–54.7 cases per million in adults, respectively (Leber et al., 2021). PAH is associated with a considerable clinical and economic burden (Ogbomo et al., 2022). According to a survey completed in 2021 on the survival status of 461 PAH patients in China, the average annual treatment cost for patients is about two to three times the disposable annual income (Luo et al., 2022). With the low employment rate of PAH patients, the resulting indirect costs are even higher (Fuge et al., 2021).

Combined treatment including targeted drugs is effective for PAH (Hassoun, 2021; Pulmonary Embolism and Pulmonary Vascular Disease Group of Chinese Thoracic Society et al., 2021; Humbert et al., 2022; Ruopp and Cockrill, 2022). In 1995, the first targeted drug, epoprostenol, began a new era of PAH treatment. With the in-depth study of PAH pathogenesis, three signal transduction pathways (the endothelin pathway, NO pathway, and prostacyclin pathway) are involved in PAH occurrence and development (Ruopp and Cockrill, 2022). Subsequently developed targeted drugs, such as endothelin receptor antagonists (ERA), phosphodiesterase 5 inhibitors (PDE5i), soluble guanylate cyclase stimulators (sGCs), prostacyclin analogs, and prostacyclin receptor agonists, also target these three signaling pathways.

Since PAH pathogenesis is unclear, the combination of drugs acting on different signal transduction pathways is a clinical consensus, and the ERA + PDE5i regimen is preferred in China, the United States, and Europe (Klinger et al., 2019; Hassoun, 2021; Pulmonary Embolism and Pulmonary Vascular Disease Group of Chinese Thoracic Society et al., 2021; Humbert et al., 2022; Ruopp and Cockrill, 2022). Nevertheless, in some patients, the disease progresses even after adequate treatment with the combination of ERA and PDE5i. The 2022 ESC/ERS guidelines have recommended that patients with PAH at intermediate-low risk after initial ERA in combination with PDE5i should be considered for sequential addition of selexipag to reduce the risk of clinical worsening. Additionally, sequential intravenous or subcutaneous administration of prostacyclin analogs should be considered in intermediate-high- or high-risk patients with PAH who have received oral therapies or sequential administration of selexipag if adding intravenous or subcutaneous prostacyclin analogs is unfeasible (Humbert et al., 2022).

Selexipag is the first marketed prostacyclin receptor agonist and is currently the only drug acting on the prostacyclin pathway that has been approved by the FDA for oral administration (Panagiotidou et al., 2021). Two randomized controlled trials (RCTs) have compared the efficacy differences in combination therapy to date. GRIPHON, the largest randomized controlled trial of selexipag, has shown that a sequential combination strategy including selexipag reduced the risk of clinical worsening events in patients receiving ERA and PDE5i therapy (hazard ratio [HR] = 0.63; 95% confidence interval [CI] 0.44–0.90) (Coghlan et al., 2018). The TRITON trial has indicated that initial triple oral therapy vs. dual oral therapy might reduce the risk of disease progression (HR = 0.59; 95%CI: 0.32–1.09) (Chin et al., 2021).

However, the combined treatment brings higher costs. Although the Chinese National Centralized Drug Procurement (NCDP) has significantly reduced the costs of ERA and PDE5i, the prices of selexipag and prostacyclin analogs are still high. Based on current drug prices, the average monthly treatment cost of selexipag is $430–2,483 (YaoZh, 2022). That is still a considerable burden for patients and the healthcare system. For the first time, we compared the cost-effectiveness of selexipag added to the combination therapy of ERA and PDE5i from Chinese healthcare system, intending to aid clinicians and decision-makers in the value assessment of this new therapeutic option.

