Comparative Efficacy of Balloon Pulmonary Angioplasty and Pharmacological Therapies in Inoperable Chronic Thromboembolic Pulmonary Hypertension: A Network Meta-Analysis

Comparative Efficacy of Balloon Pulmonary Angioplasty and Pharmacological Therapies in Inoperable Chronic Thromboembolic Pulmonary Hypertension: A Network Meta-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 Systematic Review Comparative Efficacy of Balloon Pulmonary Angioplasty and Pharmacological Therapies in Inoperable Chronic Thromboembolic Pulmonary Hypertension: A Network Meta-Analysis Suchith Boodgere Suresh, Khutaija Noor, Jane Hyun, Veronica Manchanda, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7107350/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 Background Inoperable or residual chronic thromboembolic pulmonary hypertension treatment modalities remain challenging due to limited comparison of alternatives between BPA and pharmacological agents. Objective To compare the relative efficacy and safety of BPA and pharmacological treatments in patients with inoperable or residual CTEPH. By integrating both direct and indirect comparisons, the study aims to provide a hierarchised, evidence-based framework to inform personalised treatment selection and guideline development for this high-risk population. Methods A systematic search of major databases through November 2024 identified randomized trials evaluating BPA, Riociguat, endothelin receptor antagonists (Bosentan, Ambrisentan, Macitentan), PDE-5 inhibitors (Sildenafil), and prostacyclin analogs (Selexipag). Outcomes included pulmonary vascular resistance (PVR), mean pulmonary artery pressure (mPAP), cardiac index (CI), 6-minute walk distance (6MWD), NT-proBNP, and Borg Dyspnea Index (BDI). A frequentist random-effects model was applied using the netmeta R package. Results Nine studies with 839 participants were analyzed. BPA showed the greatest reduction in PVR (MD -444.02 dyn·s·cm⁻⁵, 95% CI -606.99 to -281.05) and mPAP (MD -16.17 mmHg), with the highest SUCRA scores across outcomes. Riociguat ranked second overall, improving PVR, 6MWD, and CI. Macitentan and selexipag significantly improved CI, while bosentan reduced NT-proBNP. Ambrisentan and sildenafil did not demonstrate significant benefits over placebo. High heterogeneity was observed for PVR and BDI outcomes. Conclusions Ballon Pulmonary Angioplasty (BPA) demonstrates the most robust and consistent improvements in hemodynamics as evidenced by PVR, mPAP and mRAP measurements as well in functional and biomarker improvements (6MWD and NT-proBNP) in patients with inoperable CTEPH while Riociguat remains the most effective pharmacologic agent, offering significant benefits across multiple domains including PVR, 6MWD, mPAP and CI. Macitentan and Selexipag showed promising improvements in cardiac output while Bosentan provided NT-proBNP and pVR benefit. Ambrisentan and Sildenafil did not demonstrate significant advantages over placebo in this population. These findings support BPA as the most effective intervention for inoperable CTEPH, with Riociguat as the preferred pharmacologic therapy. However, limited direct comparisons and heterogeneity in some endpoints warrant long-term outcome studies to refine treatment sequencing, combination strategies and the consideration for future head-to-head trials between advanced oral therapies and BPA. Critical Care & Emergency Medicine Pulmonology Internal Medicine Balloon pulmonary angioplasty Chronic thromboembolic pulmonary hypertension Riociguat Pulmonary hypertension Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Chronic thromboembolic pulmonary hypertension (CTEPH) is a distinct form of pulmonary hypertension classified as Group 4 disease . It arises when organised thrombo-emboli persists in the pulmonary arteries and triggers secondary small-vessel arteriopathy, inflammation, and progressive vascular remodelling, ultimately increasing pulmonary vascular resistance and overloading the right ventricle. [1] Although CTEPH is considered rare, national registry data suggest an annual incidence of 3 to 5 cases/100,000 population. [2] After an acute pulmonary embolism (PE) the cumulative risk of developing CTEPH is about 2.3% at 3 years. (https://www.ahajournals.org/doi/10.1161/JAHA.124.035997)[1] Pulmonary endarterectomy (PEA) remains the curative standard, yet up to 24-37% of patients are deemed inoperable because of distal disease distribution, advanced comorbidity, or persistent pulmonary hypertension after surgery. [3] For these patients two therapeutic strategies have emerged: 1. Targeted pharmacotherapy —notably the soluble guanylate-cyclase stimulator riociguat , endothelin-receptor antagonists (bosentan, macitentan, ambrisentan), phosphodiesterase-5 inhibitors, and prostacyclin pathway agents such as selexipag —all shown to improve haemodynamics and functional capacity in phase II–III trial. 2. Balloon pulmonary angioplasty (BPA) —a percutaneous technique that mechanically dilates obstructed segmental branches. Randomised trials (RACE trial) demonstrate larger reductions in pulmonary vascular resistance with BPA than with riociguat, but at the cost of higher procedure-related complications. Despite these advances, direct head-to-head comparisons across the expanding array of medical and interventional options are lacking , leaving clinicians without clear guidance on how best to sequence or combine therapies in inoperable CTEPH. Objective. The present network meta-analysis will synthesise all randomised and prospective evidence to compare the relative efficacy and safety of pharmacological treatments and BPA in patients with inoperable or residual CTEPH . By integrating both direct and indirect comparisons, the study aims to provide a hierarchised, evidence-based framework to inform personalised treatment selection and guideline development for this high-risk population. Methods We conducted a NMA following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses - network meta-analysis (PRISMA NMA) guidelines. Eligibility Criteria Table 1 is the inclusion and exclusion Criteria: Inclusion Criteria Exclusion Criteria a) Human Studies a) Animal Studies b) English Text b) Non-English Texts c) Full text c) case control, cohort , case series, reviews and meta- analysis d) RCT ( randomized control trials ) d) non full text Search Strategy and Study selection A comprehensive search was conducted on PubMed, Google scholar, science direct, Cochrane, plosone and clinical trials.gov using the keywords “inoperable” and “chronic thromboembolic, pulmonary hypertension”,upto November 2024. Table 2 describes search strategies. The articles were imported onto Rayyan AI from each of the above databases. Two investigators reviewed identified titles and abstracts independently, after which complete texts of eligible articles were obtained. Any disagreement between the reviewers was resolved by discussion with a third member of the investigator team. Risk of bias assessment: The Cochrane risk-of-bias (ROB2 criteria) tool for randomized controlled trials (RCTs) was used to rate the quality of the articles. Data extraction Two investigators read each article and performed data extraction independently. Any disagreements were resolved by consultation with a third reviewer. Data on study characteristics were summarized (e.g., first author, publication year), patient characteristics [age, sex, Previous PEA (%) and baseline PVR (dyn·s·cm 5), 6MWD (m), WHO classification, Cardiac Index (l·min 1·m 2), mPAP (mm Hg), mRAP ((mm Hg), Borg Dyspnea Index, NT - proBNP (ng/l) ]and outcome measures. Outcomes measured Pulmonary vascular resistance, six minute walking distance, NT -proBNP, mean pulmonary artery pressure, mean right atrial pressure, Borg dyspnea index, cardiac index. Network Structure The network consisted of seven treatments (Ambrisentan, Bosentan, Macitentan, Riociguat, Selexipag, Sildenafil, and Placebo) across seven studies. All treatments were directly compared to Placebo, forming a star-shaped network with limited connections between active treatments. This structure precluded comprehensive inconsistency assessment due to the absence of closed loops of evidence. Data Analysis A network meta-analysis was conducted using the R package netmeta (version 2024.12.1+563), which implements frequentist methods based on a graph-theoretical approach. The analysis was performed on contrast-based data, with treatment effects expressed as mean differences (MD) and corresponding standard errors (SE). Both fixed-effect and random-effects models were fitted, with Placebo considered as the reference treatment for all comparisons. Heterogeneity Assessment Heterogeneity across studies was quantified using several complementary measures. The between-study variance was estimated using the DerSimonian-Laird method and reported as τ², with its corresponding standard deviation τ. The proportion of observed variance reflecting real differences in effect size was assessed using I² statistics, calculated as I² = 100% × (Q-df)/Q, where Q represents Cochran's homogeneity test statistic and df the degrees of freedom. The 95% confidence intervals for I² were calculated using the test-based method to indicate uncertainty in heterogeneity estimates. Inconsistency Analysis To assess the validity of the transitivity assumption, global inconsistency was evaluated using the design-by-treatment interaction model implemented in the netcomb function. This method simultaneously considers both heterogeneity and inconsistency between different studies by comparing the consistency model with an unrelated mean effects model. Local inconsistency was planned to be assessed using node-splitting analysis (netsplit function), which compares direct and indirect evidence for each treatment comparison where both sources of evidence are available. However, due to the star-shaped structure of the network with Placebo as the common comparator, no indirect evidence was available for node-splitting analysis. Additionally, deviance contribution plots were intended to identify specific studies contributing disproportionately to network inconsistency; however, these plots could not be generated due to technical limitations in plotting arguments, and their utility was limited by the absence of multi-arm studies or closed loops in the network. Visualization All analyses were performed using R software (version 2024.12.1+563) with the netmeta package. Results were visualized using network graphs depicting the geometry of the treatment network, with node sizes proportional to the number of participants receiving each treatment and edge widths proportional to the number of studies directly comparing treatments. Results Table 1. Baseline Clinical Characteristics of Included Studies Study Intervention N Age (years) Males (n, %) Previous PEA (%) PVR (dyn·s·cm⁻⁵) 6MWD (m) WHO FC (I/II/III/IV) Cardiac Index (L·min⁻¹·m⁻²) mPAP (mmHg) mRAP (mmHg) Borg Dyspnea Index NT-proBNP (ng/L) Jaïs et al. 2008 [ 4 ] Bosentan 77 63.0 ± 12.9 18 (23.4) 28.6 778 ± 323 340 ± 85 —/22/51/3 2.24 ± 0.54 44.2 ± 10.4 8.3 ± 6.1 4.4 ± 2.0 1,481 ± 1,833 Placebo 80 63.1 ± 10.3 33 (41.3) 27.5 787 ± 333 345 ± 83 —/22/56/2 2.35 ± 0.55 47.4 ± 12.5 8.4 ± 6.0 4.1 ± 2.3 1,405 ± 1,882 Suntharalingam et al. 2008 [ 5 ] Sildenafil 9 49.9 ± 13.1 2 (22.2) 22 814 ± 385 331 ± 50 —/3/6/— 2.2 ± 0.6 45.8 ± 8.0 7.4 ± 3.4 — 1,301 ± 1,393 Placebo 10 60.0 ± 14.4 7 (70.0) 70 654 ± 342 347 ± 66 —/8/2/— 2.2 ± 0.4 42.7 ± 10.1 6.9 ± 4.3 — 788 ± 842 Ghofrani et al. 2024 [ 6 ] Macitentan 40 58.2 ± 14.0 14 (35.0) — 934 ± 394 353 ± 88 —/12/28/0 2.2 ± 0.53 49.9 ± 11.7 9.3 ± 5.7 4.2 ± 2.5 2,204 ± 2,943 Placebo 40 56.9 ± 13.9 15 (37.5) — 988 ± 490 351 ± 74 —/6/33/1 2.2 ± 0.61 51.7 ± 14.1 8.7 ± 5.2 4.2 ± 2.1 1,793 ± 2,075 Kim et al. 2016 [ 7 ] Riociguat 173 59 ± 14 55 (31.8) 30 791 ± 432 342 ± 82 3/55/107/8 2.3 ± 0.7 47 ± 13 8.3 ± 5.3 — — Placebo 88 59 ± 13 34 (38.6) 23 779 ± 401 356 ± 75 0/25/60/2 2.2 ± 0.7 47 ± 9 9.2 ± 6.1 — — Escribano-Subias et al. 2019 [ 8 ] Ambrisentan 15 63 ± 8 9 (60.0) — — — —/—/—/— — — — — — Placebo 8 59 ± 8 6 (75.0) — — — —/—/—/— — — — — — Tanabe et al. 2020 [ 9 ] Selexipag 25 58 ± 15 8 (32.0) 12 700 ± 302 378 ± 77 0/13/11/1 2.4 ± 0.5 41.1 ± 11.7 5.4 ± 3.3 — 402 ± 490 Placebo 9 60 ± 5 2 (22.2) 11.1 756 ± 303 355 ± 114 0/5/3/1 2.5 ± 0.8 41.6 ± 8.5 5.1 ± 3.3 — 1,231 ± 1,601 Ogo et al. 2022 [ 10 ] Selexipag 39 66.3 ± 11.1 10 (25.6) 12.8 523 ± 133 408 ± 91 1/23/15/0 2.69 ± 0.60 35.2 ± 5.4 5.5 ± 3.2 3.26 ± 1.75 592 ± 928 Placebo 39 68.3 ± 9.6 10 (25.6) 12.8 553 ± 184 384 ± 87 2/26/11/0 2.59 ± 0.41 35.5 ± 8.3 5.4 ± 4.0 2.90 ± 1.99 512 ± 710 Jaïs et al. 2022 [1 1 ] BPA 52 68.1 ± 9.4 26 (50.0) — 767 ± 251 380 ± 103 —/12/38/2 2.3 ± 0.5 46.5 ± 8.4 8.7 ± 3.9 3.7 ± 1.6 1,887 ± 2,370 Riociguat 53 66.8 ± 10.5 26 (49.1) — 679 ± 273 390 ± 124 —/10/43/0 2.4 ± 0.6 44.7 ± 10.0 8.0 ± 3.4 3.2 ± 1.7 1,455 ± 1,701 Kawakami et al. 2022 [1 2 ] BPA 31 68.0 ± 9.1 7 (22.6) — 645 ± 267 364 ± 105 0/9/22/0 — 38.1 ± 7.9 5.1 ± 3.3 3.85 ± 2.50 — Riociguat 26 65.7 ± 10.9 3 (11.5) — 565 ± 235 343 ± 113 0/9/15/0 — Network Meta-Analysis Overview This network meta-analysis evaluated the comparative efficacy of seven active treatments against placebo for chronic thromboembolic pulmonary hypertension (CTEPH). The analysis included across seven clinical outcomes. The number of included studies ranged from 6 to 9 depending on the specific outcome analyzed, with pairwise comparisons ranging from 6 to 9 per outcome. Primary Hemodynamic Outcomes Pulmonary Vascular Resistance (PVR) The random effects model analysis of PVR included 9 studies with 9 pairwise comparisons. BPA demonstrated the most substantial reduction in PVR compared to placebo (mean difference [MD]: -444.02 dynes·sec·cm⁻⁵, 95% CI: -606.99 to -281.05, p < 0.0001), achieving the highest SUCRA score of 0.9683. Riociguat showed significant efficacy (MD: -248.75, 95% CI: -381.67 to -115.83, p = 0.0002, SUCRA: 0.7156), followed by bosentan (MD: -176.00, 95% CI: -288.69 to -63.31, p = 0.0022, SUCRA: 0.5161). Macitentan demonstrated a trend toward significance (MD: -173.00, 95% CI: -347.23 to 1.23, p = 0.0516, SUCRA: 0.5191), while selexipag showed borderline significance (MD: -104.80, 95% CI: -211.56 to 1.97, p = 0.0544, SUCRA: 0.3371). Ambrisentan and sildenafil did not demonstrate significant PVR reduction (Figure 1). The analysis revealed substantial heterogeneity (I² = 62.3% [0.0%; 89.2%], τ² = 3281.20), indicating considerable variability between studies. Sensitivity analysis excluding BPA studies showed reduced heterogeneity (I² = 0%), suggesting BPA studies contributed to the observed heterogeneity. Mean Pulmonary Arterial Pressure (mPAP) Figure 3 Analysis of mPAP included 9 studies with 9 pairwise comparisons. BPA achieved the greatest reduction in mPAP (MD: -16.17 mmHg, 95% CI: -20.42 to -11.93, p < 0.0001, SUCRA: 0.9996), followed by riociguat (MD: -5.07 mmHg, 95% CI: -8.52 to -1.62, p = 0.0040, SUCRA: 0.7719). Other treatments including bosentan, macitentan, selexipag, sildenafil, and ambrisentan did not demonstrate statistically significant reductions in mPAP. Moderate heterogeneity was observed (I² = 52.9% [0.0%; 86.5%], τ² = 2.19). Mean Right Atrial Pressure (mRAP) Figure 2 The mRAP analysis encompassed 9 studies with 9 pairwise comparisons. Only BPA achieved a statistically significant reduction in mRAP (MD: -1.75 mmHg, 95% CI: -3.46 to -0.03, p = 0.0458, SUCRA: 0.8140)1. Macitentan showed a numerical but non-significant reduction (MD: -1.50 mmHg, 95% CI: -3.51 to 0.51, p = 0.1443, SUCRA: 0.7596). No heterogeneity was detected for this outcome (I² = 0%). Functional Capacity and Quality of Life Outcomes Six-Minute Walk Distance (6MWD) Figure 4 The 6MWD analysis included 9 studies with 9 pairwise comparisons. BPA demonstrated the greatest improvement in exercise capacity (MD: 53.08 meters, 95% CI: 25.46 to 80.69, p = 0.0002, SUCRA: 0.8751), followed by riociguat (MD: 44.40 meters, 95% CI: 19.76 to 69.04, p = 0.0004, SUCRA: 0.7787)1. Macitentan achieved a modest but significant improvement (MD: 34.00 meters, 95% CI: 1.02 to 66.98, p = 0.0433, SUCRA: 0.6640). Ambrisentan, sildenafil, bosentan, and selexipag did not demonstrate significant improvements in 6MWD. Low heterogeneity was observed (I² = 13.2% [0.0%; 91.0%], τ² = 40.97). Borg Dyspnea Index (BDI) Figure 5 The BDI analysis comprised 8 studies with 8 pairwise comparisons. None of the treatments achieved statistically significant improvements in dyspnea scores compared to placebo in the random effects model1. BPA showed the numerically greatest improvement (MD: -1.99 points, 95% CI: -4.66 to 0.68, p = 0.1443, SUCRA: 0.7617), followed by ambrisentan (MD: -1.50 points, 95% CI: -3.79 to 0.79, p = 0.1998, SUCRA: 0.6503). High heterogeneity was present (I² = 89.3% [60.2%; 97.1%], τ² = 1.13), which eliminated significance in the random effects model despite significant effects observed in the common effects model. Cardiac Function and Biomarker Outcomes Cardiac Index (CI) Figure 4 The CI analysis included 9 studies with 9 pairwise comparisons and demonstrated no heterogeneity (I² = 0%). Multiple treatments showed significant improvements: macitentan (MD: 0.50 L/min/m², 95% CI: 0.27 to 0.73, p < 0.0001, SUCRA: 0.7707), selexipag (MD: 0.49 L/min/m², 95% CI: 0.28 to 0.70, p < 0.0001, SUCRA: 0.7483), riociguat (MD: 0.46 L/min/m², 95% CI: 0.31 to 0.61, p < 0.0001, SUCRA: 0.7181), and BPA (MD: 0.24 L/min/m², 95% CI: 0.01 to 0.47, p = 0.0398, SUCRA: 0.3533)1. Bosentan showed a trend toward significance (MD: 0.30 L/min/m², 95% CI: -0.02 to 0.62, p = 0.0661, SUCRA: 0.4613). N-Terminal Pro-B-Type Natriuretic Peptide (NT-proBNP) Figure 2 The NT-proBNP analysis encompassed 8 studies with 8 pairwise comparisons. BPA achieved the most substantial reduction (MD: -1479.04 pg/mL, 95% CI: -2308.99 to -649.09, p = 0.0005, SUCRA: 0.9806), followed by bosentan (MD: -600.00 pg/mL, 95% CI: -1190.78 to -9.22, p = 0.0465, SUCRA: 0.7103). Other treatments including riociguat, macitentan, sildenafil, ambrisentan, and selexipag did not achieve statistical significance. Moderate heterogeneity was observed (I² = 35%, τ² = 44606.85)1. Treatment Ranking and Comparative Efficacy Based on SUCRA (Surface Under the Cumulative Ranking Curve) scores, BPA consistently ranked highest across most outcomes, achieving the best efficacy profile for PVR (0.9683), 6MWD (0.8751), NT-proBNP (0.9806), mRAP (0.8140), and mPAP (0.9996)1. Riociguat demonstrated consistent efficacy across multiple outcomes with high SUCRA scores for PVR (0.7156), 6MWD (0.7787), CI (0.7181), and mPAP (0.7719). Among the pharmacological therapies, macitentan and selexipag showed particular strength in cardiac index improvement, while bosentan demonstrated efficacy in hemodynamic parameters and NT-proBNP reduction. Heterogeneity Assessment Heterogeneity varied considerably across outcomes. Low heterogeneity (I² < 25%) was observed for cardiac index and mean right atrial pressure, indicating consistent treatment effects across studies1. Moderate heterogeneity (I² 25-75%) was present for 6MWD, NT-proBNP, and mPAP outcomes. High heterogeneity (I² > 75%) was noted for PVR and BDI, suggesting substantial variation in treatment effects between studies, which may be attributed to differences in study populations, intervention protocols, or outcome measurement methods. Discussion This network meta-analysis aims to compare effective chronic thromboembolic pulmonary hypertension treatments across key hemodynamic, functional, and biomarker outcomes in operable patients with underlying co existing medical conditions, surgically inaccessible distal arteries or patients with the risks of major surgery deemed to outweigh the potential benefit. [ 13 ] Interpretation of Results The study highlights the impact of BPA as most significant improvement across the board spectrum from lowering pressure in the pulmonary arteries via significant reduction in Pulmonary Vascular Resistance (PVR), Mean Pulmonary Arterial Pressure (mPAP), and Mean Right Atrial Pressure (mRAP) to improving exercise capacity (6MWD) and reducing a key biomarker of heart strain (NT-proBNP) by mechanically clearing clots that obstruct pulmonary arteries and improving blood flow. [ 14 ] [ 15 ] While BPA is minimally invasive addressing the blockage directly, medical therapies also play a crucial role in inoperable cases of PTEH. Riociguat is the second most effective treatment to BPA, in improving pulmonary pressures and exercise distance, significantly improving the cardiac index. The riociguat directly stimulates soluble guanylate cyclase (sGC), causing relaxation of vascular smooth muscle, enhancing vascular blood flow in inoperable patients. [ 16 ] While other medication shows promising results, such as Macitentan and Selexipag acts on endothelin and prostacyclin pathways improving cardiac index to enhance heart function and Bosentan significantly reducing pulmonary vascular resistance and NT- pro BNP levels. Few medications such as Ambrisentan and Sildenafil demonstrated no significant advantage over placebo for most outcomes. This medication has a teratogenic effect and is to be avoided in female patients of reproductive age groups or pregnant females and in patients with underlying chronic liver disease. [ 17 ] [ 18 ] The patients demonstrated physiological benefits with minimal to no improvement in Borg Dyspnea Index (BDI), due to the study variability for measurement outcome of dyspnea in high heterogeneity studies. This finding raises important questions about the alignment between objective hemodynamic gains and patient-perceived symptom relief. The lack of improvement in BDI may reflect limitations in measurement sensitivity, heterogeneity in baseline symptoms, or insufficient follow-up duration. These results underscore the need to include standardized patient-reported outcome measures in future CTEPH trials. [ 19 ] The study findings show exceptional performance of BPA in numerous observational studies as an already established vital treatment for inoperable CTEPH, often achieving outcomes comparable to pulmonary endarterectomy. This network analysis strengthens the evidence of Riociguat reinforced in landmark CHEST-1 and PATENT-1 pivotal trials demonstrating its efficacy in CTEPH over other oral therapies. The findings also highlight the need for comprehensive outcome monitoring in clinical practice, given the multidimensional nature of treatment effects. For example, improvements in hemodynamics may not always translate into perceptible relief in dyspnea scores, emphasizing the role of serial assessment using functional, hemodynamic, and biomarker endpoints. Limitations This study has several important limitations such as selection bias, as small samples may not adequately represent the broader PAH population; reporting bias, as limited use of inferential statistics increases the risk of selective reporting of favorable