Haemodynamic and Clinical Impacts of Switching Phosphodiesterase-5 Inhibitors to Riociguat in Patients with Chronic Thromboembolic Pulmonary Hypertension (CTEPH) after Balloon Pulmonary Angioplasty (BPA) – A Prospective Cohort Study

Haemodynamic and Clinical Impacts of Switching Phosphodiesterase-5 Inhibitors to Riociguat in Patients with Chronic Thromboembolic Pulmonary Hypertension (CTEPH) after Balloon Pulmonary Angioplasty (BPA) – A Prospective Cohort Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Haemodynamic and Clinical Impacts of Switching Phosphodiesterase-5 Inhibitors to Riociguat in Patients with Chronic Thromboembolic Pulmonary Hypertension (CTEPH) after Balloon Pulmonary Angioplasty (BPA) – A Prospective Cohort Study Timothy Ho Him Kam, Kevin Ka Ho Kam, Michael Ka Lam Wong, Bryan Ping Yen Yan, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7275378/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 03 Jan, 2026 Read the published version in BMC Pulmonary Medicine → Version 1 posted 10 You are reading this latest preprint version Abstract Background For patients with chronic thromboembolic pulmonary hypertension (CTEPH), balloon pulmonary angioplasty (BPA) has been associated with superior reductions in mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance (PVR) when compared to riociguat. In patients with pulmonary arterial hypertension (PAH), greater clinical improvements were observed after switching from phosphodiesterase-5 inhibitors (PDE5i) to riociguat. However, the impact of transitioning from PDE5i to riociguat on pulmonary haemodynamics and functional outcomes after BPA remains unclear. Methods This prospective, open-label, single-arm, study enrolled CTEPH patients who remained symptomatic following BPA. After a 24-hour PDE5i washout period, patients were switched to riociguat. At week 26, primary outcomes assessed changes in haemodynamics including mPAP and PVR. Secondary endpoints evaluated cardiac index; functional status including WHO functional class, 6-minute walking distance (6MWD), REVEAL Lite 2 score; biochemical markers such as N-terminal prohormone of brain natriuretic peptide (NT-proBNP); and echocardiographic measurements of right-heart function. Treatment-related adverse events and clinical worsening were monitored throughout the study. Results From July 2024 to January 2025, 16 patients (mean age 62.3 ± 14.6 years; 75% female) were recruited, with 14 completing the 26-week follow-up. At week 26, significant reductions occurred in mPAP (-4.79 mmHg; Confidence Interval [CI] -8.05 to -1.52; p = 0.007) and PVR (-2.16 Wood units; CI -3.64 to -0.69; p = 0.007). Significant improvements were also noted in cardiac index, WHO functional class, 6MWD, REVEAL Lite 2 score and NT-proBNP levels. Echocardiographic measurements of right-heart function did not demonstrate significant improvement. Treatment-related adverse events were observed in 11 patients (68.75%). Clinical worsening occurred in four patients, including two deaths unrelated to treatment and two unplanned hospitalisations due to pulmonary hypertension. Conclusion In CTEPH patients after completion of BPA, replacing PDE5i with riociguat significantly enhanced pulmonary haemodynamics and functional capacity but was accompanied by a considerable risk of treatment-related adverse events. Trial registration: ClinicalTrials.gov Identifier NCT06715280 retrospectively registered on 26/11/2024. chronic thromboembolic pulmonary hypertension balloon pulmonary angioplasty riociguat Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Surgical pulmonary endarterectomy (PEA) is the preferred treatment for chronic thromboembolic pulmonary hypertension (CTEPH) patients with accessible pulmonary artery occlusions [ 1 , 2 ]. For those with inoperable CTEPH or persistent pulmonary hypertension after PEA, current treatment options include balloon pulmonary angioplasty (BPA) and medical therapies. Several medical therapies that target the microvascular aspects of pulmonary arterial hypertension (PAH), such as phosphodiesterase-5 inhibitors (PDE5is) and endothelin receptor antagonists (ERAs), have been used off-label in patients with inoperable CTEPH, as their effectiveness has not been proven through randomised controlled trials in this patient cohort [ 3 ]. Riociguat, a soluble guanylate cyclase stimulator (sGCs), is the first agent approved for treating symptomatic patients with inoperable CTEPH based on the results from the CHEST-1 trial, which showed that riociguat significantly reduced pulmonary vascular resistance and improved exercise capacity in patients with inoperable CTEPH or persistent/recurrent pulmonary hypertension after PEA [ 4 ]. Two clinical trials have demonstrated improvements in clinical parameters and biochemical markers after switching PDE5i to sGCs in selected patients with PAH who had an inadequate response to PDE5i [ 5 , 6 ]. While the application of this switching strategy in patients with CTEPH has not been validated in large clinical trials, a smaller prospective study [ 7 ] demonstrated the safety and effectiveness in reducing brain natriuretic peptide (BNP) levels with this approach. In addition to medical treatments, balloon pulmonary angioplasty (BPA) has emerged as a treatment option for patients with inoperable CTEPH or for those experiencing persistent or recurrent pulmonary hypertension after PEA [ 8 ]. Two randomised controlled trials comparing BPA with riociguat have demonstrated that BPA was associated with a greater reduction in mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance (PVR) in inoperable CTEPH patients [ 9 , 10 ]. However, it remains unclear whether switching from PDE5i to riociguat provides additional functional and haemodynamic benefits after the completion of BPA. Therefore, this study was designed to evaluate the safety and efficacy of switching from PDE5i to riociguat in patients with CTEPH who have completed BPA treatment. Methods Study Design This study was an investigator-initiated, prospective, open-label and single-centre cohort study. It was carried out in accordance with the principles of the Declaration of Helsinki, and written informed consent was obtained from all participating patients. Patient selection Patients with CTEPH, as defined by the ESC guideline [ 3 ], were recruited into this study if they fulfilled all of the following criteria: (1) Remained symptomatic with WHO functional class II or III after completion of balloon pulmonary angioplasty (BPA); (2) On stable and maximally tolerated dose of sildenafil for at least 6 weeks as monotherapy, or in combination with other pulmonary hypertension specific therapies; (3) No escalation in diuretic dosage within 30 days; and (4) No recent hospitalisation due to pulmonary hypertension or heart failure within 30 days. Patients were excluded from this study if they met any of the following criteria: (1) Use of nitrates or nitric oxide donors via any route of administration within 30 days; (2) Pregnant or breast-feeding women; (3) Renal impairment with glomerular filtration rate < 15mL/min/1.73 m 2 ; and (4) Child-Pugh C hepatic impairment. Study protocol This study consists of baseline evaluations, a 24-hour washout period for PDE5i, and a 26-week follow-up which consisted of an 8-week period for riociguat titration, and an 18-week maintenance phase. The overall study workflow is outlined in Fig. 1 . Riociguat (Bayer AG, Kaiser-Wilhelm-Allee, Leverkusen, Germany) was administered orally using a predefined dose titration regimen as follows: starting at 1 mg taken three times daily (TID), with incremental increases of 0.5 mg every two weeks (up to a maximum of 2.5 mg TID) if systolic blood pressure remained at or above 95 mmHg. Dose escalation occurred over an 8-week period. Concomitant use of other pulmonary hypertension-specific therapies such as ERAs at baseline was permitted. Study visits were arranged at baseline, then at weeks 2, 4, 6, 8, 16 and 26. Baseline measurements, including right heart catheterisation, echocardiogram, 6MWD, WHO functional class and NT-proBNP levels, were evaluated for each patient while on sildenafil. WHO functional class and NT-proBNP were assessed at every clinic visit. The 6MWD, along with the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL®) Lite 2 score, were evaluated at baseline, weeks 8, 16, and 26. Right heart catheterisation and echocardiogram were repeated at week 26. Safety and treatment-related adverse events were monitored throughout the study. All patients received standard medical care according to the latest treatment guidelines, and treatment escalations were permitted at the clinician's discretion. Outcome measures The primary endpoints of this study were the changes in mPAP and PVR from baseline to week 26. The secondary endpoints included the changes in cardiac index, WHO functional class, NT-proBNP levels, 6-minute walking distance (6MWD), REVEAL Lite 2 risk score, tricuspid regurgitation pressure gradient (TRPG) and tricuspid annular plane systolic excursion (TAPSE). Safety outcomes including treatment-related adverse events and clinical worsening were assessed throughout the study. Clinical worsening was defined as all-cause mortality, heart or lung transplantation, salvage PEA or BPA due to deterioration of the primary disease, unplanned hospitalisations related to pulmonary hypertension (PH), initiation of new PH treatments, a sustained decline of more than 15% from baseline or over 30% from the most recent measurement in 6MWD, persistent worsening of WHO functional class due to deterioration of the primary disease, symptoms or signs of right heart failure not responding to optimised oral diuretic therapy, with reference to the criteria