Comprehensive Clinical Evaluation of Endothelin Receptor Antagonists in Pulmonary Arterial Hypertension Using Multi-Criteria Decision Analysis

Comprehensive Clinical Evaluation of Endothelin Receptor Antagonists in Pulmonary Arterial Hypertension Using Multi-Criteria Decision Analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Comprehensive Clinical Evaluation of Endothelin Receptor Antagonists in Pulmonary Arterial Hypertension Using Multi-Criteria Decision Analysis Zihan Cao, Long Meng, Yunlong Li, Mi Zhou, Huiming Jiang, Jun Wang, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8085636/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Introduction Endothelin receptor antagonists (ERAs), including ambrisentan, bosentan, and macitentan, are central to the treatment of pulmonary arterial hypertension (PAH). As patient survival improves, long-term management increasingly requires systematic evaluation of these agents to balance their efficacy, safety, cost, and accessibility. However, standardized frameworks that integrate the multiple dimensions of clinical value remain limited. Aim This study aimed to establish and apply a six-dimensional Multi-Criteria Decision Analysis (MCDA) framework to comprehensively assess the clinical value of ambrisentan, bosentan, and macitentan in the treatment of PAH. Method A structured evaluation system was developed using Delphi expert consultation and evidence synthesis from systematic reviews, meta-analyses of randomized controlled trials (RCTs), pharmacoeconomic assessments, and regulatory documents. Six core dimensions were included: safety, efficacy, economic value, suitability, accessibility, and innovation. Quantitative and qualitative indicators were normalized and weighted using the Analytic Hierarchy Process and integrated using the MCDA model. Sensitivity analyses were performed to verify the robustness of rankings. Results The final framework comprised six primary dimensions, 13 secondary indicators, and 32 tertiary indicators. Twelve RCTs met the inclusion criteria for quantitative analysis. All three ERAs improved exercise capacity and hemodynamic parameters, whereas ambrisentan exhibited superior tolerability. Economic evaluation showed that ambrisentan and bosentan offered better cost-effectiveness, with incremental cost-effectiveness ratios of ࿥140.12 per meter and ࿥142.38 per meter, respectively, compared with ࿥1,470.71 per meter for macitentan. Suitability analysis favored ambrisentan and macitentan because of their once-daily dosing and favorable adherence profiles. Bosentan demonstrated advantages in affordability owing to its lower cost and National Reimbursement Drug List coverage. Innovation assessment ranked macitentans as the highest for technological advancement. Integrated MCDA scoring indicated that ambrisentan achieved the greatest overall clinical value. Conclusion This study developed a multidimensional, evidence-based evaluation model for PAH therapy using MCDA. Ambrisentan achieved the highest comprehensive score across the six key dimensions, reflecting its balanced efficacy, safety, and economic performance. The proposed framework provides a practical tool for clinicians, pharmacists, and policymakers to support rational drug use, formulary management, and value-based decision making in PAH and other rare diseases. Pulmonary Arterial Hypertension Endothelin Receptor Antagonists Multi-Criteria Decision Analysis Clinical Comprehensive Evaluation Impacts on practice A multidimensional MCDA framework was developed to comprehensively evaluate the clinical value of endothelin receptor antagonists for pulmonary arterial hypertension. Ambrisentan demonstrated the highest overall clinical value, balancing efficacy, safety, cost-effectiveness, and suitability compared to bosentan and macitentan. This framework provides clinicians, pharmacists, and policymakers with a transparent tool to guide rational drug selection, formulary inclusion, and value-based reimbursement decisions. Introduction Pulmonary arterial hypertension (PAH) is a progressive, life-threatening disease characterized by persistently elevated pulmonary artery pressure, which ultimately leads to right heart failure and premature death [ 1 , 2 ]. Its pathogenesis involves pulmonary vasoconstriction, endothelial dysfunction, smooth muscle proliferation, and vascular remodeling [ 3 ]. Endothelin-1 (ET-1), a potent vasoconstrictor and mitogen for vascular smooth muscle cells, plays a central role by binding to the ETA and ETB receptors and promoting fibrosis, hypertrophy, and sustained vasoconstriction [ 4 ]. To counteract vascular dysfunction, the U.S. Food and Drug Administration (FDA) has approved several targeted therapies, including endothelin receptor antagonists (ERAs). Representative agents such as bosentan, ambrisentan, and macitentan block ET-1 receptor binding, thereby reducing vasoconstriction, improving hemodynamics, enhancing exercise capacity, and slowing disease progression [ 5 ]. With improvements in survival, the long-term management of PAH increasingly depends on optimizing the clinical and economic value of pharmacotherapy. Although ERAs share similar mechanisms, they differ in their efficacy, safety, tolerability, monitoring requirements, cost, and availability. Therefore, single dimensional evaluations are insufficient to capture their overall therapeutic value. A comprehensive assessment can provide comparative evidence to guide clinical choice, reimbursement, and resource allocation [ 6 ], supporting rational drug use and better patient outcomes. Multi-Criteria Decision Analysis (MCDA) has emerged as an effective framework for integrating multiple, often conflicting, decision criteria in healthcare [ 7 ]. By quantifying and weighting factors such as efficacy, safety, and cost, MCDA enables transparent, evidence-based comparisons of therapeutic alternatives and supports rational, patient-centered decision-making in clinical pharmacy practice. Aim This study aimed to establish and apply a six-dimensional Multi-Criteria Decision Analysis framework—encompassing safety, efficacy, economic value, suitability, accessibility, and innovation—to comprehensively evaluate the clinical value of endothelin receptor antagonists (ambrisentan, bosentan, and macitentan) in the treatment of pulmonary arterial hypertension. Method Development of the Comprehensive Evaluation Framework A multidisciplinary expert panel was established using the Delphi method to ensure scientific rigor, transparency, and representativeness of the evaluation process. Experts were selected from clinical pharmacy, cardiology, pulmonology, pharmacoeconomics, and health policy, each holding an associate professor title or above and possessing more than ten years of professional experience in PAH (PAH) or related fields. Selection criteria also required prior participation in health technology assessments (HTAs), familiarity with Delphi consensus procedures, and willingness to participate in iterative review rounds. Following the 2022 ESC/ERS Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension and the 2021 Guidelines for the Management of Comprehensive Clinical Evaluation of Pharmaceutical Products, the panel designed a three-level, six-dimensional indicator framework for evaluating ERAs (ambrisentan, bosentan, and macitentan), as first-line therapies for PAH. The Delphi process involved two structured rounds of consultation, with feedback incorporated between rounds to achieve the convergence of expert opinions. The six primary evaluation dimensions were safety, efficacy, economic value, suitability, accessibility, and innovation, representing clinical, patient-centered, and societal perspectives. Within each dimension, secondary and tertiary indicators were identified through a systematic literature review and expert discussions. For example, safety included indicators such as the incidence of adverse drug reactions (ADRs), use in special populations, contraindications, and drug–drug interaction potential, whereas economic value included treatment cost and cost-effectiveness. This framework provides a basis for a quantitative and evidence-based evaluation system. Comprehensive Clinical Evaluation of ERAs Safety was assessed using qualitative and quantitative methods. Drug label data approved by the U.S. Food and Drug Administration (FDA) and China National Medical Products Administration were systematically reviewed to extract core safety information, including ADRs, contraindications, use in special populations, and overdose management. In addition, a systematic review and meta-analysis of randomized controlled trials (RCTs) was performed to evaluate ADR incidence and mortality. PubMed, Embase, and Medline were searched from inception to October 2024 using the keywords pulmonary arterial hypertension, endothelin receptor antagonists, bosentan, ambrisentan, macitentan, randomized controlled trial, adverse drug reactions, and mortality. (Fig S1 ) Eligible studies included RCTs that compared ERA monotherapy with placebo in PAH patients and reported outcomes of interest, such as all-cause mortality, ADR incidence, 6-minute walk distance (6 MWD), or mean pulmonary arterial pressure (mPAP). Studies on pregnant or pediatric patients or those with severe hepatic or renal impairment were excluded. Two reviewers independently screened and extracted data on the study design, sample size, treatment duration, and adverse outcomes. The risk of bias was assessed using Cochrane RoB 2.0, and discrepancies were resolved through discussion or by a third reviewer. Efficacy evidence was obtained from both clinical guidelines and meta-analysis data. Evidence grades and recommendation levels were extracted from international guidelines (ESC/ERS, ACCP/CHEST, WSPH, and NICE) and Chinese PAH guidelines. RCTs reporting 6 MWD and mPAP were analyzed using the same methodology as the safety evaluation. Pooled mean differences (MDs) and 95% confidence intervals (CIs) were calculated to quantify treatment benefits. The economic dimension combined cost and cost-effectiveness metrics. Annual treatment costs were calculated based on the recommended daily dosages and official retail prices. The incremental cost-effectiveness ratio (ICER) [ 9 ] was computed as the ratio of the 12-week treatment cost to the average improvement in 6 MWD derived from the meta-analysis. The drug price data were obtained from the China National Healthcare Security Administration (NHSA). A lower ICER indicates greater economic efficiency [ 10 ]. Both direct medication cost and affordability for patients were considered to reflect the real-world financial burden. Suitability was defined as the adaptability and convenience of each drug for long-term clinical use. The indicators included dosing frequency, drug formulation, required laboratory monitoring, and adherence potential. Data were derived from approved prescription information, clinical guidelines, and expert consultations. The Delphi method was again applied to integrate expert judgments, ensuring that both clinical experience and patient-centered perspectives were represented. Accessibility was evaluated by assessing (1) drug inclusion in the National Reimbursement Drug List (NRDL), representing reimbursement eligibility, and (2) affordability, expressed as the annual out-of-pocket cost relative to China’s per capita disposable income. A lower cost-to-income ratio is interpreted as better affordability and higher accessibility. Innovation was examined from three perspectives. Clinical innovation assessed first-in-class status, therapeutic novelty, and ability to address unmet needs. Technological innovation had evaluated molecular target selectivity, formulation advances, and improved safety–efficacy profiles. Industrial innovation considered contributions to pharmaceutical manufacturing and capacity for domestic drug development. MCDA Integration and Weighting To integrate findings across dimensions, a value measurement-based MCDA was conducted. Quantitative and qualitative indicators were standardized to ensure comparability across scales. Negative indicators (e.g., ADR incidence) were transformed reciprocally and qualitative descriptors were converted to numeric values using descriptive statistics. Indicator weights were determined using the Analytic Hierarchy Process (AHP), which combines pairwise expert comparisons with consensus weighting [ 12 ]. Each indicator received a weight proportional to its relative importance, which is consistent with the national guideline priorities. Individual criteria were scored on a 0–2 scale, multiplied by their weights, and summed to generate the total dimension scores. Sensitivity analyses were performed by varying the indicator weights by ± 20% to assess ranking robustness and model stability. Statistical Analysis All analyses were conducted using Stata 18.0 and Microsoft Excel 2019. Continuous variables (e.g., 6 MWD, mPAP) are summarized as mean differences (MDs) with 95% CIs, and dichotomous outcomes are presented as odds ratios (ORs) with 95% confidence intervals (CIs). A random-effects model (DerSimonian–Laird method) was applied to account for inter-study heterogeneity [ 11 ]. Economic and cost-effective outcomes were calculated using pooled clinical efficacy data. Suitability, accessibility, and innovation indicators were analyzed using descriptive statistics and expert-derived scores, followed by normalization for MCDA integration. The final results were visualized using forest plots for meta-analyses and ranking tables for MCDA outputs, allowing transparent and reproducible comparison of the overall clinical value of the three ERAs. Ethics Approval This study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of [The First Affiliated Hospital of Chongqing Medical University]. The requirement for informed consent was waived because the study used de-identified data from existing databases. Results Development of the Comprehensive