Since PAH is a progressive disease that requires lifelong targeted drug treatment, the AMBITION trial (Galiè et al., 2015), GRIPHON trial (Sitbon et al., 2015), and TRITON trial (Chin et al., 2021) have demonstrated the value of targeted drug combined treatment for PAH. In the AMBITION trial, initial combination therapy with ambrisentan and tadalafil resulted in a significantly lower risk of clinical failure events than the risk with ambrisentan or tadalafil monotherapy among participants with PAH who had not received previous treatment. GRIPHON and TRITON trials provided sufficient evidence for combined treatment including selexipag in patients receiving ERA and PDE5i combination therapy (Pulmonary Embolism and Pulmonary Vascular Disease Group of Chinese Thoracic Society et al., 2021; Humbert et al., 2022).

China, as the most populous country in the world, offers a unique way to address the PAH burden. Some targeted drugs, such as bosentan, ambrisentan, macitentan, and selexipag, are listed in the National Reimbursement Drug List. Since 2019, the Chinese government has implemented a policy of centralized procurement of drugs with involved ambrisentan, sildenafil, and tadalafil. These policies have made a big difference in reducing the PAH burden, but it is still not enough. According to a survey in China, approximately 71% of patients with PAH spend 79.8% of their family income on disease treatment, and more than 50% of patients do not use any targeted drugs due to unaffordable costs (Zhai et al., 2017). The inability to work due to the deterioration of cardiac function in PAH patients will lead to a low employment rate and greater indirect costs (Howard et al., 2012; Matura et al., 2014). Therefore, it is necessary to conduct a comprehensive economic evaluation of targeted drugs for PAH not only limited to ERA and PDE5i but also sGCs, prostacyclin analogs, and prostacyclin receptor agonists to provide a more comprehensive reference for clinical decision- and policy-making.

To the best of our knowledge, this study was the first cost-effectiveness analysis of selexipag for PAH from the perspective of the healthcare system in China. Markov model was constructed according to different WHO FC states to simulate the natural process of PAH. The cost parameters were all from the Chinese healthcare system, and other parameters were obtained from published literature and public databases. We compared the cost-effectiveness of ERA + PDE5i + selexipag and ERA + PDE5i based on the latest clinical guideline recommendations and the actual treatment situation of PAH in China. The choice of macitentan and tadalafil as the representative drug of ERA and PDE5i was based on the TRITON trial (Chin et al., 2021). Meanwhile, ambrisentan, another ERA, is a government-centralized procurement drug with a lower treatment cost than macitentan. Ambrisentan, macitentan, and tadalafil are most commonly used in the initial treatment of PAH in China. Therefore, the results of this study are generalizable. This study showed that sequential selexipag might not be cost-effective for patients with PAH who failed to control their condition after combined treatment of ERA and PDE5i when the WTP was 38,223.339 per QALY. One-way sensitivity and probability sensitivity analyses confirmed the conclusion.

Four studies on the pharmacoeconomics of selexipag have been conducted in Canada (Pharmacoeconomic Review Report: Selexipag Uptravi, 2017), Sweden (Wlodarczyk et al., 2016), and Greece (Solakidi et al., 2017a; 2017b). The last three studies have not been able to obtain the full text or specify research details. A study from Sweden has compared the cost-effectiveness of sequential administration of selexipag and inhaled iloprost for PAH patients who had received ERA and PDE5i from the societal perspective. Selexipag was more cost-effective than inhaled iloprost (ICER 37,350 SEK per QALY) (Wlodarczyk et al., 2016). A Greece study has compared the cost-effectiveness of sequential administration of selexipag and subcutaneous treprostinil in PAH patients with FC III who had received ERA and PDE5i but had insufficient efficacy from a Greek payer perspective. Selexipag was less costly and more effective than subcutaneous treprostinil, thus, making it to be a dominant strategy (Solakidi et al., 2017a). Based on the previous study, the Greek research group conducted a budget impact analysis to treat PAH with selexipag for a 5-year time horizon (2017–2021). The result showed that using a triple combination therapy containing selexipag in patients with PAH FC III could save the public payers’ budget in the Greek healthcare setting (Solakidi et al., 2017b). A study from Canada has compared the cost-effectiveness of adding selexipag to background therapy (ERA and/or PDE5i, or no intervention) using GRIPHON trial efficacy data (Sitbon et al., 2015) from a third-party payer’s perspective and calculated the ICER to be $485,000 per QALY, which was higher than Canadian 2015 WTP ($50,000 per QALY). Hence, adding selexipag to background therapy would not be cost-effective (Pharmacoeconomic Review Report: Selexipag Uptravi, 2017). However, this study did not report ICER calculated with the sequential addition of selexipag when background treatment was ERA + PDE5i. There are differences between our research and other studies in terms of research perspective, methods, and comparative treatment regimes. Our analysis is the first pharmacoeconomic assessment for evaluating the cost and effectiveness of treating PAH with selexipag added to the combination of ERA and PDE5i.