of clinical worsening established in the CHEST-1 study of riociguat [ 4 ]. Statistical analysis All data for continuous variables were expressed as mean values ± standard deviation, and categorical variables were expressed as numbers with percentages. The Shapiro-Wilk test was used to assess the normality of continuous variables. The statistical significance of changes from baseline to week 26 was calculated using paired samples t -test with the calculation of 95% confidence intervals (CIs) for mPAP, PVR, cardiac index, 6MWD, NT-proBNP, TAPSE and TRPG. The statistical significance of the changes from baseline to week 26 in WHO functional class and REVEAL Lite 2 score was calculated using the Wilcoxon signed-rank test. If a patient passed away or withdrew from the study due to clinical worsening, their last available measurements were used for analysis whenever feasible. Results Baseline patient characteristics Between July 2024 and January 2025, 19 patients who completed BPA at our centre were screened, and 16 of them (mean age 62.3 ± 14.6 years; 75% female) were recruited. Three patients were excluded: two declined to participate, and one was asymptomatic. Baseline patient characteristics are summarised in Table 1 . At baseline, all patients were in WHO functional class III, and 11 patients (68.8%) required long-term oxygen therapy. The mean duration of prior sildenafil therapy was 33.6 months. Among 16 patients, 15 (93.8%) were on concomitant endothelin receptor antagonists (14 [87.5%] macitentan and 1 [6.3%] bosentan). Two patients were on triple therapy, with the addition of prostacyclin analogue or prostacyclin receptor agonist. The mean interval between the last BPA session and study enrolment was 10.8 months. Table 1 Patient baseline characteristics Baseline Characteristics N = 16 Age, years 62.3 ± 14.6 Sex Male 4 [25%] Female 12 [75%] BMI (Kg/m 2 ) 23.5 ± 4.2 SBP (mmHg) 113.6 ± 13.2 Heart rate (beats per minute) 82.9 ± 16.8 Long-term oxygen therapy 11 [68.8%] Treatment duration with sildenafil (months) 33.6 ± 22.7 Concomitant therapies ERA 15 [93.8%] Prostacyclin receptor agonist 1 [6.3%] Prostacyclin analogue 1 [6.3%] Diuretics 8 [50%] BPA procedural characteristics Number of BPA procedures 2.1 ± 1.5 Number of segmental pulmonary arteries undergone BPA 4.4 ± 3.1 Final BPA till enrolment (months) 10.8 ± 4.7 WHO functional class II 0 [0%] III 16 [100%] 6MWD (m) 236.9 ± 130.5 NT-proBNP (ng/L) 1370.2 ± 1853.0 REVEAL Lite 2 score (Out of 14) 7.3 ± 2.3 Echocardiographic parameters TRPG (mmHg) 61.7 ± 24 TAPSE (mm) 17.7 ± 3.8 Haemodynamics variables mPAP (mmHg) 45.2 ± 11.3 PVR (Wood units) 11.1 ± 5.8 CO (L/minute) 3.5 ± 1.1 Cardiac Index (L/minute/m 2 ) 2.2 ± 0.7 PAWP (mmHg) 11.4 ± 5.1 Data are presented as n [%] or mean ± SD BMI: body mass index; SBP: systolic blood pressure; ERA: endothelin receptor antagonist; WHO: World Health Organisation; BPA: Balloon pulmonary angioplasty; REVEAL: The Registry to Evaluate Early and Long-Term PAH Disease Management; TRPG: tricuspid regurgitation pressure gradient; TAPSE: tricuspid annular plane systolic excursion; 6MWD: 6-min walking distance; NT-proBNP: N-terminal prohormone of brain natriuretic peptide; mPAP: mean pulmonary arterial pressure; PVR: pulmonary vascular resistance; CO: cardiac output; PAWP: pulmonary artery wedge pressure Of the 16 patients enrolled in this study, 14 (87.5%) completed the 26-week follow-up. The trial profile is shown in Fig. 2 . The two discontinuations were due to mortality. At week 26, 12 patients (86%) reached the maximum dose of riociguat (2.5 mg TID), while the remaining two (14%) were maintained at 1.5 mg TID due to systemic hypotension. Primary endpoints Significant improvements were observed in the primary endpoints among the 14 patients who completed 26 weeks of treatment (Fig. 3 ). The mPAP decreased from baseline by 11.1% (absolute reduction − 4.79 ± 5.66 mmHg; 95% Confidence Interval, CI, -8.05 to -1.52; p = 0.007), and the mean PVR decreased by 20.8% (-2.16 ± 2.55 Wood units; 95% CI -3.64 to -0.69; p = 0.007). Secondary endpoints Changes in secondary endpoints from baseline to week 26 are summarised in Fig. 4. The WHO functional class showed significant improvement, with 5 patients (31.3%) achieving class I and 3 (18.8%) improving to class II. However, 6 patients (37.5%) remained in class III, while 2 (12.5%) deteriorated to class IV. The mean 6MWD significantly improved by 23.09 ± 35.35 m (95% CI 3.51 to 42.66; p = 0.024). NT-proBNP levels significantly reduced by 29.6% (-405.69 ± 740.80 ng/L; 95% CI − 800.43 to -10.94; p = 0.045). The cardiac index increased significantly by 16.7% (0.37 ± 0.59 L/min/m 2 ; 95% CI 0.03 to 0.71; p = 0.036). The mean REVEAL Lite 2 score (out of a total score of 14) decreased by 1.00 ± 1.69 (p = 0.042). The echocardiographic parameters also demonstrated improvement, but the changes did not reach statistical significance. The TAPSE increased by 14.7% (2.58 ± 5.89 mm; 95% CI -0.82 to + 5.98; p = 0.125), while the TRPG decreased by 18.5% (11.07 ± 25.04 mmHg; 95% CI -25.52 to + 3.39; p = 0.122). Clinical worsening Four patients experienced predefined clinical worsening events, including two deaths which were not treatment-related: one from pneumonia on day 53 and the other from subdural haematoma following a fall on day 159. Two patients experienced unplanned hospitalisations due to pulmonary hypertension. The first patient was admitted on day 105 due to a loss of consciousness, and the second patient was admitted on day 119 due to right heart failure. No patients required salvage PEA or BPA due to disease progression, nor did they need initiation of new PH therapies or escalation of existing treatments. Treatment-related adverse events 11 patients (68.75%) reported at least one treatment-related adverse drug event during the study. The most common adverse events included hypotension (n = 4; 25%), nasopharyngitis (n = 3; 18.75%), dyspepsia (n = 2; 12.5%) and vomiting (n = 2; 12.5%). The details of the adverse events are provided in Table 2 . Four adverse events resulted in temporary interruption of riociguat, but no permanent discontinuations occurred during the study. Table 2 Treatment-related adverse events N = 16 Treatment-related adverse events Total number of patients with 1 or more adverse events 11 (68.75%) Hypotension 4 (25%) Nasopharyngitis 3 (18.75%) Dyspepsia 2 (12.5%) Vomiting 2 (12.5%) Diarrhoea 1 (6.25%) Dizziness 1 (6.25%) Headache 1 (6.25%) Palpitations 1 (6.25%) Right ventricular failure 1 (6.25%) Peripheral oedema 0 (0%) Adverse events leading to the interruption of riociguat Any 4 (25%) Dyspepsia 1 (6.25%) Headache 1 (6.25%) Nasopharyngitis 1 (6.25%) Vomiting 1 (6.25%) Data are presented as n [%] Discussion This was the first study to evaluate the safety and efficacy of switching PDE5i to riociguat in patients with CTEPH following BPA. The transition from PDE5i to riociguat resulted in significant improvements in pulmonary haemodynamics, including reductions in mPAP and PVR, as well as favourable changes in cardiac biomarkers and functional capacities, such as WHO functional class and 6MWD. These findings are consistent with the results of the landmark CHEST-1 trial, which demonstrated that riociguat significantly improved PVR, NT-proBNP levels, 6MWD and WHO functional class in inoperable CTEPH patients [ 4 ]. Specifically, the CHEST-1 trial reported reductions in mPAP (4 ± 7 mmHg) and PVR (226 ± 248 dyn·s·cm − 5 or 2.83 ± 3.1 Wood units), comparable to the reductions observed in our study. Pulmonary hypertension is associated with endothelial dysfunction of the pulmonary vasculature and reduced expression of endothelial nitric oxide synthase, leading to diminished activation of the soluble guanylate cyclase (sGC) pathway and subsequent pulmonary vasoconstriction [ 11 ]. The pathophysiology of CTEPH involves obstructive fibrotic thrombi in the pulmonary arteries [ 12 ], along with microvasculopathy, including plexiform lesions, a feature also seen in PAH [ 13 ]. Given this shared pathology, medical therapies that are approved for PAH, such as PDE5i, have been used off-label in CTEPH. Nevertheless, this off-label treatment in inoperable CTEPH only holds a Class IIB recommendation from the current ESC guideline [ 3 ], because clinical evidence supporting their efficacy in CTEPH remains limited. The existing evidence for the use of sildenafil includes a small randomised controlled trial involving 19 CTEPH patients, which showed that sildenafil improved PVR and WHO functional class but not exercise capacity [ 14 ]. In contrast, riociguat has shown significant reductions in PVR and improvements in exercise capacity in both PAH (PATENT-1 trial) and inoperable CTEPH (CHEST-1 trial) [ 4 , 15 ]. While both PDE5i and riociguat operate through the same nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) pathway to promote pulmonary vasodilation, they target different molecular mechanisms. PDE5i works by inhibiting the breakdown of cGMP, thereby prolonging the actions of cGMP to promote smooth muscle relaxation [ 16 ]. In contrast, riociguat offers a dual mechanism of action that includes direct stimulation of sGC and sensitisation of sGC to endogenous NO, resulting in smooth muscle relaxation and pulmonary vasodilation [ 17 ]. The mechanisms of action of both PDE5i and riociguat are summarised in Fig. 5 . Given this pharmacological advantage, replacing PDE5i with riociguat has emerged as a potential therapeutic strategy in PAH and CTEPH. In the present study, patients who had sildenafil for a mean duration of 33.6 months and completed BPA showed significant improvements in haemodynamics and exercise capacity after switching to riociguat. These findings strengthen the evidence that