Evaluation Framework A structured evaluation framework for ERAs in PAH was established using the Guidelines for Comprehensive Drug Evaluation (2021 edition) as a reference and multidisciplinary Delphi consultation. Nineteen experts from health authorities, medical institutions, and academia participated in this study, each with ≥ 10 years of professional experience and senior titles. Two Delphi rounds produced a consensus on six primary dimensions, 13 secondary indicators, and 32 tertiary indicators. Quality control metrics demonstrated methodological robustness; the authority coefficient was 0.82, Cronbach’s α = 0.864, and Kendall’s W = 0.412 (P < 0.01), confirming the consistency of expert opinions. The Analytic Hierarchy Process was applied to assign indicator weights, resulting in a validated, multilevel framework (Table 1 ). Table 1 Indicator System, Hierarchical Weights, and Operational Methods for the Comprehensive Evaluation of Endothelin Receptor Antagonists Primary indicator Weight assignment Secondary indicator Tertiary indicator Weight assignment for tertiary indicators Operational Methods A Safety 26.47 A1 Safety evidence quality A1-1 Safety evidence quality (Guidelines & clinical standards) 5.25 Review the Documentation A2 Basic safety information A2-1 Label clarity: Contraindications, overdose, interactions 2.13 Prescribing Information Review A2-2 Special populations usage (Children, pregnant, elderly, etc.) 2.32 A2-3 Pharmacovigilance alerts (Recalls, withdrawals, safety warnings) 2.41 A2-4 Label changes (Notable safety-related label revisions) 1.42 A2-5 All-cause mortality 3.18 Meta-analysis A3 ADR incidence A3-1 ADR incidence (Frequent adverse event rate) 5.34 Meta-analysis A3-2 ADR severity (Life-threatening, lethal, carcinogenic, etc., listed in labels) 4.42 Prescribing Information Review B Efficacy 26.34 B1 Efficacy evidence quality B1-1 Clinical treatment position (Guidelines & clinical standards) 10.32 Review the Documentation B2 Clinical treatment position B2-1 change in 6-minute walk distance 8.59 Meta-analysis B2-2 change in mPAP 7.43 C Economic 15.74 C1 Drug cost C1-1 Effectiveness-to-cost ratio 7.93 Statistical Analysis C1-2 Annual treatment cost 7.81 D Suitability 11.37 D1 Drug Appropriateness D1-1 Label information completeness 0.63 Delphi Method D1-2 Label meets clinical needs (Indications and usage as needed in practice) 0.95 D1-3 Route & formulation suitability 0.84 D1-4 Need for therapeutic monitoring 1.22 D1-5 Special device requirement 0.86 D1-6 Special storage conditions 0.85 D2 Drug Use Appropriateness D2-1 Improves patient adherence 1.54 D2-2 Dosing schedule rationality 1.01 D2-3 Risk of intolerance (Likelihood of patients cannot tolerate) 1.94 D2-4 Interaction limitations (Do drug/food interactions restrict use?) 0.76 D2-5 Easy exclusion of contraindications 0.77 E Accessibility 11.25 E1 Insurance Coverage E1-1 Reimbursed by Medical Insurance 3.36 Review the Documentation E1-2 Included in National Price Negotiation Drugs 2.23 E2 Affordability E2-1 Annual Household Drug Expenditure Ratio (%) 5.66 Statistical Analysis F Innovation 8.83 F1 Clinical Innovation F1-1 Innovative drug status (First-in-class or novel mechanism?) 2.08 Review the Documentation ༆Delphi Method F1-2 Fulfilling clinical needs (Degree to which it meets previously unmet needs) 1.64 F2 Technological Innovation F2-1 Target/Selective Mechanism 1.78 F2-2 Formulation Innovation 1.54 F3 Industrial Innovation F3-1 International patent (Global patent and novelty) 1.79 [insert Table 1 here] Safety Evaluation The safety profiles differed notably among ambrisentan, bosentan, and macitentan (Table 2 ). Ambrisentan is contraindicated during pregnancy and requires dose reduction when it is co-administered with cyclosporine. Bosentan, also contraindicated in pregnancy and in patients receiving cyclosporine or glyburide, strongly induces CYP3A4/2C9, and thus poses a high drug–drug interaction risk, necessitating strict hepatic monitoring. Macitentan should not be used with strong CYP3A4/2C9 modulators; its pediatric safety remains under study. None of the drugs had a specific antidote and overdose management was supportive. Table 2 Guideline recommendations and basic safety information for endothelin receptor antagonists in pulmonary arterial hypertension Drug Name Guideline Name Guideline Organization Recommendation Basic Safety Information Ambrisentan ESC/ERS Guidelines European Society of Cardiology/European Respiratory Society Recommended for low-risk or intermediate-risk PAH patients, used in combination with tadalafil. Contraindicated in pregnant women or women of childbearing potential due to teratogenic risk. Insufficient safety data in pediatric patients; not recommended for children, with no established clinical evidenceDose reduction to 5 mg/day required when co-administered with cyclosporine; contraindicated with sparsentan; moderate CYP-related interactions.No specific antidote; supportive treatment as needed FDA Drug Label U.S. Food and Drug Administration Recommended for PAH patients with WHO functional class II-III, including idiopathic, hereditary, and connective tissue disease-related PAH patients. Diagnosis and Treatment Guidelines for Pulmonary Arterial Hypertension (2021) Chinese Society of Cardiology Recommended for idiopathic, connective tissue disease-related, and congenital heart disease-related PAH patients, improving 6-minute walk distance (6MWD) and can be combined with tadalafil. Bosentan ESC/ERS Guidelines European Society of Cardiology/European Respiratory Society Recommended as an initial treatment for WHO functional class II-IV PAH patients. Contraindicated in pregnant women, with cyclosporine or glyburide use, or hypersensitivity to components.More pediatric data available; FDA-approved for pediatric indications with dispersible tablets, but requires strict liver function monitoring.Strong CYP3A4/2C9 inducer, significantly reduces plasma levels of many drugs; contraindicated with cyclosporine or glyburide; multiple drug interaction risks.No specific treatment guidelines; hepatotoxicity requires discontinuation and supportive care. FDA Drug Label U.S. Food and Drug Administration Recommended for WHO functional class III-IV PAH patients, including idiopathic, hereditary, connective tissue disease-related, and congenital heart disease-related PAH patients. Diagnosis and Treatment Guidelines for Pulmonary Arterial Hypertension (2021) Chinese Society of Cardiology Recommended for idiopathic, connective tissue disease-related, and congenital heart disease-related PAH patients, improving exercise capacity, functional class, hemodynamic parameters, and clinical worsening time. Macitentan ESC/ERS Guidelines European Society of Cardiology/European Respiratory Society Recommended for low-risk or intermediate-risk PAH patients, used in combination with tadalafil. Contraindicated with sparsentan due to potential risk of kidney injury and hypotension.Pediatric safety is still under clinical investigation; not yet approved for pediatric use; requires careful hepatic and renal monitoring.Avoid co-administration with strong CYP3A4/2C9 inhibitors or inducers (e.g., ketoconazole, rifampin) .Overdose may cause headache, nausea, vomiting; supportive treatment only; dialysis is ineffective. FDA Drug Label U.S. Food and Drug Administration Recommended for PAH patients with WHO functional class II-III, including idiopathic, hereditary, and connective tissue disease-related PAH patients. Diagnosis and Treatment Guidelines for Pulmonary Arterial Hypertension (2021) Chinese Society of Cardiology Recommended for idiopathic, connective tissue disease-related, and congenital heart disease-related PAH patients, improving exercise capacity, functional class, hemodynamic parameters, and clinical worsening time. A total of 12 RCTs [ 13 – 24 ] met the inclusion criteria, all with a low risk of bias per Cochrane RoB 2.0 ( Fig S2 ). Meta-analysis of ADRs showed pooled odds ratios (ORs) of 0.57 (95% CI 0.31–1.06) for ambrisentan, 1.81 (0.41–8.00) for bosentan, and 2.04 (0.56–7.52) for macitentan ( Fig S3a ). For all-cause mortality, the respective ORs were 0.34 (0.09–1.22), 0.57 (0.12–2.63), and 2.95 (0.12–73.13) ( Fig S3b ). [insert Table 2 here] Efficacy Evaluation According to the 2022 ESC/ERS and 2021 Chinese PAH Guidelines, all three ERAs are recommended as first-line or combination therapies for WHO functional class II–III PAH. Ambrisentan improves exercise capacity and cardiac function, particularly when combined with tadalafil, which enhances hemodynamics and delays clinical worsening. Macitentan reduces disease progression, mortality, and hospitalization rates while improving quality of life indicators. Meta-analysis results ( Fig S4 ) confirmed the efficacy differences. For 6MWD, mean differences (MDs) were 43.89 m (95% CI 29.97–57.80) for ambrisentan, 40.95 m (18.02–63.88) for bosentan, and 9.73 m (–8.42 to 27.88) for macitentan. For mPAP, MDs were − 0.27 mmHg (–3.57 to 3.42), − 5.36 mmHg (–7.29 to − 3.61), and − 5.99 mmHg (–8.40 to − 3.58), respectively. All agents improved the clinical outcomes to varying degrees. Economic Evaluation The unit prices for ambrisentan, bosentan, and macitentan were 2,050, 1,485, and 4,770 yuan, corresponding to annual treatment costs of ࿥24,600, ࿥17,820, and ࿥57,240, respectively. Based on the 12-week efficacy data, incremental cost-effectiveness ratios (ICERs) were ࿥140.12 per meter for ambrisentan, ࿥142.38 per meter for bosentan, and ࿥1,470.71 per meter for macitentan. Thus, ambrisentan and bosentan exhibited superior cost-effectiveness, whereas macitentan was less economical, despite its clinical benefit. Suitability Evaluation Expert consultations indicated that all ERAs provided complete labeling information and consistent therapeutic indications (Table 3 ). However, the need for hepatic monitoring may reduce adherence to all agents. The twice-daily dosing of bosentan and higher interaction potential yielded lower suitability scores, whereas ambrisentan and macitentan, both once daily and well tolerated, were considered more appropriate for long-term therapy. Table 3 Suitability Assessment of Endothelin Receptor Antagonists (ERAs) in the Treatment of PAH (Scored 0–2) Indicator Ambrisentan Score Bosentan Score Macitentan Score D1-1 Label Information Completeness Yes 2 Yes 2 Yes 2 D1-2 Label meets clinical needs (Indications and usage as needed in practice) Yes 2 Yes 2 Yes 2 D1-3 Route & Formulation Suitability Yes 2 Yes 2 Yes 2 D1-4 Need for Therapeutic Monitoring Requires periodic liver function monitoring 0.8 Requires regular liver function checks 0.5 Requires periodic liver function monitoring 0.9 D1-5 Special Device Requirement No 2 No 2 No 2 D1-6 Special Storage Conditions No 2 No 2 No 2 D2-1 Improves Patient Adherence Yes 1.8 Impact adherence 0.8 Yes 1.9 D2-2 Dosing Schedule Rationality Once-daily dosing is easy for patients to follow 1.6 Twice-daily dosing may be more challenging for patients 1.1 Once-daily dosing is easy for patients to follow 1.7 D2-3 Risk of Intolerance (Likelihood Patients Cannot Tolerate) Tolerable, some risk of peripheral edema 1.6 Risk of liver toxicity, anemia, peripheral edema 0.3 Generally well-tolerated, with minor side effects 1.5 D2-4 Interaction Limitations (Do drug/food interactions restrict use?) Avoid strong CYP3A4 inhibitors 0.9 Caution with CYP3A4 inhibitors 1.1 Avoid strong CYP3A4 inhibitors 0.8 D2-5 Easy Exclusion of Contraindications Yes 1.8 Yes 1.7 Yes 1.9 [insert Table 3 here] Accessibility Evaluation All three ERAs are included in the NRDL of China. The annual treatment costs relative to the national per-capita expenditure were 87.15% for ambrisentan, 63.13% for bosentan, and 202.78% for macitentan, indicating that macitentan imposed the greatest economic burden despite reimbursement (Table 4 ). Table 4 Assessment of Accessibility Indicators for Endothelin Receptor Antagonist Drugs (Scored 0–2) Indicator Ambrisentan Score Bosentan Score Macitentan Score E1-1 Reimbursed by Medical Insurance Yes 2 Yes 2 Yes 2 E1-2 Included in National Price Negotiation Drugs Yes 2 Yes 2 Yes 2 E2-1 Annual Household Drug Expenditure Ratio (%) 87.15% 0.3 63.13% 0.7 202.78% 0 [insert Table 4 here] Innovation Evaluation Bosentan, as the first-in-class ERA, initiated the therapeutic category, ambrisentan, a second-generation agent, achieved greater receptor selectivity and reduced hepatotoxicity, and macitentan, a third-generation compound, improved pharmacokinetics and tolerability (Table 5 ). Table 5 Assessment of Innovation Indicators for Endothelin Receptor Antagonist Drugs (Scored 0–2) Indicator Ambrisentan Score Bosentan Score Macitentan Score F1-1 Innovative drug status (First-in-class or novel mechanism) Second-generation endothelin receptor antagonist, not a first-in-class drug 0 First-generation endothelin receptor antagonist 2 Third-generation endothelin receptor antagonist, novel mechanism 1 F1-2 Fulfilling clinical needs (Degree to which it meets previously unmet needs) Addresses unmet safety needs in PAH treatment 1.3 Address an unmet medical need 1.5 Provides longer treatment duration 1.7 F2-1 Target/selectivity mechanism Selective ETA receptor antagonist 1 Non-selective ETA/ETB receptor antagonist 0 Dual ETA/ETB receptor antagonist 2 F2-2 Dosage form innovation Oral immediate-release formulation (Lack innovation) 1 Oral immediate-release formulation (Lack innovation) 1 Oral immediate-release formulation (Lack innovation) 1 F3-1 International patent (Global patent and novelty) Holds international patents 2 Holds international patents 2 Holds international patents 2 [insert Table 5 here] Integrated MCDA Results After normalization and weighting across all six dimensions, ambrisentan achieved the highest total score, followed by bosentan and macitentan (Table 6 ). Its superior efficacy, safety, suitability, and innovation contributed to its overall ranking, indicating that ambrisentan offers the greatest comprehensive clinical