This study was subject to several limitations. First, it was possible to underestimate the therapeutic effect on the assumption that FC improvement was only present in the first cycle. Although other studies hypothesized that treatment improvement existed in the entire simulation duration range (Thongsri et al., 2016), we still assumed that FC improvement only existed in the first cycle due to the lack of long-term clinical data (Chen et al., 2009; Tran et al., 2015; Coyle et al., 2016). Second, most current pharmacoeconomic studies on PAH treatment drugs set the initial cohort age at 50 years (Chen et al., 2009; Coyle et al., 2016). According to the data from real-world research in China (Zhang et al., 2011), this study set the initial cohort age at 36 years. Bias might have been present due to the epidemiological data (Zhang et al., 2011) with PAH in China published in 2011 without update for 10 years. Third, in the TRITON trial, the number of FC worsening in macitentan + tadalafil and macitentan + tadalafil + selexipag at week 26 was three and one, respectively. Hence, the transfer probabilities calculated based on these small sample data might have been biased. A small number of cases is a common problem in exploring rare diseases. Accordingly, we retrieved published literature and public databases as much as possible. There have been only three RCTs studying selexipag at present (Simonneau et al., 2012; Sitbon et al., 2015; Chin et al., 2021), and the other two (Simonneau et al., 2012; Sitbon et al., 2015), except for the TRITON trial, have yet to report the specific effectiveness data of the double combination therapy subgroup. The demographic characteristics of the initial cohort of the model were derived from real-world data from China, which differed from the baseline characteristics of the TRITON trial. However, we controlled for uncertainty in the outcome by performing sensitivity and scenario analyses. This limitation needs to be improved in combination with subsequent published clinical trials. Fourth, with reference to the economic evaluation assumptions of other oral treatments for PAH (Tran et al., 2015; Coyle et al., 2016; Thongsri et al., 2016), adverse events due to oral PAH therapies were generally minor. This study did not consider the adverse reaction management cost incurred from oral administration. Consequently, the overall treatment cost might have been underestimated. A further collection of management costs of adverse events is needed to refine our findings in the future. Fifth, the lack of clinical trial data makes it currently difficult to compare the cost-effectiveness of selexipag with other targeted drugs. If appropriate clinical trials or real-world research data become available, information on the cost-effectiveness of selexipag compared to other drugs used in clinical practice will be accessed to determine its appropriate position in the treatment pathway based on cost-effectiveness. Finally, due to the limited availability of long-term efficacy data for selexipag in treating PAH, further research is needed to collect longer-term data that can be applied in pharmacoeconomic studies.

As the only oral drug acting on the prostacyclin pathway, selexipag represents a significant breakthrough and novel addition to the available combined treatment options for PAH. Adding selexipag to the combined treatment of ERA and PDE5i was not cost-effective at a WTP threshold set as three times Chinese GDP per capita in 2022, from the perspective of the healthcare system in China. HR for mortality of patients with FC IV relative to the general population, discount rate, and the cost of selexipag appeared to be the primary drivers of ICER. Novel pricing strategies may mitigate high drug costs to make treatment options, which include selexipag, cost-effective.