transitioning from PDE5i to riociguat provides clinical benefits for CTEPH patients. Despite demonstrating efficacy in improving haemodynamic and functional parameters, riociguat treatment was associated with a considerable adverse drug events (ADEs) burden in our study population. In this study, 11 patients (68.75%) experienced at least one ADE, aligning with the known safety profile of riociguat (69–92% adverse event incidence) established in the CHEST-1, MR BPA and RACE trials [ 4 , 9 , 10 ]. While headache (15–25%) and dizziness (17–23%) were most prevalent in these landmark studies, our cohort exhibited a different adverse event pattern characterised by higher rates of hypotension (25%) and nasopharyngitis (18.75%). This discrepancy likely reflects differences in patient characteristics, particularly the fact that 93.8% of our patients received concomitant pulmonary vasodilator therapy (ERAs or prostacyclin analogues), and this group of patients were excluded from the landmark trials. In this study, the incidence of clinical worsening was higher than the 2 to 6% range reported in the major riociguat trials, including CHEST-1, MR BPA and RACE [ 4 , 9 , 10 ]. We attributed these disparities to the differences in baseline disease severity, as our cohort consisted exclusively of WHO functional class III patients with a mean intermediate-high REVEAL Lite 2 score of 7.3. Additionally, our patients demonstrated worse haemodynamics, with a mean baseline PVR of 11.1 Wood units and a cardiac output of 3.5L/min, compared to 7.1–9.9 Wood units and 4-4.6 L/min in the riociguat groups of those landmark studies. The more advanced state of CTEPH at baseline likely explains the higher incidence of clinical worsening observed in our study. An important finding of this study was that despite significant improvements in haemodynamics and functional capacity, improvements in TAPSE and TRPG were not significant – a result consistent with a retrospective study of 11 Asian CTEPH patients, where riociguat significantly improved mPAP, PVR and WHO functional class but failed to demonstrate significant improvements in TRPG or tricuspid regurgitation grading [ 18 ]. It has been proposed that the elevated PVR in CTEPH leads to maladaptive remodelling of the right ventricle, and treatment strategies that reduce the afterload of the right ventricle are less effective in reversing the maladaptive remodelling of the right ventricle [ 19 ]. Our findings therefore suggest that while riociguat effectively reduced the afterload of the right ventricle as evidenced by PVR improvement, it may have limited capacity to reverse the established remodelling of the right ventricle. It has been proposed that riociguat may complement BPA for CTEPH patients by targeting the microvasculopathy which cannot be addressed by BPA [ 9 ], formal recommendations regarding additional benefits of initiating riociguat either before or after BPA are currently lacking. The RACE trial ancillary 26-week follow-up study found that 6-month riociguat pretreatment reduced subsequent BPA complication rates by two-thirds (14% versus 42%) compared to upfront BPA, likely through hemodynamic optimisation before the procedure [ 10 ]. This finding suggested that riociguat pretreatment improved the safety profile of subsequent BPA in the management of CTEPH. On the other hand, evidence supporting the use of riociguat following BPA includes a randomised trial of 21 post-BPA CTEPH patients showed that riociguat significantly improved cardiac output and PVR at peak workload compared to controls [ 20 ]. The RACE trial ancillary study also showed that riociguat provided additional PVR reduction when added after suboptimal haemodynamic response to initial BPA [ 10 ]. Our study contributes to this evidence by demonstrating that switching from PDE5i to riociguat after the completion of BPA further improved both pulmonary haemodynamics and exercise capacity in patients with CTEPH. Limitations This study has several important limitations that should be acknowledged. Firstly, the single-arm design without a control group introduced potential observer bias and could not account for placebo effects. Secondly, the single-centre design may limit the generalisability of the findings to broader populations. Thirdly, the small sample size limited the assessment of treatment response predictors and the detection of rare adverse events. These limitations highlight the need for larger, multicentre and randomised controlled trials to validate the findings of this study. Conclusion In patients with CTEPH, switching from PDE5i to riociguat improved pulmonary haemodynamics and functional capacity after BPA treatment. However, these benefits were accompanied by significant treatment-related adverse events, highlighting the need for careful risk-benefit assessment in clinical practice. Abbreviations 6MWD 6-min walking distance BNP Brain natriuretic peptide BPA Balloon pulmonary angioplasty cGMP Cyclic guanosine monophosphate CI Confidence interval ERA Endothelin receptor antagonist mPAP Mean pulmonary arterial pressure NO Nitric oxide NT-proBNP N-terminal prohormone of brain natriuretic peptide PAH Pulmonary arterial hypertension PAWP Pulmonary artery wedge pressure PDE5i Phosphodiesterase type 5 inhibitor PEA Pulmonary endarterectomy PVR Pulmonary vascular resistance REVEAL Registry to Evaluate Early and Long-Term PAH Disease Management SD Standard deviation sGCs Soluble guanylate cyclase stimulator TAPSE Tricuspid annular plane systolic excursion TRPG Tricuspid regurgitation pressure gradient WHO World Health Organisation Declarations Ethics approval and consent to participate This study was approved by the Joint Chinese University of Hong Kong-New Territories East Cluster Clinical Research Ethics Committee (Ref: 2023.577). Written informed consent to participate in the study was obtained from all participating patients. Consent for publication Written informed consent was obtained from all participating patients for the publication of their details. Availability of data and materials The datasets analysed during the current study have been deposited in the UK data service that is accessible using the following link: https://doi.org/10.5255/UKDA-SN-857898 Competing interests The authors declare that they have no competing interests. Funding No funding was received for this study. Authors' contributions Timothy Kam (TK) drafted the main manuscript text and prepared all figures and tables. Guangming Tan (GT) and Bryan Yan (BY) conceived and designed the study. GT and TK developed the study protocol, including the inclusion and exclusion criteria. TK, GT, Michael Wong (MW) and Kevin Kam (KK) were responsible for participant recruitment and follow-up throughout the study. 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Cite Share Download PDF Status: Published Journal Publication published 03 Jan, 2026 Read the published version in BMC Pulmonary Medicine → Version 1 posted Editorial decision: Revision requested 29 Sep, 2025 Reviews received at journal 21 Sep, 2025 Reviews received at journal 08 Sep, 2025 Reviewers agreed at journal 04 Sep, 2025 Reviewers agreed at journal 30 Aug, 2025 Reviewers invited by journal 27 Aug, 2025 Editor assigned by journal 20 Aug, 2025 Editor invited by journal 14 Aug, 2025 Submission checks completed at journal 13 Aug, 2025 First submitted to journal 13 Aug, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7275378","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":508910292,"identity":"dffcc9c8-a042-477b-81c1-bf627200a0dc","order_by":0,"name":"Timothy Ho Him Kam","email":"","orcid":"","institution":"Prince of Wales Hospital","correspondingAuthor":false,"prefix":"","firstName":"Timothy","middleName":"Ho Him","lastName":"Kam","suffix":""},{"id":508910293,"identity":"f4cce290-95c3-4398-8ce5-269f02e69442","order_by":1,"name":"Kevin Ka Ho Kam","email":"","orcid":"","institution":"Prince of Wales Hospital","correspondingAuthor":false,"prefix":"","firstName":"Kevin","middleName":"Ka Ho","lastName":"Kam","suffix":""},{"id":508910294,"identity":"0fd43048-0f98-4b4a-a2b7-f1131d25b6a7","order_by":2,"name":"Michael Ka Lam Wong","email":"","orcid":"","institution":"Grantham Hospital","correspondingAuthor":false,"prefix":"","firstName":"Michael","middleName":"Ka Lam","lastName":"Wong","suffix":""},{"id":508910295,"identity":"673ecff1-affd-42a6-9468-e7ab001abcca","order_by":3,"name":"Bryan Ping Yen Yan","email":"","orcid":"","institution":"The Chinese University of Hong Kong","correspondingAuthor":false,"prefix":"","firstName":"Bryan","middleName":"Ping Yen","lastName":"Yan","suffix":""},{"id":508910296,"identity":"891bd16e-26a5-420e-a0bc-b4a756847512","order_by":4,"name":"Guangming Tan","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAv0lEQVRIiWNgGAWjYLCCDwwMCRJAGogPGBBWzsbAwDiDZC3MPCRpkY9vfvbYpuZwnmQD88HbPAx3jAlqMTzGZm6cc+xwsTQDW7I1D8MzM8Ja2hjMpHMbDifOY+Axk+ZhOGxDhBb2b9KWYC3834jTIs8GNJwRqGU2Aw8bSAthhxmw5ZRJ9hxLT5zZzGZsOcfgMGHvyzcf3ybxo8Y6ccbx5oc33lQcNmwgaMsBGIsZzCVoB9AWgoaOglEwCkbBKAAAawg2gBGLeiYAAAAASUVORK5CYII=","orcid":"","institution":"The Chinese University of Hong Kong","correspondingAuthor":true,"prefix":"","firstName":"Guangming","middleName":"","lastName":"Tan","suffix":""}],"badges":[],"createdAt":"2025-08-02 04:23:12","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7275378/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7275378/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12890-025-04069-y","type":"published","date":"2026-01-03T15:58:36+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":90792293,"identity":"1616f322-67cb-4d02-bfe1-3aad43f2dbab","added_by":"auto","created_at":"2025-09-08 08:27:14","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":80933,"visible":true,"origin":"","legend":"\u003cp\u003eStudy workflow\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7275378/v1/3fbb1a4b4798fd5e20310495.png"},{"id":90792295,"identity":"31f41fd6-a08d-4c8c-8811-4d771d59463c","added_by":"auto","created_at":"2025-09-08 08:27:14","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":54814,"visible":true,"origin":"","legend":"\u003cp\u003eTrial profile. Among 16 patients enrolled, 14 (87.5%) completed the 26-week follow-up.