value for PAH therapy. Table 6 Comprehensive MCDA Outcomes with Normalization and Ranking Tertiary indicator Weight assignment for tertiary indicators Score of Ambrisentan Score of Bosentan Score of Macitentan A1-1 Safety evidence quality (Guidelines & clinical standards) 5.25 4.46 3.94 4.73 A2-1 Label clarity: Contraindications, overdose, interactions 2.13 2.13 2.13 2.13 A2-2 Special populations usage (Children, pregnant, elderly, etc.) 2.32 0.00 1.04 0.00 A2-3 Pharmacovigilance alerts (Recalls, withdrawals, safety warnings) 2.41 1.81 1.21 1.81 A2-4 Label changes (Notable safety-related label revisions) 1.42 1.42 1.42 1.42 A2-5 All-cause mortality 3.18 2.54 2.23 0.00 A3-1 ADR incidence (Frequent adverse events rate) 5.34 4.01 0.53 0.00 A3-2 ADR severity (Life-threatening, lethal, carcinogenic, etc., listed in label) 4.42 2.87 2.43 1.99 B1-1 Clinical treatment position (Guidelines & clinical standards) 10.32 8.26 6.71 7.74 B2-1 Change in 6-minute walk distance 8.59 4.30 4.30 2.15 B2-2 Change in mPAP 7.43 1.86 5.94 6.69 C1-1 Effectiveness-to-cost ratio 7.93 6.74 5.95 1.98 C1-2 Annual treatment cost 7.81 5.08 6.64 1.17 D1-1 Label information completeness 0.63 0.63 0.63 0.63 D1-2 Label meets clinical needs (Indications and usage as needed in practice) 0.95 0.95 0.95 0.95 D1-3 Route & formulation suitability 0.84 0.84 0.84 0.84 D1-4 Need for therapeutic monitoring 1.22 0.49 0.31 0.55 D1-5 Special device requirement 0.86 0.86 0.86 0.86 D1-6 Special storage conditions 0.85 0.85 0.85 0.85 D2-1 Improves patient adherence 1.54 1.39 0.62 1.46 D2-2 Dosing schedule rationality 1.01 0.81 0.56 0.86 D2-3 Risk of intolerance (Likelihood patients cannot tolerate) 1.94 1.55 0.29 1.46 D2-4 Interaction limitations (Do drug/food interactions restrict use?) 0.76 0.34 0.42 0.30 D2-5 Easy exclusion of contraindications 0.77 0.69 0.65 0.73 E1-1 Reimbursed by Medical Insurance 3.36 3.36 3.36 3.36 E1-2 Included in National Price Negotiation Drugs 2.23 2.23 2.23 2.23 E2-1 Annual Household Drug Expenditure Ratio (%) 5.66 0.85 1.98 0.00 F1-1 Innovative drug status (First-in-class or novel mechanism?) 2.08 0.00 2.08 1.04 F1-2 Fulfilling clinical needs (Degree to which it meets previously unmet needs) 1.64 1.07 1.23 1.39 F2-1 Target/Selective Mechanism 1.78 0.89 0.00 1.78 F2-2 Formulation Innovation 1.54 0.77 0.77 0.77 F3-1 International patent (Global patent and novelty) 1.79 1.79 1.79 1.79 Total 100 65.84 64.89 53.66 [insert Table 6 here] Discussion Comprehensive Evaluation Framework for Rational Drug Use Comprehensive clinical evaluation has become an essential foundation for guiding rational drug use, informing reimbursement decisions, and shaping pharmaceutical policies in China. PAH remains a progressive, life-threatening condition requiring treatment that is not only effective, but also safe, affordable, and sustainable. ERAs, such as ambrisentan, bosentan, and macitentan, are the cornerstone of PAH therapy; however, systematic, multidimensional comparisons have been limited. Following the 2021 Guidelines for the Management of Comprehensive Clinical Evaluation of Pharmaceutical Products [ 29 ], this study applied a structured, evidence-based approach to comprehensively assess the clinical value of these three ERAs across six dimensions: safety, efficacy, economic value, suitability, accessibility, and innovation. Efficacy and Clinical Performance of ERA Therapies All three ERAs are recognized as first-line or combination therapies in both international and national guidelines and represent the backbone of PAH management [ 25 ]. Our meta-analysis confirmed meaningful differences in clinical efficacy, consistent with previously published data. Ambrisentan and macitentan demonstrated greater improvements in exercise capacity and functional class than bosentan did, supporting their preferential use in intensified or combination regimens. In particular, the ambrisentan–tadalafil combination has shown superior outcomes, significantly reducing the risk of clinical failure compared to monotherapy [ 26 ]. These findings reinforce existing strategies that favor ambrisentan or macitentan when an enhanced therapeutic response is desired [ 27 ]. Safety Differentiation and Pharmacologic Considerations Safety is a major factor in ERA differentiation.The hepatotoxicity of bosentan and its strong induction of cytochrome P450 enzymes require regular hepatic monitoring and increase the potential for drug–drug interactions, limiting its use in long-term maintenance therapy. In contrast, ambrisentan and macitentan demonstrated more favorable hepatic safety profiles, with structural optimization of macitentan further mitigating liver toxicity. Ambrisentan also caused fewer metabolic interactions, reflecting weaker CYP induction. These differences are clinically significant because hepatotoxicity may lead to treatment discontinuation, elevated healthcare costs, and reduced adherence. The expert consensus in this study similarly favored ambrisentan or macitentan for long-term administration. In special populations, bosentan currently has the most extensive pediatric safety data, whereas studies on ambrisentan and macitentan in children are ongoing. All three drugs are contraindicated during pregnancy because of their teratogenic potential, highlighting the need for strict contraception and pharmacist involvement in patient counseling. Economic Value and Affordability Economic evaluation showed that, despite NRDL inclusion, PAH therapy remains costly. Macitentan was associated with the highest annual cost and the least favorable ICER. By contrast, ambrisentan and bosentan exhibited lower ICERs, indicating greater economic efficiency. These findings highlight the importance of balancing clinical efficacy and cost-effectiveness to achieve value-based care. As healthcare systems shift toward cost-utility frameworks, such evaluations provide crucial evidence for formulary and reimbursement decisions. Policymakers and payers are more willing to support high-priced therapies when they demonstrate measurable improvements in outcome and safety. Suitability, Adherence, and Real-World Implications Suitability and adherence are pivotal for the management of chronic PAH. Ambrisentan and macitentan, with once-daily dosing and favorable tolerability, demonstrated higher suitability than bosentan, which requires twice-daily administration and frequent monitoring. These findings align with real-world data from Japan, where macitentan use is associated with longer treatment persistence and improved adherence. Practical aspects, such as dosing convenience and monitoring burden, significantly influence treatment continuity and real-world effectiveness. When the efficacy among alternatives is comparable, these patient-centric factors should be integrated into drug evaluation frameworks to ensure that clinical benefits translate into sustained outcomes in practice. Innovation and Therapeutic Evolution From an innovative perspective, bosentan pioneered the ERA class and established a therapeutic foundation for PAH management. Ambrisentan represents an incremental innovation that improves receptor selectivity and reduces hepatotoxicity, whereas macitentan, as a third-generation ERA, offers a longer duration of action, enhanced receptor affinity, and improved safety. Together, these developments reflect the continuous evolution of targeted therapy for PAH and demonstrate how pharmacological innovation can progressively refine both clinical outcomes and patient quality of life. Clinical Pharmacy and Policy Implications This MCDA-based framework also highlights the growing role of clinical pharmacists in formulary evaluations and value-based drug selection. By integrating quantitative data on safety, efficacy, and economic outcomes, pharmacists can provide objective evidence to support hospital drug and therapeutic (D&T) committees and reimbursement negotiations. The implementation of such models within clinical pharmacy systems promotes transparency and facilitates multidisciplinary decision making among physicians, pharmacists, and policymakers. Moreover, the six-dimensional approach aligns with national health policy priorities, supporting equitable drug access and optimal allocation of medical resources. The incorporation of MCDA tools into pharmacy practice can therefore bridge the gap between clinical evidence and policy execution, ensuring that therapeutic decisions are both evidence driven and patient centered. Overall Interpretation and Study Limitations Integrating the results across all six dimensions, ambrisentan achieved the highest overall score, demonstrating balanced advantages in efficacy, safety, cost-effectiveness, and patient suitability. Nonetheless, individualized treatment decisions considering comorbidities, adherence potential, and tolerance remain essential. The study followed standardized procedures and incorporated multidisciplinary perspectives to produce robust and reproducible findings. However, this study has several limitations. The analysis relied primarily on published RCT data, and real-world treatment effectiveness may vary across populations and health care systems. In addition, the evaluation index system requires further validation in a multicenter Chinese cohort. Future studies combining MCDA with real-world evidence and pharmacoeconomic modeling could refine this framework and expand its applicability to other rare or high-cost diseases. Conclusion This study established a multidimensional, evidence-based framework integrating safety, efficacy, cost-effectiveness, suitability, accessibility, and innovation to comprehensively evaluate endothelin receptor antagonists for pulmonary arterial hypertension. Ambrisentan demonstrated the highest overall clinical value, reflecting balanced advantages in therapeutic efficacy, safety, and patient suitability compared to bosentan and macitentan. Beyond PAH, this evaluation model offers a reproducible approach for guiding rational drug selection, optimizing reimbursement policies, and supporting evidence-based formulary management. The integration of this framework into clinical pharmacy and hospital decision-making processes can enhance transparency, promote value-based prescribing, and strengthen collaboration between pharmacists, clinicians, and policymakers. Ultimately, such structured assessments can improve therapeutic outcomes, ensure equitable resource allocation, and contribute to long-term sustainability of the healthcare system. Declarations Acknowledgments None. Funding This work was supported by National Natural Science Foundation of China (Funding number: 82404767). Competing Interests The authors declare no conflicts of interest. Author contributions Zihan Cao wrote the original draft. Long Meng: Writing–original draft, Yunlong Li: Data curation, software. Mi Zhou: Resources, Investigation. Huiming Jiang: Data Curation, Software. Jun Wang: Formal analysis. Ziyi Tao: Supervision. Feng Qiu: Conceptualization, Methodology, Supervision. Ethics Approval This study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of [The First Affiliated Hospital of Chongqing Medical University]. 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Baran-Kooiker A, Czech M, Kooiker C. Multi-criteria decision analysis (MCDA) models in health technology assessment of orphan drugs—a systematic literature review. Next steps in methodology development? Front Public Health. 2018;6:287. Mühlbacher AC, Kaczynski A. Making good decisions in healthcare with multi-criteria decision analysis: the use, current research and future development of MCDA. Appl Health Econ Health Policy. 2016;14(1):29–40. Bambha K, Kim WR. Cost-effectiveness analysis and incremental cost-effectiveness ratios: uses and pitfalls. Eur J Gastroenterol Hepatol. 2004;16(6):519–26. Pearson SD. The ICER value framework: integrating cost effectiveness and affordability in the assessment of health care value. Value health. 2018;21(3):258–65. Kanters S. Fixed-and random-effects models. Meta-research: Methods and protocols. Springer; 2021. pp. 41–65. Vaidya OS, Kumar S. Analytic hierarchy process: An overview of applications. Eur J Oper Res. 2006;169(1):1–29. Channick RN, Simonneau G, Sitbon O, et al. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebocontrolled study. Lancet. 2001;358(9288):1119–23. Valerio G, Bracciale P, Grazia D'Agostino A. Effect of bosentan upon pulmonary hypertension in chronic obstructive pulmonary disease. Ther Adv Respir Dis. 2009;3(1):15–21. Badesch DB, Bodin F, Channick RN, et al. Complete results of the first randomized, placebo-controlled study of bosentan, a dual endothelin receptor antagonist, in pulmonary arterial hypertension. Curr therapeutic Res. 2002;63(4):227–46. Jaïs X, D'Armini AM, Jansa P, et al. Bosentan for treatment of inoperable chronic thromboembolic pulmonary hypertension: BENEFiT (Bosentan Effects in iNopErable Forms of chronIc Thromboembolic pulmonary hypertension), a randomized, placebo-controlled trial. J Am Coll Cardiol. 2008;52(25):2127–34. Galiè N, Beghetti M, Gatzoulis MA, et al. Bosentan therapy in patients with Eisenmenger syndrome: a multicenter, double-blind, randomized, placebo-controlled study. Circulation. 2006;114(1):48–54. Galiè N, Olschewski H, Oudiz RJ, et al. Ambrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2. Circulation. 2008;117(23):3010–9. Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. 2002;346(12):896–903. Galiè N, Rubin L, Hoeper M, et al. Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomised controlled trial. Lancet. 2008;371(9630):2093–100. Sitbon O, Bosch J, Cottreel E, et al. Macitentan for the treatment of portopulmonary hypertension (PORTICO): a multicentre, randomised, double-blind, placebo-controlled, phase 4 trial. Lancet Respiratory Med. 2019;7(7):594–604. Pan Z, Marra AM, Benjamin N, et al. Early treatment with ambrisentan of mildly elevated mean pulmonary arterial pressure associated with systemic sclerosis: a randomized, controlled, double-blind, parallel group study (EDITA study). Arthritis Res therapy. 