outcomes; and attrition bias, due to missing efficacy data that may distort treatment effects if not properly accounted for. Despite these limitations, inclusion of the AMBER trial was justified by its unique focus on ambrisentan for chronic thromboembolic pulmonary hypertension (CTEPH)—a condition with relatively few available therapies—offering insights of potential clinical value. Second, the SELEXIPAG trials and the MERIT−1 trial included patients with inoperable CTEPH who were already receiving concomitant pulmonary vasodilators, provided doses remained stable. While this reflects real-world treatment conditions, it may confound the true independent effect of selexipag, making it difficult to isolate its efficacy in this subgroup. Third, the absence of trials directly comparing individual agents head to head limits the precision of relative treatment rankings. Although the network meta-analytic approach integrates both direct and indirect evidence to estimate comparative effectiveness, the lack of direct comparisons may constrain confidence in definitive treatment hierarchies. Future Directions Future research should focus on clinical trials, particularly between agents with high SUCRA rankings such as Bosentan and Riociguat. Moreover, studies incorporating longer follow-up periods and endpoints such as quality of life, hospitalization rates, and survival would provide a more comprehensive assessment of therapeutic value. Given the underrepresentation of older adults and women in PAH trials, targeted investigations in these populations are also warranted. Conclusion This network meta-analysis demonstrates that balloon pulmonary angioplasty provides the most robust and consistent improvements in hemodynamics, exercise capacity, and biomarkers for patients with inoperable or residual CTEPH, supporting its role as a first-line intervention. Despite these advances, the lack of direct head-to-head comparisons and observed heterogeneity in some outcomes highlight the need for further research to refine treatment sequencing and combination strategies. Future studies should focus on long-term outcomes, standardized patient-reported measures, and the inclusion of underrepresented populations. 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Chest , 134 (2), 229–236. https://doi.org/10.1378/chest.07-2681 Ghofrani, H. A., Simonneau, G., D'Armini, A. M., Fedullo, P., Howard, L. S., Jaïs, X., Jenkins, D. P., Jing, Z. C., Madani, M. M., Martin, N., Mayer, E., Papadakis, K., Richard, D., Kim, N. H., & MERIT study investigators (2024). Macitentan for the treatment of inoperable chronic thromboembolic pulmonary hypertension (MERIT-1): results from the multicentre, phase 2, randomised, double-blind, placebo-controlled study. The Lancet. Respiratory medicine , 12 (4), e21–e30. https://doi.org/10.1016/S2213-2600(24)00027-4 Kim NH, D'Armini AM, Grimminger F, Grünig E, Hoeper MM, Jansa P, Mayer E, Neurohr C, Simonneau G, Torbicki A, Wang C, Fritsch A, Davie N, Ghofrani HA. Haemodynamic effects of riociguat in inoperable/recurrent chronic thromboembolic pulmonary hypertension. Heart. 2017 Apr;103(8):599-606. doi: 10.1136/heartjnl-2016-309621. Epub 2016 Dec 23. PMID: 28011757; PMCID: PMC5529957. Escribano-Subias P, Bendjenana H, Curtis PS, Lang I, Vonk Noordegraaf A. Ambrisentan for treatment of inoperable chronic thromboembolic pulmonary hypertension (CTEPH). Pulm Circ. 2019 Apr-Jun;9(2):2045894019846433. doi: 10.1177/2045894019846433. PMID: 30957635; PMCID: PMC6540507. Tanabe, N., Fukuda, K., Matsubara, H., Nakanishi, N., Tahara, N., Ikeda, S., Kishi, T., Satoh, T., Hirata, K. I., Inoue, T., Kimura, H., Okano, Y., Okazaki, O., Sata, M., Tsujino, I., Ueno, S., Yamada, N., Yao, A., & Kuriyama, T. (2020). Selexipag for Chronic Thromboembolic Pulmonary Hypertension in Japanese Patients - A Double-Blind, Randomized, Placebo-Controlled, Multicenter Phase II Study. Circulation journal : official journal of the Japanese Circulation Society , 84 (10), 1866–1874. https://doi.org/10.1253/circj.CJ-20-0438 Ogo, T., Shimokawahara, H., Kinoshita, H., Sakao, S., Abe, K., Matoba, S., Motoki, H., Takama, N., Ako, J., Ikeda, Y., Joho, S., Maki, H., Saeki, T., Sugano, T., Tsujino, I., Yoshioka, K., Shiota, N., Tanaka, S., Yamamoto, C., Tanabe, N., & Tatsumi, K. (2022). Selexipag for the treatment of chronic thromboembolic pulmonary hypertension. European Respiratory Journal, 60 (1), 2101694. https://doi.org/10.1183/13993003.01694-2021 Jaïs, X., Brenot, P., Bouvaist, H., Jevnikar, M., Canuet, M., Chabanne, C., Chaouat, A., Cottin, V., De Groote, P., Favrolt, N., Horeau-Langlard, D., Magro, P., Savale, L., Prévot, G., Renard, S., Sitbon, O., Parent, F., Trésorier, R., Tromeur, C., Piedvache, C., … Simonneau, G. (2022). Balloon pulmonary angioplasty versus riociguat for the treatment of inoperable chronic thromboembolic pulmonary hypertension (RACE): a multicentre, phase 3, open-label, randomised controlled trial and ancillary follow-up study. The Lancet. Respiratory medicine , 10 (10), 961–971. https://doi.org/10.1016/S2213-2600(22)00214-4 Kawakami, T., Matsubara, H., Shinke, T., Abe, K., Kohsaka, S., Hosokawa, K., Taniguchi, Y., Shimokawahara, H., Yamada, Y., Kataoka, M., Ogawa, A., Murata, M., Jinzaki, M., Hirata, K., Tsutsui, H., Sato, Y., & Fukuda, K. (2022). Balloon pulmonary angioplasty versus riociguat in inoperable chronic thromboembolic pulmonary hypertension (MR BPA): an open-label, randomised controlled trial. The Lancet. Respiratory medicine , 10 (10), 949–960. https://doi.org/10.1016/S2213-2600(22)00171-0 Additional Declarations The authors declare no competing interests. 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Subbiah","email":"","orcid":"","institution":"Montefiore St. luke's Cornwall","correspondingAuthor":false,"prefix":"","firstName":"Rajan","middleName":"K.","lastName":"Subbiah","suffix":""}],"badges":[],"createdAt":"2025-07-12 09:57:15","currentVersionCode":1,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-7107350/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7107350/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":86769839,"identity":"1e67ba8d-5aa5-4fcc-b2e2-d7ea261f1b47","added_by":"auto","created_at":"2025-07-15 11:36:14","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":136040,"visible":true,"origin":"","legend":"\u003cp\u003eNetwork geometry, network analysis and rank plots for pulmonary vascular resistance (PVR) and sensitivity analysis\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7107350/v1/af887fef47bf22ba65f74955.png"},{"id":86769854,"identity":"32e5dda1-377e-4ee8-92cf-ab6db645a54b","added_by":"auto","created_at":"2025-07-15 11:36:15","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":207493,"visible":true,"origin":"","legend":"\u003cp\u003eNetwork geometry, network analysis and rank plots for mean Right atrial pressure (mRAP) and \u0026nbsp;Network geometry, network analysis and rank plots for NT- proBNP\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7107350/v1/0d571be40c82392669812765.png"},{"id":86769842,"identity":"405f0448-e996-494b-b15a-7011a346eef1","added_by":"auto","created_at":"2025-07-15 11:36:14","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":177614,"visible":true,"origin":"","legend":"\u003cp\u003eNetwork geometry, network analysis and rank plots for mean pulmonary artery pressure (mPAP) and sensitivity analysis\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7107350/v1/f55b0c92bc9364143f65f28f.png"},{"id":86769840,"identity":"a523e29a-ca2a-4787-aa9d-73c10044d916","added_by":"auto","created_at":"2025-07-15 11:36:14","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":107778,"visible":true,"origin":"","legend":"\u003cp\u003eNetwork geometry, network analysis and rank plots for 6MWD(6 minute walking distance) and Network geometry, network analysis and rank plots for cardiac index (CI)\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-7107350/v1/13e50136e0506969518d75ac.png"},{"id":86769848,"identity":"dd37f878-2203-433a-920b-023448937cca","added_by":"auto","created_at":"2025-07-15 11:36:15","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":213232,"visible":true,"origin":"","legend":"\u003cp\u003eNetwork geometry, network analysis and rank plots for borg dyspnea index (BDI) and sensitivity analysis\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-7107350/v1/bff21390fbbe7cb2e3bb29f5.png"},{"id":86771483,"identity":"db0965a0-2a08-4629-82c6-8c61619a5067","added_by":"auto","created_at":"2025-07-15 11:52:23","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2235102,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7107350/v1/aeb1f92e-8ead-42b2-8cc3-0c9a64c3658a.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003eComparative Efficacy of Balloon Pulmonary Angioplasty and Pharmacological Therapies in Inoperable Chronic Thromboembolic Pulmonary Hypertension: A Network Meta-Analysis\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eChronic thromboembolic pulmonary hypertension (CTEPH) is a distinct form of pulmonary hypertension classified as \u003cstrong\u003eGroup 4 disease\u003c/strong\u003e. It arises when organised thrombo-emboli persists in the pulmonary arteries and triggers secondary small-vessel arteriopathy, inflammation, and progressive vascular remodelling, ultimately increasing pulmonary vascular resistance and overloading the right ventricle. [1]\u003c/p\u003e\n\u003cp\u003eAlthough CTEPH is considered rare, national registry data suggest an annual \u003cstrong\u003eincidence of\u0026nbsp;\u003c/strong\u003e3 to 5 cases/100,000 population. [2] \u0026nbsp;After an acute pulmonary embolism (PE) the cumulative risk of developing CTEPH is about 2.3% at 3 years. \u0026nbsp; \u0026nbsp;(https://www.ahajournals.org/doi/10.1161/JAHA.124.035997)[1]\u003c/p\u003e\n\u003cp\u003ePulmonary endarterectomy (PEA) remains the curative standard, yet up to \u003cstrong\u003e24-37% of patients are deemed inoperable\u003c/strong\u003e because of distal disease distribution, advanced comorbidity, or persistent pulmonary hypertension after surgery. [3] For these patients two therapeutic strategies have emerged:\u003c/p\u003e\n\u003cp\u003e1. \u003cstrong\u003eTargeted pharmacotherapy\u003c/strong\u003e\u0026mdash;notably the soluble guanylate-cyclase stimulator \u003cem\u003eriociguat\u003c/em\u003e, endothelin-receptor antagonists (bosentan, macitentan, ambrisentan), phosphodiesterase-5 inhibitors, and prostacyclin pathway agents such as \u003cem\u003eselexipag\u003c/em\u003e\u0026mdash;all shown to improve haemodynamics and functional capacity in phase II\u0026ndash;III trial.\u003c/p\u003e\n\u003cp\u003e2. \u003cstrong\u003eBalloon pulmonary angioplasty (BPA)\u003c/strong\u003e\u0026mdash;a percutaneous technique that mechanically dilates obstructed segmental branches. Randomised trials (RACE trial) demonstrate larger reductions in pulmonary vascular resistance with BPA than with riociguat, but at the cost of higher procedure-related complications.\u003c/p\u003e\n\u003cp\u003eDespite these advances, \u003cstrong\u003edirect head-to-head comparisons across the expanding array of medical and interventional options are lacking\u003c/strong\u003e, leaving clinicians without clear guidance on how best to sequence or combine therapies in inoperable CTEPH.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjective.\u003c/strong\u003e The present network meta-analysis will synthesise all randomised and prospective evidence to \u003cstrong\u003ecompare the relative efficacy and safety of pharmacological treatments and BPA in patients with inoperable or residual CTEPH\u003c/strong\u003e. By integrating both direct and indirect comparisons, the study aims to provide a hierarchised, evidence-based framework to inform personalised treatment selection and guideline development for this high-risk population.\u003c/p\u003e"},{"header":"Methods ","content":"\u003cp\u003eWe conducted a NMA following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses - network meta-analysis (PRISMA NMA) guidelines.\u003c/p\u003e\n\u003cp\u003eEligibility Criteria\u003c/p\u003e\n\u003cp\u003eTable 1 is the inclusion and exclusion Criteria:\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"594\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 192px;\"\u003e\n \u003cp\u003eInclusion Criteria\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 402px;\"\u003e\n \u003cp\u003eExclusion Criteria\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 192px;\"\u003e\n \u003cp\u003ea) Human Studies\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 402px;\"\u003e\n \u003cp\u003ea) Animal Studies\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 192px;\"\u003e\n \u003cp\u003eb) English Text\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 402px;\"\u003e\n \u003cp\u003eb) Non-English Texts\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 192px;\"\u003e\n \u003cp\u003ec) Full text\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 402px;\"\u003e\n \u003cp\u003ec) \u0026nbsp;case control, cohort , case series, reviews and meta- analysis\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 192px;\"\u003e\n \u003cp\u003ed) RCT ( \u0026nbsp;randomized control trials )\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 402px;\"\u003e\n \u003cp\u003ed) non full text\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eSearch Strategy and Study selection\u003c/p\u003e\n\u003cp\u003eA comprehensive search was conducted on PubMed, Google scholar, science direct, Cochrane, plosone and clinical trials.gov using the keywords \u0026ldquo;inoperable\u0026rdquo; and \u0026ldquo;chronic thromboembolic, pulmonary hypertension\u0026rdquo;,upto November 2024. Table 2 describes search strategies. The articles were imported onto Rayyan AI from each of the above databases. Two investigators reviewed identified titles and abstracts independently, after which complete texts of eligible articles were obtained. Any disagreement between the reviewers was resolved by discussion with a third member of the investigator team.\u003c/p\u003e\n\u003cp\u003eRisk of bias assessment:\u003c/p\u003e\n\u003cp\u003eThe Cochrane risk-of-bias (ROB2 criteria) tool for randomized controlled trials (RCTs) was used to rate the quality of the articles.\u003c/p\u003e\n\u003cp\u003eData extraction\u003c/p\u003e\n\u003cp\u003eTwo investigators read each article and performed data extraction independently. Any disagreements were resolved by consultation with a third reviewer.\u003c/p\u003e\n\u003cp\u003eData on study characteristics were summarized (e.g., first author, publication year), patient characteristics [age, sex, Previous PEA (%) and baseline PVR (dyn\u0026middot;s\u0026middot;cm 5), 6MWD (m), WHO classification, Cardiac Index (l\u0026middot;min 1\u0026middot;m 2), mPAP (mm Hg), mRAP ((mm Hg), Borg Dyspnea Index, NT - proBNP (ng/l) ]and outcome measures.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOutcomes measured\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePulmonary vascular resistance, six minute walking distance, NT -proBNP, mean pulmonary artery pressure, mean right atrial pressure, Borg dyspnea index, cardiac index.\u003c/p\u003e\n\u003cp\u003eNetwork Structure\u003c/p\u003e\n\u003cp\u003eThe network consisted of seven treatments (Ambrisentan, Bosentan, Macitentan, Riociguat, Selexipag, Sildenafil, and Placebo) across seven studies. All treatments were directly compared to Placebo, forming a star-shaped network with limited connections between active treatments. This structure precluded comprehensive inconsistency assessment due to the absence of closed loops of evidence.\u003c/p\u003e\n\u003cp\u003eData Analysis\u003c/p\u003e\n\u003cp\u003eA network meta-analysis was conducted using the R package netmeta (version 2024.12.1+563), which implements frequentist methods based on a graph-theoretical approach. The analysis was performed on contrast-based data, with treatment effects expressed as mean differences (MD) and corresponding standard errors (SE). Both fixed-effect and random-effects models were fitted, with Placebo considered as the reference treatment for all comparisons.\u003c/p\u003e\n\u003cp\u003eHeterogeneity Assessment\u003c/p\u003e\n\u003cp\u003eHeterogeneity across studies was quantified using several complementary measures. The between-study variance was estimated using the DerSimonian-Laird method and reported as \u0026tau;\u0026sup2;, with its corresponding standard deviation \u0026tau;. The proportion of observed variance reflecting real differences in effect size was assessed using I\u0026sup2; statistics, calculated as I\u0026sup2; = 100% \u0026times; (Q-df)/Q, where Q represents Cochran\u0026apos;s homogeneity test statistic and df the degrees of freedom. The 95% confidence intervals for I\u0026sup2; were calculated using the test-based method to indicate uncertainty in heterogeneity estimates.\u003c/p\u003e\n\u003cp\u003eInconsistency Analysis\u003c/p\u003e\n\u003cp\u003eTo assess the validity of the transitivity assumption, global inconsistency was evaluated using the design-by-treatment interaction model implemented in the netcomb function. This method simultaneously considers both heterogeneity and inconsistency between different studies by comparing the consistency model with an unrelated mean effects model.\u003c/p\u003e\n\u003cp\u003eLocal inconsistency was planned to be assessed using node-splitting analysis (netsplit function), which compares direct and indirect evidence for each treatment comparison where both sources of evidence are available. However, due to the star-shaped structure of the network with Placebo as the common comparator, no indirect evidence was available for node-splitting analysis.\u003c/p\u003e\n\u003cp\u003eAdditionally, deviance contribution plots were intended to identify specific studies contributing disproportionately to network inconsistency; however, these plots could not be generated due to technical limitations in plotting arguments, and their utility was limited by the absence of multi-arm studies or closed loops in the network.\u003c/p\u003e\n\u003cp\u003eVisualization\u003c/p\u003e\n\u003cp\u003eAll analyses were performed using R software (version 2024.12.1+563) with the\u0026nbsp;netmeta\u0026nbsp;package. Results were visualized using network graphs depicting the geometry of the treatment network, with node sizes proportional to the number of participants receiving each treatment and edge widths proportional to the number of studies directly comparing treatments.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eTable 1. Baseline Clinical Characteristics of Included Studies\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"554\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eStudy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIntervention\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eN\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge (years)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 29px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMales (n, %)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 39px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePrevious PEA (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 49px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePVR (dyn\u0026middot;s\u0026middot;cm⁻⁵)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e6MWD (m)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 45px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eWHO FC (I/II/III/IV)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCardiac Index (L\u0026middot;min⁻\u0026sup1;\u0026middot;m⁻\u0026sup2;)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e\u003cstrong\u003emPAP (mmHg)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e\u003cstrong\u003emRAP (mmHg)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 39px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBorg Dyspnea Index\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNT-proBNP (ng/L)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eJa\u0026iuml;s et al. 2008 [\u003c/strong\u003e\u003cstrong\u003e4\u003c/strong\u003e\u003cstrong\u003e]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBosentan\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e77\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e63.0 \u0026plusmn; 12.9\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 29px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e18 (23.4)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 39px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e28.6\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 49px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e778 \u0026plusmn; 323\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e340 \u0026plusmn; 85\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 45px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026mdash;/22/51/3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e2.24 \u0026plusmn; 0.54\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e44.2 \u0026plusmn; 10.4\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e8.3 \u0026plusmn; 6.1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 39px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e4.4 \u0026plusmn; 2.0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1,481 \u0026plusmn; 1,833\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePlacebo\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e80\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e63.1 \u0026plusmn; 10.3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 29px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e33 (41.3)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 39px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e27.5\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 49px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e787 \u0026plusmn; 333\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e345 \u0026plusmn; 83\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 45px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026mdash;/22/56/2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e2.35 \u0026plusmn; 0.55\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e47.4 \u0026plusmn; 12.5\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e8.4 \u0026plusmn; 6.0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 39px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e4.1 \u0026plusmn; 2.3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1,405 \u0026plusmn; 1,882\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSuntharalingam et al. 2008 [\u003c/strong\u003e\u003cstrong\u003e5\u003c/strong\u003e\u003cstrong\u003e]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSildenafil\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e9\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e49.9 \u0026plusmn; 13.1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 29px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e2 (22.2)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 39px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e22\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 49px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e814 \u0026plusmn; 385\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e331 \u0026plusmn; 50\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 45px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026mdash;/3/6/\u0026mdash;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e2.2 \u0026plusmn; 0.6\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e45.8 \u0026plusmn; 8.0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e7.4 \u0026plusmn; 3.4\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 39px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026mdash;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1,301 \u0026plusmn; 1,393\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePlacebo\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e10\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e60.0 \u0026plusmn; 14.4\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 29px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e7 (70.0)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 39px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e70\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 49px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e654 \u0026plusmn; 342\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e347 \u0026plusmn; 66\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 45px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026mdash;/8/2/\u0026mdash;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e2.2 \u0026plusmn; 0.4\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e42.7 \u0026plusmn; 10.1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e6.9 \u0026plusmn; 4.3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 39px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026mdash;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e788 \u0026plusmn; 842\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGhofrani et al. 2024 [\u003c/strong\u003e\u003cstrong\u003e6\u003c/strong\u003e\u003cstrong\u003e]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMacitentan\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e40\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e58.2 \u0026plusmn; 14.0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 29px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e14 (35.0)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 39px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026mdash;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 49px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e934 \u0026plusmn; 394\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e353 \u0026plusmn; 88\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 45px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026mdash;/12/28/0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e2.2 \u0026plusmn; 0.53\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e49.9 \u0026plusmn; 11.7\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e9.3 \u0026plusmn; 5.7\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 39px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e4.2 \u0026plusmn; 2.5\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e2,204 \u0026plusmn; 2,943\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePlacebo\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e40\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e56.9 \u0026plusmn; 13.9\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 29px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e15 (37.5)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 39px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026mdash;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 49px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e988 \u0026plusmn; 490\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e351 \u0026plusmn; 74\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 45px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026mdash;/6/33/1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e2.2 \u0026plusmn; 0.61\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e51.7 \u0026plusmn; 14.1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e8.7 \u0026plusmn; 5.2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 39px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e4.2 \u0026plusmn; 2.1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1,793 \u0026plusmn; 2,075\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eKim et al. 2016 [\u003c/strong\u003e\u003cstrong\u003e7\u003c/strong\u003e\u003cstrong\u003e]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRiociguat\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e173\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e59 \u0026plusmn; 14\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 29px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e55 (31.8)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 39px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e30\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 49px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e791 \u0026plusmn; 432\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e342 \u0026plusmn; 82\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 45px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e3/55/107/8\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e2.3 \u0026plusmn; 0.7\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e47 \u0026plusmn; 13\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e8.3 \u0026plusmn; 5.3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 39px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026mdash;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026mdash;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePlacebo\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e88\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e59 \u0026plusmn; 13\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 29px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e34 (38.6)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 39px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e23\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 49px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e779 \u0026plusmn; 401\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e356 \u0026plusmn; 75\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 45px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0/25/60/2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e2.2 \u0026plusmn; 0.7\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e47 \u0026plusmn; 9\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e9.2 \u0026plusmn; 6.1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 39px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026mdash;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026mdash;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEscribano-Subias et al. 2019 [\u003c/strong\u003e\u003cstrong\u003e8\u003c/strong\u003e\u003cstrong\u003e]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAmbrisentan\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e15\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e63 \u0026plusmn; 8\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 29px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e9 (60.0)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 39px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026mdash;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 49px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026mdash;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026mdash;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 45px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026mdash;/\u0026mdash;/\u0026mdash;/\u0026mdash;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026mdash;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026mdash;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026mdash;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 39px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026mdash;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026mdash;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePlacebo\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e8\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e59 \u0026plusmn; 8\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 29px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e6 (75.0)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 39px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026mdash;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 49px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026mdash;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026mdash;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 45px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026mdash;/\u0026mdash;/\u0026mdash;/\u0026mdash;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026mdash;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026mdash;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026mdash;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 39px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026mdash;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026mdash;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTanabe et al. 2020 [\u003c/strong\u003e\u003cstrong\u003e9\u003c/strong\u003e\u003cstrong\u003e]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSelexipag\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e25\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e58 \u0026plusmn; 15\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 29px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e8 (32.0)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 39px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e12\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 49px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e700 \u0026plusmn; 302\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e378 \u0026plusmn; 77\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 45px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0/13/11/1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e2.4 \u0026plusmn; 0.5\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e41.1 \u0026plusmn; 11.7\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e5.4 \u0026plusmn; 3.3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 39px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026mdash;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e402 \u0026plusmn; 490\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePlacebo\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e9\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e60 \u0026plusmn; 5\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 29px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e2 (22.2)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 39px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e11.1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 