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-7275378/v1/e78b9b5eab9aeeacc780b1f3.png"},{"id":90792291,"identity":"fa48abd2-adc6-4d5d-abad-0eee651b6b66","added_by":"auto","created_at":"2025-09-08 08:27:14","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":46924,"visible":true,"origin":"","legend":"\u003cp\u003eEffect of riociguat on primary endpoints: (a) mPAP and (b) PVR. Data are presented as mean ± SD\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-7275378/v1/d440cbf475e469c6bb6bca0d.png"},{"id":90792297,"identity":"228f5d3f-cc21-410f-b384-783a11b678f6","added_by":"auto","created_at":"2025-09-08 08:27:14","extension":"jpeg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":388409,"visible":true,"origin":"","legend":"\u003cp\u003eEffect of riociguat on secondary endpoints: (a) WHO Functional class; (b) 6MWD; (c) NT-proBNP; (d) Cardiac index; (e) REVEAL Lite 2 score; (f) TAPSE and (g) TRPG. Data are presented as mean ± SD\u003c/p\u003e","description":"","filename":"floatimage4.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7275378/v1/d9b5270af8d6a3ea3d281cfe.jpeg"},{"id":90792305,"identity":"73d81010-ac44-4527-af44-4f15a7189c0e","added_by":"auto","created_at":"2025-09-08 08:27:14","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":119403,"visible":true,"origin":"","legend":"\u003cp\u003eMechanism of actions of riociguat and PDE5 inhibitor. cGMP: cyclic guanosine monophosphate; GMP: guanosine monophosphate; GTP: guanosine triphosphate; NO: nitric oxide; sGC: soluble guanylate cyclase; PDE: phosphodiesterase\u003c/p\u003e","description":"","filename":"floatimage6.png","url":"https://assets-eu.researchsquare.com/files/rs-7275378/v1/29000f488261eb35300aa506.png"},{"id":99545393,"identity":"07b77a41-654d-475a-95cd-a8ce52a882f8","added_by":"auto","created_at":"2026-01-05 16:07:00","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1252294,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7275378/v1/e68e1f0e-120a-471f-9987-4c1f0fd0fa7d.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Haemodynamic and Clinical Impacts of Switching Phosphodiesterase-5 Inhibitors to Riociguat in Patients with Chronic Thromboembolic Pulmonary Hypertension (CTEPH) after Balloon Pulmonary Angioplasty (BPA) – A Prospective Cohort Study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eSurgical pulmonary endarterectomy (PEA) is the preferred treatment for chronic thromboembolic pulmonary hypertension (CTEPH) patients with accessible pulmonary artery occlusions [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. For those with inoperable CTEPH or persistent pulmonary hypertension after PEA, current treatment options include balloon pulmonary angioplasty (BPA) and medical therapies. Several medical therapies that target the microvascular aspects of pulmonary arterial hypertension (PAH), such as phosphodiesterase-5 inhibitors (PDE5is) and endothelin receptor antagonists (ERAs), have been used off-label in patients with inoperable CTEPH, as their effectiveness has not been proven through randomised controlled trials in this patient cohort [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Riociguat, a soluble guanylate cyclase stimulator (sGCs), is the first agent approved for treating symptomatic patients with inoperable CTEPH based on the results from the CHEST-1 trial, which showed that riociguat significantly reduced pulmonary vascular resistance and improved exercise capacity in patients with inoperable CTEPH or persistent/recurrent pulmonary hypertension after PEA [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eTwo clinical trials have demonstrated improvements in clinical parameters and biochemical markers after switching PDE5i to sGCs in selected patients with PAH who had an inadequate response to PDE5i [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. While the application of this switching strategy in patients with CTEPH has not been validated in large clinical trials, a smaller prospective study [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] demonstrated the safety and effectiveness in reducing brain natriuretic peptide (BNP) levels with this approach.\u003c/p\u003e\u003cp\u003eIn addition to medical treatments, balloon pulmonary angioplasty (BPA) has emerged as a treatment option for patients with inoperable CTEPH or for those experiencing persistent or recurrent pulmonary hypertension after PEA [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Two randomised controlled trials comparing BPA with riociguat have demonstrated that BPA was associated with a greater reduction in mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance (PVR) in inoperable CTEPH patients [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. However, it remains unclear whether switching from PDE5i to riociguat provides additional functional and haemodynamic benefits after the completion of BPA. Therefore, this study was designed to evaluate the safety and efficacy of switching from PDE5i to riociguat in patients with CTEPH who have completed BPA treatment.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eStudy Design\u003c/p\u003e\u003cp\u003eThis study was an investigator-initiated, prospective, open-label and single-centre cohort study. It was carried out in accordance with the principles of the Declaration of Helsinki, and written informed consent was obtained from all participating patients.\u003c/p\u003e\u003cp\u003ePatient selection\u003c/p\u003e\u003cp\u003ePatients with CTEPH, as defined by the ESC guideline [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], were recruited into this study if they fulfilled all of the following criteria: (1) Remained symptomatic with WHO functional class II or III after completion of balloon pulmonary angioplasty (BPA); (2) On stable and maximally tolerated dose of sildenafil for at least 6 weeks as monotherapy, or in combination with other pulmonary hypertension specific therapies; (3) No escalation in diuretic dosage within 30 days; and (4) No recent hospitalisation due to pulmonary hypertension or heart failure within 30 days.\u003c/p\u003e\u003cp\u003ePatients were excluded from this study if they met any of the following criteria: (1) Use of nitrates or nitric oxide donors via any route of administration within 30 days; (2) Pregnant or breast-feeding women; (3) Renal impairment with glomerular filtration rate\u0026thinsp;\u0026lt;\u0026thinsp;15mL/min/1.73 m\u003csup\u003e2\u003c/sup\u003e; and (4) Child-Pugh C hepatic impairment.\u003c/p\u003e\u003cp\u003eStudy protocol\u003c/p\u003e\u003cp\u003eThis study consists of baseline evaluations, a 24-hour washout period for PDE5i, and a 26-week follow-up which consisted of an 8-week period for riociguat titration, and an 18-week maintenance phase. The overall study workflow is outlined in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003cp\u003eRiociguat (Bayer AG, Kaiser-Wilhelm-Allee, Leverkusen, Germany) was administered orally using a predefined dose titration regimen as follows: starting at 1 mg taken three times daily (TID), with incremental increases of 0.5 mg every two weeks (up to a maximum of 2.5 mg TID) if systolic blood pressure remained at or above 95 mmHg. Dose escalation occurred over an 8-week period. Concomitant use of other pulmonary hypertension-specific therapies such as ERAs at baseline was permitted.\u003c/p\u003e\u003cp\u003eStudy visits were arranged at baseline, then at weeks 2, 4, 6, 8, 16 and 26. Baseline measurements, including right heart catheterisation, echocardiogram, 6MWD, WHO functional class and NT-proBNP levels, were evaluated for each patient while on sildenafil. WHO functional class and NT-proBNP were assessed at every clinic visit. The 6MWD, along with the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL\u0026reg;) Lite 2 score, were evaluated at baseline, weeks 8, 16, and 26. Right heart catheterisation and echocardiogram were repeated at week 26. Safety and treatment-related adverse events were monitored throughout the study. All patients received standard medical care according to the latest treatment guidelines, and treatment escalations were permitted at the clinician's discretion.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eOutcome measures\u003c/p\u003e\u003cp\u003eThe primary endpoints of this study were the changes in mPAP and PVR from baseline to week 26. The secondary endpoints included the changes in cardiac index, WHO functional class, NT-proBNP levels, 6-minute walking distance (6MWD), REVEAL Lite 2 risk score, tricuspid regurgitation pressure gradient (TRPG) and tricuspid annular plane systolic excursion (TAPSE).