2019;21(1):217. Pulido T, Adzerikho I, Channick RN, et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med. 2013;369(9):809–18. Denton CP, Humbert M, Rubin L, Black CM. Bosentan treatment for pulmonary arterial hypertension related to connective tissue disease: a subgroup analysis of the pivotal clinical trials and their open-label extensions. Ann Rheum Dis. 2006;65(10):1336–40. Wong AK, Channick RN. Safety and tolerability of macitentan in the management of pulmonary arterial hypertension: an update. Drug Healthc Patient Saf. 2019:71–85. Vachiéry J-L, Galiè N, Barberá JA, et al. Initial combination therapy with ambrisentan + tadalafil on pulmonary arterial hypertension–related hospitalization in the AMBITION trial. J Heart Lung Transplantation. 2019;38(2):194–202. Souza R, Delcroix M, Galie N, et al. Long-term safety, tolerability and survival in patients with pulmonary arterial hypertension treated with macitentan: results from the SERAPHIN open-label extension. Adv therapy. 2022;39(9):4374–90. Gu J, Guo Y, Wu B, He J. Liver injury associated with endothelin receptor antagonists: a pharmacovigilance study based on FDA adverse event reporting system data. Int J Clin Pharm. 2024;46(6):1307–16. Laba T-L, Jiwani B, Crossland R, Mitton C. Can multi-criteria decision analysis (MCDA) be implemented into real-world drug decision-making processes? A Canadian provincial experience. Int J Technol Assess Health Care. 2020;36(4):434–9. Additional Declarations No competing interests reported. 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\u003cli\u003eThis framework provides clinicians, pharmacists, and policymakers with a transparent tool to guide rational drug selection, formulary inclusion, and value-based reimbursement decisions.\u003c/li\u003e\n\u003c/ul\u003e\n"},{"header":"Introduction","content":"\u003cp\u003ePulmonary arterial hypertension (PAH) is a progressive, life-threatening disease characterized by persistently elevated pulmonary artery pressure, which ultimately leads to right heart failure and premature death [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Its pathogenesis involves pulmonary vasoconstriction, endothelial dysfunction, smooth muscle proliferation, and vascular remodeling [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Endothelin-1 (ET-1), a potent vasoconstrictor and mitogen for vascular smooth muscle cells, plays a central role by binding to the ETA and ETB receptors and promoting fibrosis, hypertrophy, and sustained vasoconstriction [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eTo counteract vascular dysfunction, the U.S. Food and Drug Administration (FDA) has approved several targeted therapies, including endothelin receptor antagonists (ERAs). Representative agents such as bosentan, ambrisentan, and macitentan block ET-1 receptor binding, thereby reducing vasoconstriction, improving hemodynamics, enhancing exercise capacity, and slowing disease progression [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eWith improvements in survival, the long-term management of PAH increasingly depends on optimizing the clinical and economic value of pharmacotherapy. Although ERAs share similar mechanisms, they differ in their efficacy, safety, tolerability, monitoring requirements, cost, and availability. Therefore, single dimensional evaluations are insufficient to capture their overall therapeutic value. A comprehensive assessment can provide comparative evidence to guide clinical choice, reimbursement, and resource allocation [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], supporting rational drug use and better patient outcomes.\u003c/p\u003e\u003cp\u003eMulti-Criteria Decision Analysis (MCDA) has emerged as an effective framework for integrating multiple, often conflicting, decision criteria in healthcare [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. By quantifying and weighting factors such as efficacy, safety, and cost, MCDA enables transparent, evidence-based comparisons of therapeutic alternatives and supports rational, patient-centered decision-making in clinical pharmacy practice.\u003c/p\u003e\n\u003ch3\u003eAim\u003c/h3\u003e\n\u003cp\u003eThis study aimed to establish and apply a six-dimensional Multi-Criteria Decision Analysis framework—encompassing safety, efficacy, economic value, suitability, accessibility, and innovation—to comprehensively evaluate the clinical value of endothelin receptor antagonists (ambrisentan, bosentan, and macitentan) in the treatment of pulmonary arterial hypertension.\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003cdiv id=\"Sec4\" class=\"Section3\"\u003e\u003c/div\u003e\u003c/div\u003e\n\n\n\n"},{"header":"Method","content":"\u003ch2\u003eDevelopment of the Comprehensive Evaluation Framework\u003c/h2\u003e\u003cp\u003eA multidisciplinary expert panel was established using the Delphi method to ensure scientific rigor, transparency, and representativeness of the evaluation process. Experts were selected from clinical pharmacy, cardiology, pulmonology, pharmacoeconomics, and health policy, each holding an associate professor title or above and possessing more than ten years of professional experience in PAH (PAH) or related fields. Selection criteria also required prior participation in health technology assessments (HTAs), familiarity with Delphi consensus procedures, and willingness to participate in iterative review rounds.\u003c/p\u003e\u003cp\u003eFollowing the 2022 ESC/ERS Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension and the 2021 Guidelines for the Management of Comprehensive Clinical Evaluation of Pharmaceutical Products, the panel designed a three-level, six-dimensional indicator framework for evaluating ERAs (ambrisentan, bosentan, and macitentan), as first-line therapies for PAH. The Delphi process involved two structured rounds of consultation, with feedback incorporated between rounds to achieve the convergence of expert opinions.\u003c/p\u003e\u003cp\u003eThe six primary evaluation dimensions were safety, efficacy, economic value, suitability, accessibility, and innovation, representing clinical, patient-centered, and societal perspectives. Within each dimension, secondary and tertiary indicators were identified through a systematic literature review and expert discussions. For example, safety included indicators such as the incidence of adverse drug reactions (ADRs), use in special populations, contraindications, and drug–drug interaction potential, whereas economic value included treatment cost and cost-effectiveness. This framework provides a basis for a quantitative and evidence-based evaluation system.\u003c/p\u003e\u003ch3\u003eComprehensive Clinical Evaluation of ERAs\u003c/h3\u003e\u003cp\u003eSafety was assessed using qualitative and quantitative methods. Drug label data approved by the U.S. Food and Drug Administration (FDA) and China National Medical Products Administration were systematically reviewed to extract core safety information, including ADRs, contraindications, use in special populations, and overdose management. In addition, a systematic review and meta-analysis of randomized controlled trials (RCTs) was performed to evaluate ADR incidence and mortality. PubMed, Embase, and Medline were searched from inception to October 2024 using the keywords pulmonary arterial hypertension, endothelin receptor antagonists, bosentan, ambrisentan, macitentan, randomized controlled trial, adverse drug reactions, and mortality. (Fig \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e)\u003c/p\u003e\u003cp\u003eEligible studies included RCTs that compared ERA monotherapy with placebo in PAH patients and reported outcomes of interest, such as all-cause mortality, ADR incidence, 6-minute walk distance (6 MWD), or mean pulmonary arterial pressure (mPAP). Studies on pregnant or pediatric patients or those with severe hepatic or renal impairment were excluded. Two reviewers independently screened and extracted data on the study design, sample size, treatment duration, and adverse outcomes. The risk of bias was assessed using Cochrane RoB 2.0, and discrepancies were resolved through discussion or by a third reviewer.\u003c/p\u003e\u003cp\u003eEfficacy evidence was obtained from both clinical guidelines and meta-analysis data. Evidence grades and recommendation levels were extracted from international guidelines (ESC/ERS, ACCP/CHEST, WSPH, and NICE) and Chinese PAH guidelines. RCTs reporting 6 MWD and mPAP were analyzed using the same methodology as the safety evaluation. Pooled mean differences (MDs) and 95% confidence intervals (CIs) were calculated to quantify treatment benefits.\u003c/p\u003e\u003cp\u003eThe economic dimension combined cost and cost-effectiveness metrics. Annual treatment costs were calculated based on the recommended daily dosages and official retail prices. The incremental cost-effectiveness ratio (ICER) [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] was computed as the ratio of the 12-week treatment cost to the average improvement in 6 MWD derived from the meta-analysis. The drug price data were obtained from the China National Healthcare Security Administration (NHSA). A lower ICER indicates greater economic efficiency [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Both direct medication cost and affordability for patients were considered to reflect the real-world financial burden.\u003c/p\u003e\u003cp\u003eSuitability was defined as the adaptability and convenience of each drug for long-term clinical use. The indicators included dosing frequency, drug formulation, required laboratory monitoring, and adherence potential. Data were derived from approved prescription information, clinical guidelines, and expert consultations. The Delphi method was again applied to integrate expert judgments, ensuring that both clinical experience and patient-centered perspectives were represented.\u003c/p\u003e\u003cp\u003eAccessibility was evaluated by assessing (1) drug inclusion in the National Reimbursement Drug List (NRDL), representing reimbursement eligibility, and (2) affordability, expressed as the annual out-of-pocket cost relative to China’s per capita disposable income. A lower cost-to-income ratio is interpreted as better affordability and higher accessibility.\u003c/p\u003e\u003cp\u003eInnovation was examined from three perspectives. Clinical innovation assessed first-in-class status, therapeutic novelty, and ability to address unmet needs. Technological innovation had evaluated molecular target selectivity, formulation advances, and improved safety–efficacy profiles. Industrial innovation considered contributions to pharmaceutical manufacturing and capacity for domestic drug development.\u003c/p\u003e\u003ch3\u003eMCDA Integration and Weighting\u003c/h3\u003e\u003cp\u003eTo integrate findings across dimensions, a value measurement-based MCDA was conducted. Quantitative and qualitative indicators were standardized to ensure comparability across scales. Negative indicators (e.g., ADR incidence) were transformed reciprocally and qualitative descriptors were converted to numeric values using descriptive statistics.\u003c/p\u003e\u003cp\u003eIndicator weights were determined using the Analytic Hierarchy Process (AHP), which combines pairwise expert comparisons with consensus weighting [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Each indicator received a weight proportional to its relative importance, which is consistent with the national guideline priorities. Individual criteria were scored on a 0–2 scale, multiplied by their weights, and summed to generate the total dimension scores. Sensitivity analyses were performed by varying the indicator weights by ± 20% to assess ranking robustness and model stability.\u003c/p\u003e\u003ch2\u003eStatistical Analysis\u003c/h2\u003e\u003cp\u003eAll analyses were conducted using Stata 18.0 and Microsoft Excel 2019. Continuous variables (e.g., 6 MWD, mPAP) are summarized as mean differences (MDs) with 95% CIs, and dichotomous outcomes are presented as odds ratios (ORs) with 95% confidence intervals (CIs). A random-effects model (DerSimonian–Laird method) was applied to account for inter-study heterogeneity [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eEconomic and cost-effective outcomes were calculated using pooled clinical efficacy data. Suitability, accessibility, and innovation indicators were analyzed using descriptive statistics and expert-derived scores, followed by normalization for MCDA integration. The final results were visualized using forest plots for meta-analyses and ranking tables for MCDA outputs, allowing transparent and reproducible comparison of the overall clinical value of the three ERAs.\u003c/p\u003e\u003ch2\u003eEthics Approval\u003c/h2\u003e\u003cp\u003eThis study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of [The First Affiliated Hospital of Chongqing Medical University]. The requirement for informed consent was waived because the study used de-identified data from existing databases.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\u003ch2\u003eDevelopment of the Comprehensive Evaluation Framework\u003c/h2\u003e\u003cp\u003eA structured evaluation framework for ERAs in PAH was established using the Guidelines for Comprehensive Drug Evaluation (2021 edition) as a reference and multidisciplinary Delphi consultation. Nineteen experts from health authorities, medical institutions, and academia participated in this study, each with \u0026ge;\u0026thinsp;10 years of professional experience and senior titles. Two Delphi rounds produced a consensus on six primary dimensions, 13 secondary indicators, and 32 tertiary indicators.