49px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e756 \u0026plusmn; 303\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e355 \u0026plusmn; 114\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 45px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0/5/3/1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e2.5 \u0026plusmn; 0.8\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e41.6 \u0026plusmn; 8.5\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e5.1 \u0026plusmn; 3.3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 39px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026mdash;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1,231 \u0026plusmn; 1,601\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOgo et al. 2022 [\u003c/strong\u003e\u003cstrong\u003e10\u003c/strong\u003e\u003cstrong\u003e]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSelexipag\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e39\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e66.3 \u0026plusmn; 11.1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 29px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e10 (25.6)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 39px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e12.8\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 49px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e523 \u0026plusmn; 133\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e408 \u0026plusmn; 91\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 45px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1/23/15/0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e2.69 \u0026plusmn; 0.60\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e35.2 \u0026plusmn; 5.4\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e5.5 \u0026plusmn; 3.2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 39px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e3.26 \u0026plusmn; 1.75\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e592 \u0026plusmn; 928\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePlacebo\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e39\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e68.3 \u0026plusmn; 9.6\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 29px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e10 (25.6)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 39px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e12.8\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 49px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e553 \u0026plusmn; 184\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e384 \u0026plusmn; 87\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 45px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e2/26/11/0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e2.59 \u0026plusmn; 0.41\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e35.5 \u0026plusmn; 8.3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e5.4 \u0026plusmn; 4.0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 39px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e2.90 \u0026plusmn; 1.99\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e512 \u0026plusmn; 710\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eJa\u0026iuml;s et al. 2022 [1\u003c/strong\u003e\u003cstrong\u003e1\u003c/strong\u003e\u003cstrong\u003e]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBPA\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e52\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e68.1 \u0026plusmn; 9.4\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 29px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e26 (50.0)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 39px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026mdash;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 49px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e767 \u0026plusmn; 251\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e380 \u0026plusmn; 103\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 45px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026mdash;/12/38/2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e2.3 \u0026plusmn; 0.5\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e46.5 \u0026plusmn; 8.4\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e8.7 \u0026plusmn; 3.9\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 39px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e3.7 \u0026plusmn; 1.6\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1,887 \u0026plusmn; 2,370\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRiociguat\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e53\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e66.8 \u0026plusmn; 10.5\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 29px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e26 (49.1)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 39px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026mdash;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 49px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e679 \u0026plusmn; 273\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e390 \u0026plusmn; 124\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 45px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026mdash;/10/43/0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e2.4 \u0026plusmn; 0.6\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e44.7 \u0026plusmn; 10.0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e8.0 \u0026plusmn; 3.4\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 39px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e3.2 \u0026plusmn; 1.7\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1,455 \u0026plusmn; 1,701\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eKawakami et al. 2022 [1\u003c/strong\u003e\u003cstrong\u003e2\u003c/strong\u003e\u003cstrong\u003e]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBPA\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e31\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e68.0 \u0026plusmn; 9.1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 29px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e7 (22.6)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 39px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026mdash;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 49px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e645 \u0026plusmn; 267\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e364 \u0026plusmn; 105\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 45px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0/9/22/0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026mdash;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e38.1 \u0026plusmn; 7.9\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e5.1 \u0026plusmn; 3.3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 39px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e3.85 \u0026plusmn; 2.50\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026mdash;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRiociguat\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e26\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e65.7 \u0026plusmn; 10.9\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 29px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e3 (11.5)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 39px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026mdash;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 49px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e565 \u0026plusmn; 235\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e343 \u0026plusmn; 113\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 45px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0/9/15/0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026mdash;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 36px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 39px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eNetwork Meta-Analysis Overview\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis network meta-analysis evaluated the comparative efficacy of seven active treatments against placebo for chronic thromboembolic pulmonary hypertension (CTEPH). The analysis included\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eacross seven clinical outcomes. The number of included studies ranged from 6 to 9 depending on the specific outcome analyzed, with pairwise comparisons ranging from 6 to 9 per outcome.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePrimary Hemodynamic Outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePulmonary Vascular Resistance (PVR)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe random effects model analysis of PVR included 9 studies with 9 pairwise comparisons. BPA demonstrated the most substantial reduction in PVR compared to placebo (mean difference [MD]: -444.02 dynes\u0026middot;sec\u0026middot;cm⁻⁵, 95% CI: -606.99 to -281.05, p \u0026lt; 0.0001), achieving the highest SUCRA score of 0.9683. Riociguat showed significant efficacy (MD: -248.75, 95% CI: -381.67 to -115.83, p = 0.0002, SUCRA: 0.7156), followed by bosentan (MD: -176.00, 95% CI: -288.69 to -63.31, p = 0.0022, SUCRA: 0.5161). Macitentan demonstrated a trend toward significance (MD: -173.00, 95% CI: -347.23 to 1.23, p = 0.0516, SUCRA: 0.5191), while selexipag showed borderline significance (MD: -104.80, 95% CI: -211.56 to 1.97, p = 0.0544, SUCRA: 0.3371). Ambrisentan and sildenafil did not demonstrate significant PVR reduction (Figure 1).\u003c/p\u003e\n\u003cp\u003eThe analysis revealed substantial heterogeneity (I\u0026sup2; = 62.3% [0.0%; 89.2%], \u0026tau;\u0026sup2; = 3281.20), indicating considerable variability between studies. Sensitivity analysis excluding BPA studies showed reduced heterogeneity (I\u0026sup2; = 0%), suggesting BPA studies contributed to the observed heterogeneity.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMean Pulmonary Arterial Pressure (mPAP)\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;Figure 3\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAnalysis of mPAP included 9 studies with 9 pairwise comparisons. BPA achieved the greatest reduction in mPAP (MD: -16.17 mmHg, 95% CI: -20.42 to -11.93, p \u0026lt; 0.0001, SUCRA: 0.9996), followed by riociguat (MD: -5.07 mmHg, 95% CI: -8.52 to -1.62, p = 0.0040, SUCRA: 0.7719). Other treatments including bosentan, macitentan, selexipag, sildenafil, and ambrisentan did not demonstrate statistically significant reductions in mPAP. Moderate heterogeneity was observed (I\u0026sup2; = 52.9% [0.0%; 86.5%], \u0026tau;\u0026sup2; = 2.19).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMean Right Atrial Pressure (mRAP)\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;Figure 2\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe mRAP analysis encompassed 9 studies with 9 pairwise comparisons. Only BPA achieved a statistically significant reduction in mRAP (MD: -1.75 mmHg, 95% CI: -3.46 to -0.03, p = 0.0458, SUCRA: 0.8140)1. Macitentan showed a numerical but non-significant reduction (MD: -1.50 mmHg, 95% CI: -3.51 to 0.51, p = 0.1443, SUCRA: 0.7596). No heterogeneity was detected for this outcome (I\u0026sup2; = 0%).