\u003c/p\u003e\u003cp\u003eSafety outcomes including treatment-related adverse events and clinical worsening were assessed throughout the study. Clinical worsening was defined as all-cause mortality, heart or lung transplantation, salvage PEA or BPA due to deterioration of the primary disease, unplanned hospitalisations related to pulmonary hypertension (PH), initiation of new PH treatments, a sustained decline of more than 15% from baseline or over 30% from the most recent measurement in 6MWD, persistent worsening of WHO functional class due to deterioration of the primary disease, symptoms or signs of right heart failure not responding to optimised oral diuretic therapy, with reference to the criteria of clinical worsening established in the CHEST-1 study of riociguat [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e\u003cdiv id=\"Sec2\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eAll data for continuous variables were expressed as mean values\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation, and categorical variables were expressed as numbers with percentages. The Shapiro-Wilk test was used to assess the normality of continuous variables. The statistical significance of changes from baseline to week 26 was calculated using paired samples \u003cem\u003et\u003c/em\u003e-test with the calculation of 95% confidence intervals (CIs) for mPAP, PVR, cardiac index, 6MWD, NT-proBNP, TAPSE and TRPG. The statistical significance of the changes from baseline to week 26 in WHO functional class and REVEAL Lite 2 score was calculated using the Wilcoxon signed-rank test. If a patient passed away or withdrew from the study due to clinical worsening, their last available measurements were used for analysis whenever feasible.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eBaseline patient characteristics\u003c/p\u003e\u003cp\u003eBetween July 2024 and January 2025, 19 patients who completed BPA at our centre were screened, and 16 of them (mean age 62.3\u0026thinsp;\u0026plusmn;\u0026thinsp;14.6 years; 75% female) were recruited. Three patients were excluded: two declined to participate, and one was asymptomatic. Baseline patient characteristics are summarised in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. At baseline, all patients were in WHO functional class III, and 11 patients (68.8%) required long-term oxygen therapy. The mean duration of prior sildenafil therapy was 33.6 months. Among 16 patients, 15 (93.8%) were on concomitant endothelin receptor antagonists (14 [87.5%] macitentan and 1 [6.3%] bosentan). Two patients were on triple therapy, with the addition of prostacyclin analogue or prostacyclin receptor agonist. The mean interval between the last BPA session and study enrolment was 10.8 months.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003ePatient baseline characteristics\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"2\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBaseline Characteristics\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eN\u0026thinsp;=\u0026thinsp;16\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge, years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e62.3\u0026thinsp;\u0026plusmn;\u0026thinsp;14.6\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSex\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4 [25%]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e12 [75%]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBMI (Kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e23.5\u0026thinsp;\u0026plusmn;\u0026thinsp;4.2\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSBP (mmHg)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e113.6\u0026thinsp;\u0026plusmn;\u0026thinsp;13.2\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHeart rate (beats per minute)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e82.9\u0026thinsp;\u0026plusmn;\u0026thinsp;16.8\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLong-term oxygen therapy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e11 [68.8%]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTreatment duration with sildenafil (months)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e33.6\u0026thinsp;\u0026plusmn;\u0026thinsp;22.7\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eConcomitant therapies\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eERA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e15 [93.8%]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eProstacyclin receptor agonist\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1 [6.3%]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eProstacyclin analogue\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1 [6.3%]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDiuretics\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8 [50%]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBPA procedural characteristics\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNumber of BPA procedures\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.1\u0026thinsp;\u0026plusmn;\u0026thinsp;1.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNumber of segmental pulmonary arteries undergone BPA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4.4\u0026thinsp;\u0026plusmn;\u0026thinsp;3.1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFinal BPA till enrolment (months)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e10.8\u0026thinsp;\u0026plusmn;\u0026thinsp;4.7\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eWHO functional class\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eII\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0 [0%]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIII\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e16 [100%]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e6MWD (m)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e236.9\u0026thinsp;\u0026plusmn;\u0026thinsp;130.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNT-proBNP (ng/L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1370.2\u0026thinsp;\u0026plusmn;\u0026thinsp;1853.0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eREVEAL Lite 2 score (Out of 14)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7.3\u0026thinsp;\u0026plusmn;\u0026thinsp;2.3\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEchocardiographic parameters\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTRPG (mmHg)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e61.7\u0026thinsp;\u0026plusmn;\u0026thinsp;24\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTAPSE (mm)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e17.7\u0026thinsp;\u0026plusmn;\u0026thinsp;3.8\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHaemodynamics variables\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003emPAP (mmHg)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e45.2\u0026thinsp;\u0026plusmn;\u0026thinsp;11.3\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePVR (Wood units)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e11.1\u0026thinsp;\u0026plusmn;\u0026thinsp;5.8\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCO (L/minute)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3.5\u0026thinsp;\u0026plusmn;\u0026thinsp;1.1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCardiac Index (L/minute/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.2\u0026thinsp;\u0026plusmn;\u0026thinsp;0.7\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePAWP (mmHg)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e11.4\u0026thinsp;\u0026plusmn;\u0026thinsp;5.1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eData are presented as n [%] or mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\u003cp\u003eBMI: body mass index; SBP: systolic blood pressure; ERA: endothelin receptor antagonist; WHO: World Health Organisation; BPA: Balloon pulmonary angioplasty; REVEAL: The Registry to Evaluate Early and Long-Term PAH Disease Management; TRPG: tricuspid regurgitation pressure gradient; TAPSE: tricuspid annular plane systolic excursion; 6MWD: 6-min walking distance; NT-proBNP: N-terminal prohormone of brain natriuretic peptide; mPAP: mean pulmonary arterial pressure; PVR: pulmonary vascular resistance; CO: cardiac output; PAWP: pulmonary artery wedge pressure\u003c/p\u003e\u003cp\u003eOf the 16 patients enrolled in this study, 14 (87.5%) completed the 26-week follow-up. The trial profile is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. The two discontinuations were due to mortality. At week 26, 12 patients (86%) reached the maximum dose of riociguat (2.5 mg TID), while the remaining two (14%) were maintained at 1.5 mg TID due to systemic hypotension.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003ePrimary endpoints\u003c/p\u003e\u003cp\u003eSignificant improvements were observed in the primary endpoints among the 14 patients who completed 26 weeks of treatment (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). The mPAP decreased from baseline by 11.1% (absolute reduction \u0026minus;\u0026thinsp;4.79\u0026thinsp;\u0026plusmn;\u0026thinsp;5.66 mmHg; 95% Confidence Interval, CI, -8.05 to -1.52; p\u0026thinsp;=\u0026thinsp;0.007), and the mean PVR decreased by 20.8% (-2.16\u0026thinsp;\u0026plusmn;\u0026thinsp;2.55 Wood units; 95% CI -3.64 to -0.69; p\u0026thinsp;=\u0026thinsp;0.007).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eSecondary endpoints\u003c/p\u003e\u003cp\u003eChanges in secondary endpoints from baseline to week 26 are summarised in Fig.\u0026nbsp;4. The WHO functional class showed significant improvement, with 5 patients (31.3%) achieving class I and 3 (18.8%) improving to class II. However, 6 patients (37.5%) remained in class III, while 2 (12.5%) deteriorated to class IV. The mean 6MWD significantly improved by 23.09\u0026thinsp;\u0026plusmn;\u0026thinsp;35.35 m (95% CI 3.51 to 42.66; p\u0026thinsp;=\u0026thinsp;0.024). NT-proBNP levels significantly reduced by 29.6% (-405.69\u0026thinsp;\u0026plusmn;\u0026thinsp;740.80 ng/L; 95% CI \u0026minus;\u0026thinsp;800.43 to -10.94; p\u0026thinsp;=\u0026thinsp;0.045). The cardiac index increased significantly by 16.7% (0.37\u0026thinsp;\u0026plusmn;\u0026thinsp;0.59 L/min/m\u003csup\u003e2\u003c/sup\u003e; 95% CI 0.03 to 0.71; p\u0026thinsp;=\u0026thinsp;0.036). The mean REVEAL Lite 2 score (out of a total score of 14) decreased by 1.00\u0026thinsp;\u0026plusmn;\u0026thinsp;1.69 (p\u0026thinsp;=\u0026thinsp;0.042).