\u003c/p\u003e\u003cp\u003eQuality control metrics demonstrated methodological robustness; the authority coefficient was 0.82, Cronbach\u0026rsquo;s α\u0026thinsp;=\u0026thinsp;0.864, and Kendall\u0026rsquo;s W\u0026thinsp;=\u0026thinsp;0.412 (P\u0026thinsp;\u0026lt;\u0026thinsp;0.01), confirming the consistency of expert opinions. The Analytic Hierarchy Process was applied to assign indicator weights, resulting in a validated, multilevel framework (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eIndicator System, Hierarchical Weights, and Operational Methods for the Comprehensive Evaluation of Endothelin Receptor Antagonists\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePrimary indicator\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eWeight assignment\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSecondary indicator\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eTertiary indicator\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eWeight assignment for tertiary indicators\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eOperational Methods\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"7\" rowspan=\"8\"\u003e\u003cp\u003eA Safety\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\" morerows=\"7\" rowspan=\"8\"\u003e\u003cp\u003e26.47\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eA1 Safety evidence quality\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eA1-1 Safety evidence quality (Guidelines \u0026amp; clinical standards)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e5.25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eReview the Documentation\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c3\" morerows=\"4\" rowspan=\"5\"\u003e\u003cp\u003eA2 Basic safety information\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eA2-1 Label clarity: Contraindications, overdose, interactions\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e2.13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\" morerows=\"3\" rowspan=\"4\"\u003e\u003cp\u003ePrescribing Information Review\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eA2-2 Special populations usage (Children, pregnant, elderly, etc.)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e2.32\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eA2-3 Pharmacovigilance alerts (Recalls, withdrawals, safety warnings)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e2.41\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eA2-4 Label changes (Notable safety-related label revisions)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.42\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eA2-5 All-cause mortality\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e3.18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMeta-analysis\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eA3 ADR incidence\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eA3-1 ADR incidence (Frequent adverse event rate)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e5.34\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMeta-analysis\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eA3-2 ADR severity (Life-threatening, lethal, carcinogenic, etc., listed in labels)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e4.42\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003ePrescribing Information Review\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003eB Efficacy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e26.34\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eB1 Efficacy evidence quality\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eB1-1 Clinical treatment position (Guidelines \u0026amp; clinical standards)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e10.32\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eReview the Documentation\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eB2 Clinical treatment position\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eB2-1 change in 6-minute walk distance\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e8.59\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eMeta-analysis\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eB2-2 change in mPAP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e7.43\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eC Economic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e15.74\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eC1 Drug cost\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eC1-1 Effectiveness-to-cost ratio\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e7.93\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eStatistical Analysis\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eC1-2 Annual treatment cost\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e7.81\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"10\" rowspan=\"11\"\u003e\u003cp\u003eD Suitability\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\" morerows=\"10\" rowspan=\"11\"\u003e\u003cp\u003e11.37\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\" morerows=\"5\" rowspan=\"6\"\u003e\u003cp\u003eD1 Drug Appropriateness\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eD1-1 Label information completeness\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.63\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\" morerows=\"10\" rowspan=\"11\"\u003e\u003cp\u003eDelphi Method\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eD1-2 Label meets clinical needs (Indications and usage as needed in practice)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.95\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eD1-3 Route \u0026amp; formulation suitability\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.84\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eD1-4 Need for therapeutic monitoring\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.22\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eD1-5 Special device requirement\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.86\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eD1-6 Special storage conditions\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.85\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c3\" morerows=\"4\" rowspan=\"5\"\u003e\u003cp\u003eD2 Drug Use Appropriateness\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eD2-1 Improves patient adherence\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.54\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eD2-2 Dosing schedule rationality\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.01\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eD2-3 Risk of intolerance (Likelihood of patients cannot tolerate)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.94\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eD2-4 Interaction limitations (Do drug/food interactions restrict use?)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.76\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eD2-5 Easy exclusion of contraindications\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.77\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003eE Accessibility\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e11.25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eE1 Insurance Coverage\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eE1-1 Reimbursed by Medical Insurance\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e3.36\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eReview the Documentation\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eE1-2 Included in National Price Negotiation Drugs\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e2.23\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eE2 Affordability\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eE2-1 Annual Household Drug Expenditure Ratio (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e5.66\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eStatistical Analysis\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"4\" rowspan=\"5\"\u003e\u003cp\u003eF Innovation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\" morerows=\"4\" rowspan=\"5\"\u003e\u003cp\u003e8.83\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eF1 Clinical Innovation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eF1-1 Innovative drug status (First-in-class or novel mechanism?)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e2.08\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\" morerows=\"3\" rowspan=\"4\"\u003e\u003cp\u003eReview the Documentation\u003c/p\u003e\u003cp\u003e༆Delphi Method\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eF1-2 Fulfilling clinical needs (Degree to which it meets previously unmet needs)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.64\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eF2 Technological Innovation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eF2-1 Target/Selective Mechanism\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.78\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eF2-2 Formulation Innovation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.54\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eF3 Industrial Innovation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eF3-1 International patent (Global patent and novelty)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.79\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cem\u003e[insert\u003c/em\u003e Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e \u003cem\u003ehere]\u003c/em\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eSafety Evaluation\u003c/h2\u003e\u003cp\u003eThe safety profiles differed notably among ambrisentan, bosentan, and macitentan (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Ambrisentan is contraindicated during pregnancy and requires dose reduction when it is co-administered with cyclosporine. Bosentan, also contraindicated in pregnancy and in patients receiving cyclosporine or glyburide, strongly induces CYP3A4/2C9, and thus poses a high drug\u0026ndash;drug interaction risk, necessitating strict hepatic monitoring. Macitentan should not be used with strong CYP3A4/2C9 modulators; its pediatric safety remains under study. None of the drugs had a specific antidote and overdose management was supportive.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eGuideline recommendations and basic safety information for endothelin receptor antagonists in pulmonary arterial hypertension\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDrug Name\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eGuideline Name\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eGuideline Organization\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eRecommendation\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eBasic Safety Information\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAmbrisentan\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eESC/ERS Guidelines\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eEuropean Society of Cardiology/European Respiratory Society\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eRecommended for low-risk or intermediate-risk PAH patients, used in combination with tadalafil.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003eContraindicated in pregnant women or women of childbearing potential due to teratogenic risk. Insufficient safety data in pediatric patients; not recommended for children, with no established clinical evidenceDose reduction to 5 mg/day required when co-administered with cyclosporine; contraindicated with sparsentan; moderate CYP-related interactions.No specific antidote; supportive treatment as needed\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eFDA Drug Label\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eU.S. Food and Drug Administration\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eRecommended for PAH patients with WHO functional class II-III, including idiopathic, hereditary, and connective tissue disease-related PAH patients.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDiagnosis and Treatment Guidelines for Pulmonary Arterial Hypertension (2021)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eChinese Society of Cardiology\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eRecommended for idiopathic, connective tissue disease-related, and congenital heart disease-related PAH patients, improving 6-minute walk distance (6MWD) and can be combined with tadalafil.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBosentan\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eESC/ERS Guidelines\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eEuropean Society of Cardiology/European Respiratory Society\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eRecommended as an initial treatment for WHO functional class II-IV PAH patients.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003eContraindicated in pregnant women, with cyclosporine or glyburide use, or hypersensitivity to components.More pediatric data available; FDA-approved for pediatric indications with dispersible tablets, but requires strict liver function monitoring.Strong CYP3A4/2C9 inducer, significantly reduces plasma levels of many drugs; contraindicated with cyclosporine or glyburide; multiple drug interaction risks.No specific treatment guidelines; hepatotoxicity requires discontinuation and supportive care.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eFDA Drug Label\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eU.S. Food and Drug Administration\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eRecommended for WHO functional class III-IV PAH patients, including idiopathic, hereditary, connective tissue disease-related, and congenital heart disease-related PAH patients.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDiagnosis and Treatment Guidelines for Pulmonary Arterial Hypertension (2021)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eChinese Society of Cardiology\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eRecommended for idiopathic, connective tissue disease-related, and congenital heart disease-related PAH patients, improving exercise capacity, functional class, hemodynamic parameters, and clinical worsening time.