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunctional Capacity and Quality of Life Outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSix-Minute Walk Distance (6MWD)\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;Figure 4\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe 6MWD analysis included 9 studies with 9 pairwise comparisons. BPA demonstrated the greatest improvement in exercise capacity (MD: 53.08 meters, 95% CI: 25.46 to 80.69, p = 0.0002, SUCRA: 0.8751), followed by riociguat (MD: 44.40 meters, 95% CI: 19.76 to 69.04, p = 0.0004, SUCRA: 0.7787)1. Macitentan achieved a modest but significant improvement (MD: 34.00 meters, 95% CI: 1.02 to 66.98, p = 0.0433, SUCRA: 0.6640). Ambrisentan, sildenafil, bosentan, and selexipag did not demonstrate significant improvements in 6MWD. Low heterogeneity was observed (I\u0026sup2; = 13.2% [0.0%; 91.0%], \u0026tau;\u0026sup2; = 40.97).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBorg Dyspnea Index (BDI)\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;Figure 5\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe BDI analysis comprised 8 studies with 8 pairwise comparisons. None of the treatments achieved statistically significant improvements in dyspnea scores compared to placebo in the random effects model1. BPA showed the numerically greatest improvement (MD: -1.99 points, 95% CI: -4.66 to 0.68, p = 0.1443, SUCRA: 0.7617), followed by ambrisentan (MD: -1.50 points, 95% CI: -3.79 to 0.79, p = 0.1998, SUCRA: 0.6503). High heterogeneity was present (I\u0026sup2; = 89.3% [60.2%; 97.1%], \u0026tau;\u0026sup2; = 1.13), which eliminated significance in the random effects model despite significant effects observed in the common effects model.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCardiac Function and Biomarker Outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCardiac Index (CI)\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;Figure 4\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe CI analysis included 9 studies with 9 pairwise comparisons and demonstrated no heterogeneity (I\u0026sup2; = 0%). Multiple treatments showed significant improvements: macitentan (MD: 0.50 L/min/m\u0026sup2;, 95% CI: 0.27 to 0.73, p \u0026lt; 0.0001, SUCRA: 0.7707), selexipag (MD: 0.49 L/min/m\u0026sup2;, 95% CI: 0.28 to 0.70, p \u0026lt; 0.0001, SUCRA: 0.7483), riociguat (MD: 0.46 L/min/m\u0026sup2;, 95% CI: 0.31 to 0.61, p \u0026lt; 0.0001, SUCRA: 0.7181), and BPA (MD: 0.24 L/min/m\u0026sup2;, 95% CI: 0.01 to 0.47, p = 0.0398, SUCRA: 0.3533)1. Bosentan showed a trend toward significance (MD: 0.30 L/min/m\u0026sup2;, 95% CI: -0.02 to 0.62, p = 0.0661, SUCRA: 0.4613).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eN-Terminal Pro-B-Type Natriuretic Peptide (NT-proBNP)\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;Figure 2\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe NT-proBNP analysis encompassed 8 studies with 8 pairwise comparisons. BPA achieved the most substantial reduction (MD: -1479.04 pg/mL, 95% CI: -2308.99 to -649.09, p = 0.0005, SUCRA: 0.9806), followed by bosentan (MD: -600.00 pg/mL, 95% CI: -1190.78 to -9.22, p = 0.0465, SUCRA: 0.7103). Other treatments including riociguat, macitentan, sildenafil, ambrisentan, and selexipag did not achieve statistical significance. Moderate heterogeneity was observed (I\u0026sup2; = 35%, \u0026tau;\u0026sup2; = 44606.85)1.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTreatment Ranking and Comparative Efficacy\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBased on SUCRA (Surface Under the Cumulative Ranking Curve) scores, BPA consistently ranked highest across most outcomes, achieving the best efficacy profile for PVR (0.9683), 6MWD (0.8751), NT-proBNP (0.9806), mRAP (0.8140), and mPAP (0.9996)1. Riociguat demonstrated consistent efficacy across multiple outcomes with high SUCRA scores for PVR (0.7156), 6MWD (0.7787), CI (0.7181), and mPAP (0.7719). Among the pharmacological therapies, macitentan and selexipag showed particular strength in cardiac index improvement, while bosentan demonstrated efficacy in hemodynamic parameters and NT-proBNP reduction.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHeterogeneity Assessment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHeterogeneity varied considerably across outcomes. Low heterogeneity (I\u0026sup2; \u0026lt; 25%) was observed for cardiac index and mean right atrial pressure, indicating consistent treatment effects across studies1. Moderate heterogeneity (I\u0026sup2; 25-75%) was present for 6MWD, NT-proBNP, and mPAP outcomes. High heterogeneity (I\u0026sup2; \u0026gt; 75%) was noted for PVR and BDI, suggesting substantial variation in treatment effects between studies, which may be attributed to differences in study populations, intervention protocols, or outcome measurement methods.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis network meta-analysis aims to compare effective chronic thromboembolic pulmonary hypertension treatments across key hemodynamic, functional, and biomarker outcomes in operable patients with underlying co existing medical conditions, surgically inaccessible distal arteries or patients with the risks of major surgery deemed to outweigh the potential benefit. [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/p\u003e\u003cp\u003eInterpretation of Results\u003c/p\u003e\u003cp\u003eThe study highlights the impact of BPA as most significant improvement across the board spectrum from lowering pressure in the pulmonary arteries via significant reduction in Pulmonary Vascular Resistance (PVR), Mean Pulmonary Arterial Pressure (mPAP), and Mean Right Atrial Pressure (mRAP) to improving exercise capacity (6MWD) and reducing a key biomarker of heart strain (NT-proBNP) by mechanically clearing clots that obstruct pulmonary arteries and improving blood flow. [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/p\u003e\u003cp\u003eWhile BPA is minimally invasive addressing the blockage directly, medical therapies also play a crucial role in inoperable cases of PTEH. Riociguat is the second most effective treatment to BPA, in improving pulmonary pressures and exercise distance, significantly improving the cardiac index. The riociguat directly stimulates soluble guanylate cyclase (sGC), causing relaxation of vascular smooth muscle, enhancing vascular blood flow in inoperable patients. [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/p\u003e\u003cp\u003eWhile other medication shows promising results, such as Macitentan and Selexipag acts on endothelin and prostacyclin pathways improving cardiac index to enhance heart function and Bosentan significantly reducing pulmonary vascular resistance and NT- pro BNP levels. Few medications such as Ambrisentan and Sildenafil demonstrated no significant advantage over placebo for most outcomes. This medication has a teratogenic effect and is to be avoided in female patients of reproductive age groups or pregnant females and in patients with underlying chronic liver disease. [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/p\u003e\u003cp\u003eThe patients demonstrated physiological benefits with minimal to no improvement in Borg Dyspnea Index (BDI), due to the study variability for measurement outcome of dyspnea in high heterogeneity studies. This finding raises important questions about the alignment between objective hemodynamic gains and patient-perceived symptom relief. The lack of improvement in BDI may reflect limitations in measurement sensitivity, heterogeneity in baseline symptoms, or insufficient follow-up duration. These results underscore the need to include standardized patient-reported outcome measures in future CTEPH trials. [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/p\u003e\u003cp\u003eThe study findings show exceptional performance of BPA in numerous observational studies as an already established vital treatment for inoperable CTEPH, often achieving outcomes comparable to pulmonary endarterectomy. This network analysis strengthens the evidence of Riociguat reinforced in landmark CHEST-1 and PATENT-1 pivotal trials demonstrating its efficacy in CTEPH over other oral therapies.\u003c/p\u003e\u003cp\u003eThe findings also highlight the need for comprehensive outcome monitoring in clinical practice, given the multidimensional nature of treatment effects. For example, improvements in hemodynamics may not always translate into perceptible relief in dyspnea scores, emphasizing the role of serial assessment using functional, hemodynamic, and biomarker endpoints.\u003c/p\u003e\u003cp\u003eLimitations\u003c/p\u003e\u003cp\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003eThis study has several important limitations such as selection bias, as small samples may not adequately represent the broader PAH population; reporting bias, as limited use of inferential statistics increases the risk of selective reporting of favorable outcomes; and attrition bias, due to missing efficacy data that may distort treatment effects if not properly accounted for. Despite these limitations, inclusion of the AMBER trial was justified by its unique focus on ambrisentan for chronic thromboembolic pulmonary hypertension (CTEPH)\u0026mdash;a condition with relatively few available therapies\u0026mdash;offering insights of potential clinical value.\u003c/span\u003e\u003c/p\u003e\u003cp\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003eSecond, the SELEXIPAG trials and the MERIT\u0026minus;1 trial included patients with inoperable CTEPH who were already receiving concomitant pulmonary vasodilators, provided doses remained stable. While this reflects real-world treatment conditions, it may confound the true independent effect of selexipag, making it difficult to isolate its efficacy in this subgroup.\u003c/span\u003e\u003c/p\u003e\u003cp\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003eThird, the absence of trials directly comparing individual agents head to head limits the precision of relative treatment rankings. Although the network meta-analytic approach integrates both direct and indirect evidence to estimate comparative effectiveness, the lack of direct comparisons may constrain confidence in definitive treatment hierarchies.\u003c/span\u003e\u003c/p\u003e\u003cp\u003eFuture Directions\u003c/p\u003e\u003cp\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003eFuture research should focus on clinical trials, particularly between agents with high SUCRA rankings such as Bosentan and Riociguat. Moreover, studies incorporating longer follow-up periods and endpoints such as quality of life, hospitalization rates, and survival would provide a more comprehensive assessment of therapeutic value. Given the underrepresentation of older adults and women in PAH trials, targeted investigations in these populations are also warranted.\u003c/span\u003e\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis network meta-analysis demonstrates that balloon pulmonary angioplasty provides the most robust and consistent improvements in hemodynamics, exercise capacity, and biomarkers for patients with inoperable or residual CTEPH, supporting its role as a first-line intervention. Despite these advances, the lack of direct head-to-head comparisons and observed heterogeneity in some outcomes highlight the need for further research to refine treatment sequencing and combination strategies. Future studies should focus on long-term outcomes, standardized patient-reported measures, and the inclusion of underrepresented populations. These findings emphasizes the importance of individualized, multidisciplinary care and ongoing evaluation to optimize patient outcomes and advance guideline development for this high-risk group.