\u003c/p\u003e\u003cp\u003eThe echocardiographic parameters also demonstrated improvement, but the changes did not reach statistical significance. The TAPSE increased by 14.7% (2.58\u0026thinsp;\u0026plusmn;\u0026thinsp;5.89 mm; 95% CI -0.82 to +\u0026thinsp;5.98; p\u0026thinsp;=\u0026thinsp;0.125), while the TRPG decreased by 18.5% (11.07\u0026thinsp;\u0026plusmn;\u0026thinsp;25.04 mmHg; 95% CI -25.52 to +\u0026thinsp;3.39; p\u0026thinsp;=\u0026thinsp;0.122).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eClinical worsening\u003c/p\u003e\u003cp\u003eFour patients experienced predefined clinical worsening events, including two deaths which were not treatment-related: one from pneumonia on day 53 and the other from subdural haematoma following a fall on day 159. Two patients experienced unplanned hospitalisations due to pulmonary hypertension. The first patient was admitted on day 105 due to a loss of consciousness, and the second patient was admitted on day 119 due to right heart failure. No patients required salvage PEA or BPA due to disease progression, nor did they need initiation of new PH therapies or escalation of existing treatments.\u003c/p\u003e\u003cp\u003eTreatment-related adverse events\u003c/p\u003e\u003cp\u003e11 patients (68.75%) reported at least one treatment-related adverse drug event during the study. The most common adverse events included hypotension (n\u0026thinsp;=\u0026thinsp;4; 25%), nasopharyngitis (n\u0026thinsp;=\u0026thinsp;3; 18.75%), dyspepsia (n\u0026thinsp;=\u0026thinsp;2; 12.5%) and vomiting (n\u0026thinsp;=\u0026thinsp;2; 12.5%). The details of the adverse events are provided in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Four adverse events resulted in temporary interruption of riociguat, but no permanent discontinuations occurred during the study.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eTreatment-related adverse events\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"2\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eN\u0026thinsp;=\u0026thinsp;16\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eTreatment-related adverse events\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTotal number of patients with 1 or more adverse events\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e11 (68.75%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHypotension\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4 (25%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNasopharyngitis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3 (18.75%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDyspepsia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2 (12.5%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVomiting\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2 (12.5%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDiarrhoea\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1 (6.25%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDizziness\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1 (6.25%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHeadache\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1 (6.25%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePalpitations\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1 (6.25%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRight ventricular failure\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1 (6.25%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePeripheral oedema\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eAdverse events leading to the interruption of riociguat\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAny\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4 (25%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDyspepsia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1 (6.25%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHeadache\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1 (6.25%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNasopharyngitis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1 (6.25%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVomiting\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1 (6.25%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"2\"\u003eData are presented as n [%]\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis was the first study to evaluate the safety and efficacy of switching PDE5i to riociguat in patients with CTEPH following BPA. The transition from PDE5i to riociguat resulted in significant improvements in pulmonary haemodynamics, including reductions in mPAP and PVR, as well as favourable changes in cardiac biomarkers and functional capacities, such as WHO functional class and 6MWD. These findings are consistent with the results of the landmark CHEST-1 trial, which demonstrated that riociguat significantly improved PVR, NT-proBNP levels, 6MWD and WHO functional class in inoperable CTEPH patients [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Specifically, the CHEST-1 trial reported reductions in mPAP (4\u0026thinsp;\u0026plusmn;\u0026thinsp;7 mmHg) and PVR (226\u0026thinsp;\u0026plusmn;\u0026thinsp;248 dyn\u0026middot;s\u0026middot;cm\u003csup\u003e\u0026minus;\u0026thinsp;5\u003c/sup\u003e or 2.83\u0026thinsp;\u0026plusmn;\u0026thinsp;3.1 Wood units), comparable to the reductions observed in our study.\u003c/p\u003e\u003cp\u003ePulmonary hypertension is associated with endothelial dysfunction of the pulmonary vasculature and reduced expression of endothelial nitric oxide synthase, leading to diminished activation of the soluble guanylate cyclase (sGC) pathway and subsequent pulmonary vasoconstriction [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. The pathophysiology of CTEPH involves obstructive fibrotic thrombi in the pulmonary arteries [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], along with microvasculopathy, including plexiform lesions, a feature also seen in PAH [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Given this shared pathology, medical therapies that are approved for PAH, such as PDE5i, have been used off-label in CTEPH. Nevertheless, this off-label treatment in inoperable CTEPH only holds a Class IIB recommendation from the current ESC guideline [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], because clinical evidence supporting their efficacy in CTEPH remains limited. The existing evidence for the use of sildenafil includes a small randomised controlled trial involving 19 CTEPH patients, which showed that sildenafil improved PVR and WHO functional class but not exercise capacity [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. In contrast, riociguat has shown significant reductions in PVR and improvements in exercise capacity in both PAH (PATENT-1 trial) and inoperable CTEPH (CHEST-1 trial) [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. While both PDE5i and riociguat operate through the same nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) pathway to promote pulmonary vasodilation, they target different molecular mechanisms. PDE5i works by inhibiting the breakdown of cGMP, thereby prolonging the actions of cGMP to promote smooth muscle relaxation [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. In contrast, riociguat offers a dual mechanism of action that includes direct stimulation of sGC and sensitisation of sGC to endogenous NO, resulting in smooth muscle relaxation and pulmonary vasodilation [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. The mechanisms of action of both PDE5i and riociguat are summarised in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e5\u003c/span\u003e. Given this pharmacological advantage, replacing PDE5i with riociguat has emerged as a potential therapeutic strategy in PAH and CTEPH. In the present study, patients who had sildenafil for a mean duration of 33.6 months and completed BPA showed significant improvements in haemodynamics and exercise capacity after switching to riociguat. These findings strengthen the evidence that transitioning from PDE5i to riociguat provides clinical benefits for CTEPH patients.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eDespite demonstrating efficacy in improving haemodynamic and functional parameters, riociguat treatment was associated with a considerable adverse drug events (ADEs) burden in our study population. In this study, 11 patients (68.75%) experienced at least one ADE, aligning with the known safety profile of riociguat (69\u0026ndash;92% adverse event incidence) established in the CHEST-1, MR BPA and RACE trials [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. While headache (15\u0026ndash;25%) and dizziness (17\u0026ndash;23%) were most prevalent in these landmark studies, our cohort exhibited a different adverse event pattern characterised by higher rates of hypotension (25%) and nasopharyngitis (18.75%). This discrepancy likely reflects differences in patient characteristics, particularly the fact that 93.8% of our patients received concomitant pulmonary vasodilator therapy (ERAs or prostacyclin analogues), and this group of patients were excluded from the landmark trials.