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMacitentan\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eESC/ERS Guidelines\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eEuropean Society of Cardiology/European Respiratory Society\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eRecommended for low-risk or intermediate-risk PAH patients, used in combination with tadalafil.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003eContraindicated with sparsentan due to potential risk of kidney injury and hypotension.Pediatric safety is still under clinical investigation; not yet approved for pediatric use; requires careful hepatic and renal monitoring.Avoid co-administration with strong CYP3A4/2C9 inhibitors or inducers (e.g., ketoconazole, rifampin) .Overdose may cause headache, nausea, vomiting; supportive treatment only; dialysis is ineffective.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eFDA Drug Label\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eU.S. Food and Drug Administration\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eRecommended for PAH patients with WHO functional class II-III, including idiopathic, hereditary, and connective tissue disease-related PAH patients.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDiagnosis and Treatment Guidelines for Pulmonary Arterial Hypertension (2021)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eChinese Society of Cardiology\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eRecommended for idiopathic, connective tissue disease-related, and congenital heart disease-related PAH patients, improving exercise capacity, functional class, hemodynamic parameters, and clinical worsening time.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eA total of 12 RCTs [\u003cspan additionalcitationids=\"CR14 CR15 CR16 CR17 CR18 CR19 CR20 CR21 CR22 CR23\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e] met the inclusion criteria, all with a low risk of bias per Cochrane RoB 2.0 (\u003cb\u003eFig S2\u003c/b\u003e). Meta-analysis of ADRs showed pooled odds ratios (ORs) of 0.57 (95% CI 0.31\u0026ndash;1.06) for ambrisentan, 1.81 (0.41\u0026ndash;8.00) for bosentan, and 2.04 (0.56\u0026ndash;7.52) for macitentan (\u003cb\u003eFig S3a\u003c/b\u003e). For all-cause mortality, the respective ORs were 0.34 (0.09\u0026ndash;1.22), 0.57 (0.12\u0026ndash;2.63), and 2.95 (0.12\u0026ndash;73.13) (\u003cb\u003eFig S3b\u003c/b\u003e).\u003c/p\u003e\u003cp\u003e[insert Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e here]\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003eEfficacy Evaluation\u003c/h2\u003e\u003cp\u003eAccording to the 2022 ESC/ERS and 2021 Chinese PAH Guidelines, all three ERAs are recommended as first-line or combination therapies for WHO functional class II\u0026ndash;III PAH. Ambrisentan improves exercise capacity and cardiac function, particularly when combined with tadalafil, which enhances hemodynamics and delays clinical worsening. Macitentan reduces disease progression, mortality, and hospitalization rates while improving quality of life indicators.\u003c/p\u003e\u003cp\u003eMeta-analysis results (\u003cb\u003eFig S4\u003c/b\u003e) confirmed the efficacy differences. For 6MWD, mean differences (MDs) were 43.89 m (95% CI 29.97\u0026ndash;57.80) for ambrisentan, 40.95 m (18.02\u0026ndash;63.88) for bosentan, and 9.73 m (\u0026ndash;8.42 to 27.88) for macitentan. For mPAP, MDs were \u0026minus;\u0026thinsp;0.27 mmHg (\u0026ndash;3.57 to 3.42), \u0026minus;\u0026thinsp;5.36 mmHg (\u0026ndash;7.29 to \u0026minus;\u0026thinsp;3.61), and \u0026minus;\u0026thinsp;5.99 mmHg (\u0026ndash;8.40 to \u0026minus;\u0026thinsp;3.58), respectively. All agents improved the clinical outcomes to varying degrees.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003eEconomic Evaluation\u003c/h2\u003e\u003cp\u003eThe unit prices for ambrisentan, bosentan, and macitentan were 2,050, 1,485, and 4,770 yuan, corresponding to annual treatment costs of ࿥24,600, ࿥17,820, and ࿥57,240, respectively. Based on the 12-week efficacy data, incremental cost-effectiveness ratios (ICERs) were ࿥140.12 per meter for ambrisentan, ࿥142.38 per meter for bosentan, and ࿥1,470.71 per meter for macitentan. Thus, ambrisentan and bosentan exhibited superior cost-effectiveness, whereas macitentan was less economical, despite its clinical benefit.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003eSuitability Evaluation\u003c/h2\u003e\u003cp\u003eExpert consultations indicated that all ERAs provided complete labeling information and consistent therapeutic indications (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). However, the need for hepatic monitoring may reduce adherence to all agents. The twice-daily dosing of bosentan and higher interaction potential yielded lower suitability scores, whereas ambrisentan and macitentan, both once daily and well tolerated, were considered more appropriate for long-term therapy.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eSuitability Assessment of Endothelin Receptor Antagonists (ERAs) in the Treatment of PAH (Scored 0\u0026ndash;2)\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"7\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIndicator\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAmbrisentan\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eScore\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eBosentan\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eScore\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMacitentan\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eScore\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eD1-1 Label Information Completeness\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eD1-2 Label meets clinical needs (Indications and usage as needed in practice)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eD1-3 Route \u0026amp; Formulation Suitability\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eD1-4 Need for Therapeutic Monitoring\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eRequires periodic liver function monitoring\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eRequires regular liver function checks\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eRequires periodic liver function monitoring\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.9\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eD1-5 Special Device Requirement\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eD1-6 Special Storage Conditions\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eD2-1 Improves Patient Adherence\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eImpact adherence\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e1.9\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eD2-2 Dosing Schedule Rationality\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eOnce-daily dosing is easy for patients to follow\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eTwice-daily dosing may be more challenging for patients\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eOnce-daily dosing is easy for patients to follow\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e1.7\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eD2-3 Risk of Intolerance (Likelihood Patients Cannot Tolerate)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTolerable, some risk of peripheral edema\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eRisk of liver toxicity, anemia, peripheral edema\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eGenerally well-tolerated, with minor side effects\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e1.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eD2-4 Interaction Limitations (Do drug/food interactions restrict use?)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAvoid strong CYP3A4 inhibitors\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eCaution with CYP3A4 inhibitors\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eAvoid strong CYP3A4 inhibitors\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.8\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eD2-5 Easy Exclusion of Contraindications\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e1.9\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e[insert Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e here]\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\u003ch2\u003eAccessibility Evaluation\u003c/h2\u003e\u003cp\u003eAll three ERAs are included in the NRDL of China. The annual treatment costs relative to the national per-capita expenditure were 87.15% for ambrisentan, 63.13% for bosentan, and 202.78% for macitentan, indicating that macitentan imposed the greatest economic burden despite reimbursement (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eAssessment of Accessibility Indicators for Endothelin Receptor Antagonist Drugs (Scored 0\u0026ndash;2)\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"7\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIndicator\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAmbrisentan\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eScore\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eBosentan\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eScore\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMacitentan\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eScore\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eE1-1 Reimbursed by Medical Insurance\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eE1-2 Included in National Price Negotiation Drugs\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eE2-1 Annual Household Drug Expenditure Ratio (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e87.15%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e63.13%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e202.78%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e[insert Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e here]\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\u003ch2\u003eInnovation Evaluation\u003c/h2\u003e\u003cp\u003eBosentan, as the first-in-class ERA, initiated the therapeutic category, ambrisentan, a second-generation agent, achieved greater receptor selectivity and reduced hepatotoxicity, and macitentan, a third-generation compound, improved pharmacokinetics and tolerability (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eAssessment of Innovation Indicators for Endothelin Receptor Antagonist Drugs (Scored 0\u0026ndash;2)\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"7\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIndicator\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAmbrisentan\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eScore\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eBosentan\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eScore\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMacitentan\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eScore\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eF1-1 Innovative drug status (First-in-class or novel mechanism)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSecond-generation endothelin receptor antagonist, not a first-in-class drug\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eFirst-generation endothelin receptor antagonist\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eThird-generation endothelin receptor antagonist, novel mechanism\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eF1-2 Fulfilling clinical needs (Degree to which it meets previously unmet needs)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAddresses unmet safety needs in PAH treatment\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAddress an unmet medical need\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eProvides longer treatment duration\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e1.7\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eF2-1 Target/selectivity mechanism\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSelective ETA receptor antagonist\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNon-selective ETA/ETB receptor antagonist\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eDual ETA/ETB receptor antagonist\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eF2-2 Dosage form innovation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eOral immediate-release formulation (Lack innovation)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eOral immediate-release formulation (Lack innovation)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eOral immediate-release formulation (Lack innovation)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eF3-1 International patent (Global patent and novelty)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHolds international patents\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eHolds international patents\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eHolds international patents\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e[insert Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e here]\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\u003ch2\u003eIntegrated MCDA Results\u003c/h2\u003e\u003cp\u003eAfter normalization and weighting across all six dimensions, ambrisentan achieved the highest total score, followed by bosentan and macitentan (Table\u0026nbsp;\u003cspan refid=\"Tab6\" class=\"InternalRef\"\u003e6\u003c/span\u003e). Its superior efficacy, safety, suitability, and innovation contributed to its overall ranking, indicating that ambrisentan offers the greatest comprehensive clinical value for PAH therapy.