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eMedrek S, Safdar Z. Epidemiology and Pathophysiology of Chronic Thromboembolic Pulmonary Hypertension: Risk Factors and Mechanisms. Methodist Debakey Cardiovasc J. 2016 Oct-Dec;12(4):195-198. doi: 10.14797/mdcj-12-4-195. PMID: 28289493; PMCID: PMC5344468.\u003c/li\u003e\n\u003cli\u003eSabbula, B. R., \u0026amp; Sankari, A. (2024). Chronic thromboembolic pulmonary hypertension. In \u003cem\u003eStatPearls\u003c/em\u003e. StatPearls Publishing. Retrieved July 6, 2025, from https://www.ncbi.nlm.nih.gov/books/NBK549836/12\u003c/li\u003e\n\u003cli\u003eKurzyna, P., Witowicz, A., Kędzierski, P., Florczyk, M., Banaszkiewicz, M., Szwed, P., Piłka, M., Gąsecka, A., Pietrasik, A., Torbicki, A., Kurzyna, M., \u0026amp; Darocha, S. (2025). Sex-Specific Differences in Chronic Thromboembolic Pulmonary Hypertension Treated with Balloon Pulmonary Angioplasty. \u003cem\u003eJournal of Clinical Medicine\u003c/em\u003e, \u003cem\u003e14\u003c/em\u003e(3), 899.https://doi.org/10.3390/jcm14030899\u003c/li\u003e\n\u003cli\u003eLang, I. M., \u0026amp; Madani, M. (2014). Update on chronic thromboembolic pulmonary hypertension. \u003cem\u003eCirculation\u003c/em\u003e, \u003cem\u003e130\u003c/em\u003e(6), 508\u0026ndash;518.https://doi.org/10.1161/CIRCULATIONAHA.114.009309\u003c/li\u003e\n\u003cli\u003eSugiyama, K., Suzuki, S., Maruno, K., Fujiyoshi, T., Koizumi, N., \u0026amp; Ogino, H. (2019). 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Chronic thromboembolic pulmonary hypertension. \u003cem\u003eCirculation\u003c/em\u003e, \u003cem\u003e113\u003c/em\u003e(16), 2011\u0026ndash;2020. https://doi.org/10.1161/CIRCULATIONAHA.105.602565\u003c/li\u003e\n\u003cli\u003eGhofrani, H.-A., D\u0026apos;Armini, A. M., Grimminger, F., Hoeper, M. M., Jansa, P., Kim, N. H., Mayer, E., Simonneau, G., Wilkins, M. R., Fritsch, A., Neuser, D., Weimann, G., \u0026amp; Wang, C., for the CHEST-1 Study Group. (2013). Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. \u003cem\u003eThe New England Journal of Medicine, 369\u003c/em\u003e(4), 319\u0026ndash;329. https://doi.org/10.1056/NEJMoa1209657\u003c/li\u003e\n\u003cli\u003eJa\u0026iuml;s, X., D\u0026apos;Armini, A. M., Jansa, P., Torbicki, A., Delcroix, M., Ghofrani, H. A., Hoeper, M. M., Lang, I. M., Mayer, E., Pepke-Zaba, J., Perchenet, L., Morganti, A., Simonneau, G., Rubin, L. J., \u0026amp; Bosentan Effects in iNopErable Forms of chronIc Thromboembolic pulmonary hypertension Study Group (2008). 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. \u003cem\u003eJournal of the American College of Cardiology\u003c/em\u003e, \u003cem\u003e52\u003c/em\u003e(25), 2127\u0026ndash;2134. https://doi.org/10.1016/j.jacc.2008.08.059\u003c/li\u003e\n\u003cli\u003eSuntharalingam, J., Treacy, C. M., Doughty, N. J., Goldsmith, K., Soon, E., Toshner, M. R., Sheares, K. K., Hughes, R., Morrell, N. W., \u0026amp; Pepke-Zaba, J. (2008). Long-term use of sildenafil in inoperable chronic thromboembolic pulmonary hypertension. \u003cem\u003eChest\u003c/em\u003e, \u003cem\u003e134\u003c/em\u003e(2), 229\u0026ndash;236. https://doi.org/10.1378/chest.07-2681\u003c/li\u003e\n\u003cli\u003eGhofrani, H. A., Simonneau, G., D\u0026apos;Armini, A. M., Fedullo, P., Howard, L. S., Ja\u0026iuml;s, X., Jenkins, D. P., Jing, Z. C., Madani, M. M., Martin, N., Mayer, E., Papadakis, K., Richard, D., Kim, N. H., \u0026amp; MERIT study investigators (2024). Macitentan for the treatment of inoperable chronic thromboembolic pulmonary hypertension (MERIT-1): results from the multicentre, phase 2, randomised, double-blind, placebo-controlled study. \u003cem\u003eThe Lancet. Respiratory medicine\u003c/em\u003e, \u003cem\u003e12\u003c/em\u003e(4), e21\u0026ndash;e30. https://doi.org/10.1016/S2213-2600(24)00027-4\u003c/li\u003e\n\u003cli\u003eKim NH, D\u0026apos;Armini AM, Grimminger F, Gr\u0026uuml;nig E, Hoeper MM, Jansa P, Mayer E, Neurohr C, Simonneau G, Torbicki A, Wang C, Fritsch A, Davie N, Ghofrani HA. Haemodynamic effects of riociguat in inoperable/recurrent chronic thromboembolic pulmonary hypertension. Heart. 2017 Apr;103(8):599-606. doi: 10.1136/heartjnl-2016-309621. Epub 2016 Dec 23. PMID: 28011757; PMCID: PMC5529957.\u003c/li\u003e\n\u003cli\u003eEscribano-Subias P, Bendjenana H, Curtis PS, Lang I, Vonk Noordegraaf A. Ambrisentan for treatment of inoperable chronic thromboembolic pulmonary hypertension (CTEPH). Pulm Circ. 2019 Apr-Jun;9(2):2045894019846433. doi: 10.1177/2045894019846433. PMID: 30957635; PMCID: PMC6540507.\u003c/li\u003e\n\u003cli\u003eTanabe, N., Fukuda, K., Matsubara, H., Nakanishi, N., Tahara, N., Ikeda, S., Kishi, T., Satoh, T., Hirata, K. I., Inoue, T., Kimura, H., Okano, Y., Okazaki, O., Sata, M., Tsujino, I., Ueno, S., Yamada, N., Yao, A., \u0026amp; Kuriyama, T. (2020). Selexipag for Chronic Thromboembolic Pulmonary Hypertension in Japanese Patients - A Double-Blind, Randomized, Placebo-Controlled, Multicenter Phase II Study. \u003cem\u003eCirculation journal : official journal of the Japanese Circulation Society\u003c/em\u003e, \u003cem\u003e84\u003c/em\u003e(10), 1866\u0026ndash;1874. https://doi.org/10.1253/circj.CJ-20-0438\u003c/li\u003e\n\u003cli\u003eOgo, T., Shimokawahara, H., Kinoshita, H., Sakao, S., Abe, K., Matoba, S., Motoki, H., Takama, N., Ako, J., Ikeda, Y., Joho, S., Maki, H., Saeki, T., Sugano, T., Tsujino, I., Yoshioka, K., Shiota, N., Tanaka, S., Yamamoto, C., Tanabe, N., \u0026amp; Tatsumi, K. (2022). Selexipag for the treatment of chronic thromboembolic pulmonary hypertension. \u003cem\u003eEuropean Respiratory Journal, 60\u003c/em\u003e(1), 2101694. https://doi.org/10.1183/13993003.01694-2021\u003c/li\u003e\n\u003cli\u003eJa\u0026iuml;s, X., Brenot, P., Bouvaist, H., Jevnikar, M., Canuet, M., Chabanne, C., Chaouat, A., Cottin, V., De Groote, P., Favrolt, N., Horeau-Langlard, D., Magro, P., Savale, L., Pr\u0026eacute;vot, G., Renard, S., Sitbon, O., Parent, F., Tr\u0026eacute;sorier, R., Tromeur, C., Piedvache, C., \u0026hellip; Simonneau, G. (2022). Balloon pulmonary angioplasty versus riociguat for the treatment of inoperable chronic thromboembolic pulmonary hypertension (RACE): a multicentre, phase 3, open-label, randomised controlled trial and ancillary follow-up study. \u003cem\u003eThe Lancet. Respiratory medicine\u003c/em\u003e, \u003cem\u003e10\u003c/em\u003e(10), 961\u0026ndash;971. https://doi.org/10.1016/S2213-2600(22)00214-4\u003c/li\u003e\n\u003cli\u003eKawakami, T., Matsubara, H., Shinke, T., Abe, K., Kohsaka, S., Hosokawa, K., Taniguchi, Y., Shimokawahara, H., Yamada, Y., Kataoka, M., Ogawa, A., Murata, M., Jinzaki, M., Hirata, K., Tsutsui, H., Sato, Y., \u0026amp; Fukuda, K. (2022). Balloon pulmonary angioplasty versus riociguat in inoperable chronic thromboembolic pulmonary hypertension (MR BPA): an open-label, randomised controlled trial. \u003cem\u003eThe Lancet. Respiratory medicine\u003c/em\u003e, \u003cem\u003e10\u003c/em\u003e(10), 949\u0026ndash;960. https://doi.org/10.1016/S2213-2600(22)00171-0\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"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":"Balloon pulmonary angioplasty, Chronic thromboembolic pulmonary hypertension, Riociguat, Pulmonary hypertension","lastPublishedDoi":"10.21203/rs.3.rs-7107350/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7107350/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInoperable or residual chronic thromboembolic pulmonary hypertension treatment modalities remain challenging due to limited comparison of alternatives between BPA and pharmacological agents.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjective\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo compare the relative efficacy and safety of BPA and pharmacological treatments in patients with inoperable or residual CTEPH. By integrating both direct and indirect comparisons, the study aims to provide a hierarchised, evidence-based framework to inform personalised treatment selection and guideline development for this high-risk population.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA systematic search of major databases through November 2024 identified randomized trials evaluating BPA, Riociguat, endothelin receptor antagonists (Bosentan, Ambrisentan, Macitentan), PDE-5 inhibitors (Sildenafil), and prostacyclin analogs (Selexipag). Outcomes included pulmonary vascular resistance (PVR), mean pulmonary artery pressure (mPAP), cardiac index (CI), 6-minute walk distance (6MWD), NT-proBNP, and Borg Dyspnea Index (BDI). A frequentist random-effects model was applied using the netmeta R package.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNine studies with 839 participants were analyzed. BPA showed the greatest reduction in PVR (MD -444.02 dyn·s·cm⁻⁵, 95% CI -606.99 to -281.05) and mPAP (MD -16.17 mmHg), with the highest SUCRA scores across outcomes. Riociguat ranked second overall, improving PVR, 6MWD, and CI. Macitentan and selexipag significantly improved CI, while bosentan reduced NT-proBNP. Ambrisentan and sildenafil did not demonstrate significant benefits over placebo. High heterogeneity was observed for PVR and BDI outcomes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBallon Pulmonary Angioplasty (BPA) demonstrates the most robust and consistent improvements in hemodynamics as evidenced by PVR, mPAP and mRAP measurements as well in functional and biomarker improvements (6MWD and NT-proBNP) in patients with inoperable CTEPH while Riociguat remains the most effective pharmacologic agent, offering significant benefits across multiple domains including PVR, 6MWD, mPAP and CI. Macitentan and Selexipag showed promising improvements in cardiac output while Bosentan provided NT-proBNP and pVR benefit. Ambrisentan and Sildenafil did not demonstrate significant advantages over placebo in this population.\u003c/p\u003e\n\u003cp\u003eThese findings support BPA as the most effective intervention for inoperable CTEPH, with Riociguat as the preferred pharmacologic therapy. However, limited direct comparisons and heterogeneity in some endpoints warrant long-term outcome studies to refine treatment sequencing, combination strategies and the consideration for future head-to-head trials between advanced oral therapies and BPA.\u003c/p\u003e","manuscriptTitle":"Comparative Efficacy of Balloon Pulmonary Angioplasty and Pharmacological Therapies in Inoperable Chronic Thromboembolic Pulmonary Hypertension: A Network Meta-Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-15 11:36:09","doi":"10.21203/rs.3.rs-7107350/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":"5334613d-8905-43c4-9224-0d2e28396b48","owner":[],"postedDate":"July 15th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":51444100,"name":"Critical Care \u0026 Emergency Medicine"},{"id":51444101,"name":"Pulmonology"},{"id":51444102,"name":"Internal Medicine"}],"tags":[],"updatedAt":"2025-07-15T11:36:10+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-15 11:36:09","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7107350","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7107350","identity":"rs-7107350","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}