\u003c/p\u003e\u003cp\u003eIn this study, the incidence of clinical worsening was higher than the 2 to 6% range reported in the major riociguat trials, including CHEST-1, MR BPA and RACE [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. We attributed these disparities to the differences in baseline disease severity, as our cohort consisted exclusively of WHO functional class III patients with a mean intermediate-high REVEAL Lite 2 score of 7.3. Additionally, our patients demonstrated worse haemodynamics, with a mean baseline PVR of 11.1 Wood units and a cardiac output of 3.5L/min, compared to 7.1\u0026ndash;9.9 Wood units and 4-4.6 L/min in the riociguat groups of those landmark studies. The more advanced state of CTEPH at baseline likely explains the higher incidence of clinical worsening observed in our study.\u003c/p\u003e\u003cp\u003eAn important finding of this study was that despite significant improvements in haemodynamics and functional capacity, improvements in TAPSE and TRPG were not significant \u0026ndash; a result consistent with a retrospective study of 11 Asian CTEPH patients, where riociguat significantly improved mPAP, PVR and WHO functional class but failed to demonstrate significant improvements in TRPG or tricuspid regurgitation grading [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. It has been proposed that the elevated PVR in CTEPH leads to maladaptive remodelling of the right ventricle, and treatment strategies that reduce the afterload of the right ventricle are less effective in reversing the maladaptive remodelling of the right ventricle [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Our findings therefore suggest that while riociguat effectively reduced the afterload of the right ventricle as evidenced by PVR improvement, it may have limited capacity to reverse the established remodelling of the right ventricle.\u003c/p\u003e\u003cp\u003eIt has been proposed that riociguat may complement BPA for CTEPH patients by targeting the microvasculopathy which cannot be addressed by BPA [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], formal recommendations regarding additional benefits of initiating riociguat either before or after BPA are currently lacking. The RACE trial ancillary 26-week follow-up study found that 6-month riociguat pretreatment reduced subsequent BPA complication rates by two-thirds (14% versus 42%) compared to upfront BPA, likely through hemodynamic optimisation before the procedure [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. This finding suggested that riociguat pretreatment improved the safety profile of subsequent BPA in the management of CTEPH. On the other hand, evidence supporting the use of riociguat following BPA includes a randomised trial of 21 post-BPA CTEPH patients showed that riociguat significantly improved cardiac output and PVR at peak workload compared to controls [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. The RACE trial ancillary study also showed that riociguat provided additional PVR reduction when added after suboptimal haemodynamic response to initial BPA [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Our study contributes to this evidence by demonstrating that switching from PDE5i to riociguat after the completion of BPA further improved both pulmonary haemodynamics and exercise capacity in patients with CTEPH.\u003c/p\u003e\u003cp\u003eLimitations\u003c/p\u003e\u003cp\u003eThis study has several important limitations that should be acknowledged. Firstly, the single-arm design without a control group introduced potential observer bias and could not account for placebo effects. Secondly, the single-centre design may limit the generalisability of the findings to broader populations. Thirdly, the small sample size limited the assessment of treatment response predictors and the detection of rare adverse events. These limitations highlight the need for larger, multicentre and randomised controlled trials to validate the findings of this study.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn patients with CTEPH, switching from PDE5i to riociguat improved pulmonary haemodynamics and functional capacity after BPA treatment. However, these benefits were accompanied by significant treatment-related adverse events, highlighting the need for careful risk-benefit assessment in clinical practice.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003e6MWD\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;6-min walking distance\u003c/p\u003e\n\u003cp\u003eBNP\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Brain natriuretic peptide\u003c/p\u003e\n\u003cp\u003eBPA \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Balloon pulmonary angioplasty\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ecGMP\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Cyclic guanosine monophosphate\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCI \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Confidence interval\u003c/p\u003e\n\u003cp\u003eERA\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Endothelin receptor antagonist\u003c/p\u003e\n\u003cp\u003emPAP\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Mean pulmonary arterial pressure\u003c/p\u003e\n\u003cp\u003eNO\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Nitric oxide\u003c/p\u003e\n\u003cp\u003eNT-proBNP\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;N-terminal prohormone of brain natriuretic peptide\u003c/p\u003e\n\u003cp\u003ePAH \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Pulmonary arterial hypertension\u003c/p\u003e\n\u003cp\u003ePAWP \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Pulmonary artery wedge pressure\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePDE5i\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Phosphodiesterase type 5 inhibitor\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePEA \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Pulmonary endarterectomy\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePVR\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Pulmonary vascular resistance\u003c/p\u003e\n\u003cp\u003eREVEAL \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Registry to Evaluate Early and Long-Term PAH Disease Management\u003c/p\u003e\n\u003cp\u003eSD\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Standard deviation\u003c/p\u003e\n\u003cp\u003esGCs \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Soluble guanylate cyclase stimulator\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTAPSE\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Tricuspid annular plane systolic excursion\u003c/p\u003e\n\u003cp\u003eTRPG \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Tricuspid regurgitation pressure gradient\u003c/p\u003e\n\u003cp\u003eWHO \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; World Health Organisation\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eEthics approval and consent to participate\u003c/h2\u003e\n\u003cp\u003eThis study was approved by the Joint Chinese University of Hong Kong-New Territories East Cluster Clinical Research Ethics Committee (Ref: 2023.577). Written informed consent to participate in the study was obtained from all participating patients.\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eConsent for publication\u003c/h2\u003e\n\u003cp\u003eWritten informed consent was obtained from all participating patients for the publication of their details.\u003c/p\u003e\n\u003ch2\u003eAvailability of data and materials\u003c/h2\u003e\n\u003cp\u003eThe datasets analysed during the current study have been deposited in the UK data service that is accessible using the following link: https://doi.org/10.5255/UKDA-SN-857898\u003c/p\u003e\n\u003ch2\u003eCompeting interests\u003c/h2\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003ch2\u003eFunding\u003c/h2\u003e\n\u003cp\u003eNo funding was received for this study.\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eAuthors' contributions\u003c/h2\u003e\n\u003cp\u003eTimothy Kam (TK) drafted the main manuscript text and prepared all figures and tables. Guangming Tan (GT) and Bryan Yan (BY) conceived and designed the study. GT and TK developed the study protocol, including the inclusion and exclusion criteria. TK, GT, Michael Wong (MW) and Kevin Kam (KK) were responsible for participant recruitment and follow-up throughout the study. GT, BY and TK performed balloon pulmonary angioplasty for all patients. GT made substantial revisions to the manuscript. All authors contributed to data analysis and interpretation, critically reviewed the manuscript, and approved the final submitted version.\u003c/p\u003e\n\u003ch2\u003eAcknowledgements\u003c/h2\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eMadani MM, Auger WR, Pretorius V, Sakakibara N, Kerr KM, Kim NH, et al. Pulmonary endarterectomy: recent changes in a single institution's experience of more than 2,700 patients. Ann Thorac Surg. 2012;94(1):97\u0026ndash;103.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMayer E, Jenkins D, Lindner J, D\u0026rsquo;armini A, Kloek J, Meyns B, et al. Surgical management and outcome of patients with chronic thromboembolic pulmonary hypertension: results from an international prospective registry. J Thorac Cardiovasc Surg. 2011;141(3):702\u0026ndash;10.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHumbert M, Kovacs G, Hoeper MM, Badagliacca R, Berger RMF, Brida M, et al. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: Developed by the task force for the diagnosis and treatment of pulmonary hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS). Endorsed by the International Society for Heart and Lung Transplantation (ISHLT) and the European Reference Network on rare respiratory diseases (ERN-LUNG). Eur Heart J. 2022;43(38):3618\u0026ndash;731.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGhofrani H-A, D'Armini AM, Grimminger F, Hoeper MM, Jansa P, Kim NH, et al. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med. 2013;369(4):319\u0026ndash;29.