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab6\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 6\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eComprehensive MCDA Outcomes with Normalization and Ranking\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTertiary indicator\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eWeight assignment for tertiary indicators\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eScore of Ambrisentan\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eScore of Bosentan\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eScore of Macitentan\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eA1-1 Safety evidence quality (Guidelines \u0026amp; clinical standards)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5.25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4.46\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e3.94\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e4.73\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eA2-1 Label clarity: Contraindications, overdose, interactions\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e2.13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2.13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e2.13\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eA2-2 Special populations usage (Children, pregnant, elderly, etc.)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.32\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.04\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.00\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eA2-3 Pharmacovigilance alerts (Recalls, withdrawals, safety warnings)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.41\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.81\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.21\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.81\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eA2-4 Label changes (Notable safety-related label revisions)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.42\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.42\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.42\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.42\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eA2-5 All-cause mortality\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3.18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e2.54\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2.23\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.00\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eA3-1 ADR incidence (Frequent adverse events rate)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5.34\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4.01\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.53\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.00\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eA3-2 ADR severity (Life-threatening, lethal, carcinogenic, etc., listed in label)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4.42\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e2.87\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2.43\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.99\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eB1-1 Clinical treatment position (Guidelines \u0026amp; clinical standards)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e10.32\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e8.26\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e6.71\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e7.74\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eB2-1 Change in 6-minute walk distance\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8.59\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4.30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e4.30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e2.15\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eB2-2 Change in mPAP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7.43\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.86\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e5.94\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e6.69\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eC1-1 Effectiveness-to-cost ratio\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7.93\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e6.74\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e5.95\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.98\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eC1-2 Annual treatment cost\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7.81\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e5.08\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e6.64\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.17\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eD1-1 Label information completeness\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.63\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.63\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.63\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.63\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eD1-2 Label meets clinical needs (Indications and usage as needed in practice)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.95\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.95\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.95\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.95\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eD1-3 Route \u0026amp; formulation suitability\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.84\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.84\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.84\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.84\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eD1-4 Need for therapeutic monitoring\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.22\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.49\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.31\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.55\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eD1-5 Special device requirement\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.86\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.86\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.86\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.86\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eD1-6 Special storage conditions\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.85\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.85\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.85\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.85\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eD2-1 Improves patient adherence\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.54\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.39\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.62\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.46\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eD2-2 Dosing schedule rationality\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.01\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.81\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.56\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.86\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eD2-3 Risk of intolerance (Likelihood patients cannot tolerate)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.94\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.55\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.29\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.46\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eD2-4 Interaction limitations (Do drug/food interactions restrict use?)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.76\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.34\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.42\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.30\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eD2-5 Easy exclusion of contraindications\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.77\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.69\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.65\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.73\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eE1-1 Reimbursed by Medical Insurance\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3.36\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3.36\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e3.36\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e3.36\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eE1-2 Included in National Price Negotiation Drugs\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.23\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e2.23\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2.23\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e2.23\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eE2-1 Annual Household Drug Expenditure Ratio (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5.66\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.85\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.98\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.00\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eF1-1 Innovative drug status (First-in-class or novel mechanism?)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.08\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2.08\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.04\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eF1-2 Fulfilling clinical needs (Degree to which it meets previously unmet needs)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.64\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.07\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.23\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.39\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eF2-1 Target/Selective Mechanism\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.78\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.89\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.78\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eF2-2 Formulation Innovation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.54\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.77\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.77\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.77\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eF3-1 International patent (Global patent and novelty)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.79\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.79\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.79\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.79\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTotal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e65.84\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e64.89\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e53.66\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e[insert Table\u0026nbsp;\u003cspan refid=\"Tab6\" class=\"InternalRef\"\u003e6\u003c/span\u003e here]\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cdiv id=\"Sec19\" class=\"Section2\"\u003e\u003ch2\u003eComprehensive Evaluation Framework for Rational Drug Use\u003c/h2\u003e\u003cp\u003eComprehensive clinical evaluation has become an essential foundation for guiding rational drug use, informing reimbursement decisions, and shaping pharmaceutical policies in China. PAH remains a progressive, life-threatening condition requiring treatment that is not only effective, but also safe, affordable, and sustainable. ERAs, such as ambrisentan, bosentan, and macitentan, are the cornerstone of PAH therapy; however, systematic, multidimensional comparisons have been limited. Following the 2021 Guidelines for the Management of Comprehensive Clinical Evaluation of Pharmaceutical Products [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e], this study applied a structured, evidence-based approach to comprehensively assess the clinical value of these three ERAs across six dimensions: safety, efficacy, economic value, suitability, accessibility, and innovation.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec20\" class=\"Section2\"\u003e\u003ch2\u003eEfficacy and Clinical Performance of ERA Therapies\u003c/h2\u003e\u003cp\u003eAll three ERAs are recognized as first-line or combination therapies in both international and national guidelines and represent the backbone of PAH management [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Our meta-analysis confirmed meaningful differences in clinical efficacy, consistent with previously published data. Ambrisentan and macitentan demonstrated greater improvements in exercise capacity and functional class than bosentan did, supporting their preferential use in intensified or combination regimens. In particular, the ambrisentan\u0026ndash;tadalafil combination has shown superior outcomes, significantly reducing the risk of clinical failure compared to monotherapy [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. These findings reinforce existing strategies that favor ambrisentan or macitentan when an enhanced therapeutic response is desired [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec21\" class=\"Section2\"\u003e\u003ch2\u003eSafety Differentiation and Pharmacologic Considerations\u003c/h2\u003e\u003cp\u003eSafety is a major factor in ERA differentiation.The hepatotoxicity of bosentan and its strong induction of cytochrome P450 enzymes require regular hepatic monitoring and increase the potential for drug\u0026ndash;drug interactions, limiting its use in long-term maintenance therapy. In contrast, ambrisentan and macitentan demonstrated more favorable hepatic safety profiles, with structural optimization of macitentan further mitigating liver toxicity. Ambrisentan also caused fewer metabolic interactions, reflecting weaker CYP induction. These differences are clinically significant because hepatotoxicity may lead to treatment discontinuation, elevated healthcare costs, and reduced adherence. The expert consensus in this study similarly favored ambrisentan or macitentan for long-term administration.