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHoeper MM, Al-Hiti H, Benza RL, Chang S-A, Corris PA, Gibbs JSR, et al. Switching to riociguat versus maintenance therapy with phosphodiesterase-5 inhibitors in patients with pulmonary arterial hypertension (REPLACE): a multicentre, open-label, randomised controlled trial. Lancet Respiratory Med. 2021;9(6):573\u0026ndash;84.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHoeper MM, Simonneau G, Corris PA, Ghofrani H-A, Klinger JR, Langleben D et al. RESPITE: switching to riociguat in pulmonary arterial hypertension patients with inadequate response to phosphodiesterase-5 inhibitors. Eur Respir J. 2017;50(3).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eYamamoto K, Tanabe N, Suda R, Sasaki A, Matsumura A, Ema R, et al. Riociguat for patients with chronic thromboembolic pulmonary hypertension: Usefulness of transitioning from phosphodiesterase type 5 inhibitor. Respiratory Invest. 2017;55(4):270\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDelcroix M, Torbicki A, Gopalan D, Sitbon O, Klok FA, Lang I et al. ERS statement on chronic thromboembolic pulmonary hypertension. Eur Respir J. 2021;57(6).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKawakami T, Matsubara H, Shinke T, Abe K, Kohsaka S, Hosokawa K, et al. Balloon pulmonary angioplasty versus riociguat in inoperable chronic thromboembolic pulmonary hypertension (MR BPA): an open-label, randomised controlled trial. Lancet Respiratory Med. 2022;10(10):949\u0026ndash;60.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJa\u0026iuml;s X, Brenot P, Bouvaist H, Jevnikar M, Canuet M, Chabanne C, et al. 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. Lancet Respiratory Med. 2022;10(10):961\u0026ndash;71.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGiaid A, Saleh D. Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N Engl J Med. 1995;333(4):214\u0026ndash;21.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLang IM, Pesavento R, Bonderman D, Yuan JX. Risk factors and basic mechanisms of chronic thromboembolic pulmonary hypertension: a current understanding. Eur Respir J. 2013;41(2):462\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMoser KM, Bioor CM. Pulmonary vascular lesions occurring in patients with chronic major vessel thromboembolic pulmonary hypertension. Chest. 1993;103(3):685\u0026ndash;92.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSuntharalingam J, Treacy CM, Doughty NJ, Goldsmith K, Soon E, Toshner MR, et al. Long-term use of sildenafil in inoperable chronic thromboembolic pulmonary hypertension. Chest. 2008;134(2):229\u0026ndash;36.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGhofrani H-A, Gali\u0026egrave; N, Grimminger F, Gr\u0026uuml;nig E, Humbert M, Jing Z-C, et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013;369(4):330\u0026ndash;40.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWharton J, Strange JW, M\u0026oslash;ller GM, Growcott EJ, Ren X, Franklyn AP, et al. Antiproliferative effects of phosphodiesterase type 5 inhibition in human pulmonary artery cells. Am J Respir Crit Care Med. 2005;172(1):105\u0026ndash;13.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eStasch J-P, Pacher P, Evgenov OV. Soluble guanylate cyclase as an emerging therapeutic target in cardiopulmonary disease. Circulation. 2011;123(20):2263\u0026ndash;73.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTsai C-H, Wu C-K, Kuo P-H, Hsu H-H, Chen Z-W, Hwang J-J, et al. Riociguat improves pulmonary hemodynamics in patients with inoperable chronic thromboembolic pulmonary hypertension. Acta Cardiol Sinica. 2020;36(1):64.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLiu J, Yang P, Tian H, Zhen K, McCabe C, Zhao L, et al. Right ventricle remodeling in chronic thromboembolic pulmonary hypertension. J Translational Intern Med. 2022;10(2):125\u0026ndash;33.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAoki T, Sugimura K, Terui Y, Tatebe S, Fukui S, Miura M, et al. Beneficial effects of riociguat on hemodynamic responses to exercise in CTEPH patients after balloon pulmonary angioplasty\u0026ndash;A randomized controlled study. IJC Heart Vasculature. 2020;29:100579.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-pulmonary-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pulm","sideBox":"Learn more about [BMC Pulmonary Medicine](http://bmcpulmmed.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/pulm/default.aspx","title":"BMC Pulmonary Medicine","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"chronic thromboembolic pulmonary hypertension, balloon pulmonary angioplasty, riociguat","lastPublishedDoi":"10.21203/rs.3.rs-7275378/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7275378/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eFor patients with chronic thromboembolic pulmonary hypertension (CTEPH), balloon pulmonary angioplasty (BPA) has been associated with superior reductions in mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance (PVR) when compared to riociguat. In patients with pulmonary arterial hypertension (PAH), greater clinical improvements were observed after switching from phosphodiesterase-5 inhibitors (PDE5i) to riociguat. However, the impact of transitioning from PDE5i to riociguat on pulmonary haemodynamics and functional outcomes after BPA remains unclear.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eThis prospective, open-label, single-arm, study enrolled CTEPH patients who remained symptomatic following BPA. After a 24-hour PDE5i washout period, patients were switched to riociguat. At week 26, primary outcomes assessed changes in haemodynamics including mPAP and PVR. Secondary endpoints evaluated cardiac index; functional status including WHO functional class, 6-minute walking distance (6MWD), REVEAL Lite 2 score; biochemical markers such as N-terminal prohormone of brain natriuretic peptide (NT-proBNP); and echocardiographic measurements of right-heart function. Treatment-related adverse events and clinical worsening were monitored throughout the study.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eFrom July 2024 to January 2025, 16 patients (mean age 62.3\u0026thinsp;\u0026plusmn;\u0026thinsp;14.6 years; 75% female) were recruited, with 14 completing the 26-week follow-up. At week 26, significant reductions occurred in mPAP (-4.79 mmHg; Confidence Interval [CI] -8.05 to -1.52; p\u0026thinsp;=\u0026thinsp;0.007) and PVR (-2.16 Wood units; CI -3.64 to -0.69; p\u0026thinsp;=\u0026thinsp;0.007). Significant improvements were also noted in cardiac index, WHO functional class, 6MWD, REVEAL Lite 2 score and NT-proBNP levels. Echocardiographic measurements of right-heart function did not demonstrate significant improvement. Treatment-related adverse events were observed in 11 patients (68.75%). Clinical worsening occurred in four patients, including two deaths unrelated to treatment and two unplanned hospitalisations due to pulmonary hypertension.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eIn CTEPH patients after completion of BPA, replacing PDE5i with riociguat significantly enhanced pulmonary haemodynamics and functional capacity but was accompanied by a considerable risk of treatment-related adverse events.\u003c/p\u003e\u003ch2\u003eTrial registration:\u003c/h2\u003e\u003cp\u003eClinicalTrials.gov Identifier NCT06715280 retrospectively registered on 26/11/2024.\u003c/p\u003e","manuscriptTitle":"Haemodynamic and Clinical Impacts of Switching Phosphodiesterase-5 Inhibitors to Riociguat in Patients with Chronic Thromboembolic Pulmonary Hypertension (CTEPH) after Balloon Pulmonary Angioplasty (BPA) – A Prospective Cohort Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-08 08:27:09","doi":"10.21203/rs.3.rs-7275378/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-09-29T07:05:38+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-21T14:38:34+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-08T09:00:25+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"307210034399713202820142605144105734525","date":"2025-09-04T09:25:15+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"47366309170043202783767325073323711868","date":"2025-08-30T08:38:53+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-08-27T18:04:59+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-08-20T07:18:28+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-08-14T07:07:38+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-08-13T14:19:36+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pulmonary Medicine","date":"2025-08-13T14:16:48+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pulmonary-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pulm","sideBox":"Learn more about [BMC Pulmonary Medicine](http://bmcpulmmed.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/pulm/default.aspx","title":"BMC Pulmonary Medicine","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6d0ded7a-cafe-487c-b72e-84384363ecdb","owner":[],"postedDate":"September 8th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-01-05T16:02:25+00:00","versionOfRecord":{"articleIdentity":"rs-7275378","link":"https://doi.org/10.1186/s12890-025-04069-y","journal":{"identity":"bmc-pulmonary-medicine","isVorOnly":false,"title":"BMC Pulmonary Medicine"},"publishedOn":"2026-01-03 15:58:36","publishedOnDateReadable":"January 3rd, 2026"},"versionCreatedAt":"2025-09-08 08:27:09","video":"","vorDoi":"10.1186/s12890-025-04069-y","vorDoiUrl":"https://doi.org/10.1186/s12890-025-04069-y","workflowStages":[]},"version":"v1","identity":"rs-7275378","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7275378","identity":"rs-7275378","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}