\u003c/p\u003e\u003cp\u003eIn special populations, bosentan currently has the most extensive pediatric safety data, whereas studies on ambrisentan and macitentan in children are ongoing. All three drugs are contraindicated during pregnancy because of their teratogenic potential, highlighting the need for strict contraception and pharmacist involvement in patient counseling.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec22\" class=\"Section2\"\u003e\u003ch2\u003eEconomic Value and Affordability\u003c/h2\u003e\u003cp\u003eEconomic evaluation showed that, despite NRDL inclusion, PAH therapy remains costly. Macitentan was associated with the highest annual cost and the least favorable ICER. By contrast, ambrisentan and bosentan exhibited lower ICERs, indicating greater economic efficiency. These findings highlight the importance of balancing clinical efficacy and cost-effectiveness to achieve value-based care. As healthcare systems shift toward cost-utility frameworks, such evaluations provide crucial evidence for formulary and reimbursement decisions. Policymakers and payers are more willing to support high-priced therapies when they demonstrate measurable improvements in outcome and safety.\u003c/p\u003e\u003cdiv id=\"Sec23\" class=\"Section3\"\u003e\u003ch2\u003eSuitability, Adherence, and Real-World Implications\u003c/h2\u003e\u003cp\u003eSuitability and adherence are pivotal for the management of chronic PAH. Ambrisentan and macitentan, with once-daily dosing and favorable tolerability, demonstrated higher suitability than bosentan, which requires twice-daily administration and frequent monitoring. These findings align with real-world data from Japan, where macitentan use is associated with longer treatment persistence and improved adherence. Practical aspects, such as dosing convenience and monitoring burden, significantly influence treatment continuity and real-world effectiveness. When the efficacy among alternatives is comparable, these patient-centric factors should be integrated into drug evaluation frameworks to ensure that clinical benefits translate into sustained outcomes in practice.\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv id=\"Sec24\" class=\"Section2\"\u003e\u003ch2\u003eInnovation and Therapeutic Evolution\u003c/h2\u003e\u003cp\u003eFrom an innovative perspective, bosentan pioneered the ERA class and established a therapeutic foundation for PAH management. Ambrisentan represents an incremental innovation that improves receptor selectivity and reduces hepatotoxicity, whereas macitentan, as a third-generation ERA, offers a longer duration of action, enhanced receptor affinity, and improved safety. Together, these developments reflect the continuous evolution of targeted therapy for PAH and demonstrate how pharmacological innovation can progressively refine both clinical outcomes and patient quality of life.\u003c/p\u003e\u003cdiv id=\"Sec25\" class=\"Section3\"\u003e\u003ch2\u003eClinical Pharmacy and Policy Implications\u003c/h2\u003e\u003cp\u003eThis MCDA-based framework also highlights the growing role of clinical pharmacists in formulary evaluations and value-based drug selection. By integrating quantitative data on safety, efficacy, and economic outcomes, pharmacists can provide objective evidence to support hospital drug and therapeutic (D\u0026amp;T) committees and reimbursement negotiations. The implementation of such models within clinical pharmacy systems promotes transparency and facilitates multidisciplinary decision making among physicians, pharmacists, and policymakers. Moreover, the six-dimensional approach aligns with national health policy priorities, supporting equitable drug access and optimal allocation of medical resources. The incorporation of MCDA tools into pharmacy practice can therefore bridge the gap between clinical evidence and policy execution, ensuring that therapeutic decisions are both evidence driven and patient centered.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec26\" class=\"Section3\"\u003e\u003ch2\u003eOverall Interpretation and Study Limitations\u003c/h2\u003e\u003cp\u003eIntegrating the results across all six dimensions, ambrisentan achieved the highest overall score, demonstrating balanced advantages in efficacy, safety, cost-effectiveness, and patient suitability. Nonetheless, individualized treatment decisions considering comorbidities, adherence potential, and tolerance remain essential.\u003c/p\u003e\u003cp\u003eThe study followed standardized procedures and incorporated multidisciplinary perspectives to produce robust and reproducible findings. However, this study has several limitations. The analysis relied primarily on published RCT data, and real-world treatment effectiveness may vary across populations and health care systems. In addition, the evaluation index system requires further validation in a multicenter Chinese cohort. Future studies combining MCDA with real-world evidence and pharmacoeconomic modeling could refine this framework and expand its applicability to other rare or high-cost diseases.\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis study established a multidimensional, evidence-based framework integrating safety, efficacy, cost-effectiveness, suitability, accessibility, and innovation to comprehensively evaluate endothelin receptor antagonists for pulmonary arterial hypertension. Ambrisentan demonstrated the highest overall clinical value, reflecting balanced advantages in therapeutic efficacy, safety, and patient suitability compared to bosentan and macitentan. Beyond PAH, this evaluation model offers a reproducible approach for guiding rational drug selection, optimizing reimbursement policies, and supporting evidence-based formulary management. The integration of this framework into clinical pharmacy and hospital decision-making processes can enhance transparency, promote value-based prescribing, and strengthen collaboration between pharmacists, clinicians, and policymakers. Ultimately, such structured assessments can improve therapeutic outcomes, ensure equitable resource allocation, and contribute to long-term sustainability of the healthcare system.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by National Natural Science Foundation of China (Funding number: 82404767).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eZihan Cao wrote the original draft. Long Meng: Writing–original draft, Yunlong Li: Data curation, software. Mi Zhou: Resources, Investigation. Huiming Jiang: Data Curation, Software. Jun Wang: Formal analysis. Ziyi Tao: Supervision. \u0026nbsp;Feng Qiu: Conceptualization, Methodology, Supervision.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics Approval\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of [The First Affiliated Hospital of Chongqing Medical University]. The requirement for informed consent was waived because the study used de-identified data from existing databases.\u003c/p\u003e\n"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eFarber HW, Loscalzo J. Pulmonary arterial hypertension. N Engl J Med. 2004;351(16):1655\u0026ndash;65.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eEmmons-Bell S, Johnson C, Boon‐Dooley A, et al. 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Bosentan therapy in patients with Eisenmenger syndrome: a multicenter, double-blind, randomized, placebo-controlled study. Circulation. 2006;114(1):48\u0026ndash;54.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGali\u0026egrave; N, Olschewski H, Oudiz RJ, et al. Ambrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2. Circulation. 2008;117(23):3010\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. 2002;346(12):896\u0026ndash;903.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGali\u0026egrave; N, Rubin L, Hoeper M, et al. Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomised controlled trial. Lancet. 2008;371(9630):2093\u0026ndash;100.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSitbon O, Bosch J, Cottreel E, et al. Macitentan for the treatment of portopulmonary hypertension (PORTICO): a multicentre, randomised, double-blind, placebo-controlled, phase 4 trial. Lancet Respiratory Med. 2019;7(7):594\u0026ndash;604.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePan Z, Marra AM, Benjamin N, et al. Early treatment with ambrisentan of mildly elevated mean pulmonary arterial pressure associated with systemic sclerosis: a randomized, controlled, double-blind, parallel group study (EDITA study). Arthritis Res therapy. 2019;21(1):217.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePulido T, Adzerikho I, Channick RN, et al. 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J Heart Lung Transplantation. 2019;38(2):194\u0026ndash;202.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSouza R, Delcroix M, Galie N, et al. Long-term safety, tolerability and survival in patients with pulmonary arterial hypertension treated with macitentan: results from the SERAPHIN open-label extension. Adv therapy. 2022;39(9):4374\u0026ndash;90.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGu J, Guo Y, Wu B, He J. Liver injury associated with endothelin receptor antagonists: a pharmacovigilance study based on FDA adverse event reporting system data. Int J Clin Pharm. 2024;46(6):1307\u0026ndash;16.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLaba T-L, Jiwani B, Crossland R, Mitton C. Can multi-criteria decision analysis (MCDA) be implemented into real-world drug decision-making processes? A Canadian provincial experience. Int J Technol Assess Health Care. 2020;36(4):434\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Pulmonary Arterial Hypertension, Endothelin Receptor Antagonists, Multi-Criteria Decision Analysis, Clinical Comprehensive Evaluation","lastPublishedDoi":"10.21203/rs.3.rs-8085636/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8085636/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eIntroduction\u003c/h2\u003e\u003cp\u003eEndothelin receptor antagonists (ERAs), including ambrisentan, bosentan, and macitentan, are central to the treatment of pulmonary arterial hypertension (PAH). As patient survival improves, long-term management increasingly requires systematic evaluation of these agents to balance their efficacy, safety, cost, and accessibility. However, standardized frameworks that integrate the multiple dimensions of clinical value remain limited.\u003c/p\u003e\u003ch2\u003eAim\u003c/h2\u003e\u003cp\u003eThis study aimed to establish and apply a six-dimensional Multi-Criteria Decision Analysis (MCDA) framework to comprehensively assess the clinical value of ambrisentan, bosentan, and macitentan in the treatment of PAH.\u003c/p\u003e\u003ch2\u003eMethod\u003c/h2\u003e\u003cp\u003eA structured evaluation system was developed using Delphi expert consultation and evidence synthesis from systematic reviews, meta-analyses of randomized controlled trials (RCTs), pharmacoeconomic assessments, and regulatory documents. Six core dimensions were included: safety, efficacy, economic value, suitability, accessibility, and innovation. Quantitative and qualitative indicators were normalized and weighted using the Analytic Hierarchy Process and integrated using the MCDA model. Sensitivity analyses were performed to verify the robustness of rankings.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eThe final framework comprised six primary dimensions, 13 secondary indicators, and 32 tertiary indicators. Twelve RCTs met the inclusion criteria for quantitative analysis. All three ERAs improved exercise capacity and hemodynamic parameters, whereas ambrisentan exhibited superior tolerability. Economic evaluation showed that ambrisentan and bosentan offered better cost-effectiveness, with incremental cost-effectiveness ratios of ࿥140.12 per meter and ࿥142.38 per meter, respectively, compared with ࿥1,470.71 per meter for macitentan. Suitability analysis favored ambrisentan and macitentan because of their once-daily dosing and favorable adherence profiles. Bosentan demonstrated advantages in affordability owing to its lower cost and National Reimbursement Drug List coverage. Innovation assessment ranked macitentans as the highest for technological advancement. Integrated MCDA scoring indicated that ambrisentan achieved the greatest overall clinical value.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eThis study developed a multidimensional, evidence-based evaluation model for PAH therapy using MCDA. Ambrisentan achieved the highest comprehensive score across the six key dimensions, reflecting its balanced efficacy, safety, and economic performance. The proposed framework provides a practical tool for clinicians, pharmacists, and policymakers to support rational drug use, formulary management, and value-based decision making in PAH and other rare diseases.\u003c/p\u003e","manuscriptTitle":"Comprehensive Clinical Evaluation of Endothelin Receptor Antagonists in Pulmonary Arterial Hypertension Using Multi-Criteria Decision Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-27 11:59:30","doi":"10.21203/rs.3.rs-8085636/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"25d51b5f-100f-4aa0-ada3-d509290b34ac","owner":[],"postedDate":"November 27th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-01-08T14:39:17+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-27 11:59:30","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8085636","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8085636","identity":"rs-8085636","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}