Background: Sotatercept is a first-in-class activin signaling inhibitor, developed for the treatment of pulmonary arterial hypertension (PAH). Objectives: This open-label single-arm, multicenter, phase 3 study was initiated to evaluate the efficacy and safety of sotatercept in Japanese participants with PAH. Methods: Forty-six adult Japanese participants with PAH on stable background therapy were enrolled and received subcutaneous sotatercept starting at 0.3 mg/kg with a target dose of 0.7 mg/kg administered every 3 weeks. The primary efficacy endpoint was the change from baseline in pulmonary vascular resistance at 24 weeks. Results: Of 46 participants, 29 (63%) were WHO functional class II and 17 (37%) were class III. At 24 weeks, pulmonary vascular resistance decreased 99.2 (95% CI: –129.6 to –68.4) dynes·s/cm5 and, 6-minute walk distance (key secondary endpoint) increased 41.8 (95% CI: 27.8-55.5) meters. There were 6 (13%) serious adverse events (AEs) and no discontinuations due to AEs in the primary period. Safety was consistent with the known safety profile for sotatercept with AEs that were clinically manageable. Conclusions: In this study of Japanese participants with PAH, improvements in pulmonary vascular resistance and 6-minute walk distance were observed, consistent with the pivotal phase 3 STELLAR (A Study of Sotatercept for the Treatment of Pulmonary Arterial Hypertension [MK-7692-003/A011-11]) trial. These data suggest that sotatercept may be an important treatment option for Japanese patients with PAH. (A Study of Sotatercept in Japanese Pulmonary Arterial Hypertension [PAH] Participants [MK-7962-020], NCT05818137; Japan Registry of Clinical Trials, jRCT2031230046)

Reduced diffusing capacity of the lungs for carbon monoxide (DLco) reflects microvasculopathy in chronic thromboembolic pulmonary hypertension, yet its clinical value is uncertain. In a Japanese nationwide registry (2018-2023) we studied 1270 patients: 486 formed an event cohort and 299 a treatment cohort who underwent pulmonary endarterectomy or balloon pulmonary angioplasty. Lower baseline DLco was indicative of smaller postprocedural improvements in mean pulmonary artery pressure, pulmonary vascular resistance and cardiac index (all p≤0.023) and a higher risk of clinical events (HR 0.971, p=0.005). Outcomes deteriorated below 59.6%, indicating DLco may help stratify prognosis and treatment benefit.

BACKGROUND:Long-term real-world outcomes of edoxaban in chronic thromboembolic pulmonary hypertension (CTEPH) remain incompletely characterized despite emerging evidence, including the KABUKI randomized trial. OBJECTIVES:To evaluate long-term effectiveness and safety of edoxaban in patients with CTEPH using a nationwide registry. METHODS:We analyzed the CTEPH AC Registry, a multicenter prospective observational cohort. Patients with CTEPH receiving edoxaban at registration were included. The primary effectiveness endpoint was morbidity and mortality events, a composite of all-cause death, lung transplantation, rescue pulmonary endarterectomy or balloon pulmonary angioplasty, ≥15% decline in 6-minute walk distance with worsening World Health Organization functional class, or symptomatic venous thromboembolism. The primary safety endpoint was clinically relevant bleeding according to International Society on Thrombosis and Haemostasis criteria. RESULTS:Among 408 patients, median follow-up was 552 days. The cumulative incidence of morbidity and mortality events was 4.7%, 10.0%, and 14.1% at 1, 3, and 5 years, respectively. The cumulative incidence of clinically relevant bleeding was 3.2%, 4.8%, and 5.6%, respectively, and major bleeding occurred in 2.4% at 5 years. Symptomatic venous thromboembolism occurred in 1.5% at 5 years. Outcomes were broadly consistent across reperfusion history, World Health Organization functional class, edoxaban dose, and renal function strata. CONCLUSIONS:In this Japanese nationwide registry, long-term edoxaban therapy was associated with sustained clinical stability in patients with CTEPH. No clear late-emerging safety signal was observed, but extrapolation beyond Japan requires caution, particularly in patients with different body size, renal function, or concomitant medication profiles.

We aimed to evaluate the role of medical therapy before and after balloon pulmonary angioplasty (BPA) for non-operable chronic thromboembolic pulmonary hypertension (CTEPH) in the modern management era. This Japanese nationwide, multicenter, prospective observational registry, including 37 centers, analyzed data newly registered from August 2018-December 2023. Pretreatment before BPA was analyzed in patients who were treatment naïve or received medical therapy only at registration (n = 557). De-escalation or escalation of medical therapy after BPA was analyzed in patients who underwent BPA (n = 966). The BPA pretreatment analysis in 557 patients showed that approximately 70% of the patients received medical therapy, of which 18% received combination therapy. Patients who received monotherapy or combination therapy had more severe baseline hemodynamics than those who did not. The 3-year survival did not significantly differ between the no, mono, and combination pretreatment groups (94%, 98%, and 97%, respectively; p = 0.852). The BPA post-treatment analysis in 966 patients showed that 20% of patients underwent de-escalation of medical therapy. Patients with de-escalation of medical therapy had lower mean pulmonary artery pressure (PAP) (20.9 ± 5.8 vs. 24.1 ± 7.3 mmHg, p < 0.01); however, they had a lower cardiac index at last follow-up compared to patients without de-escalation (2.66 ± 0.61 vs. 2.84 ± 0.70 L/min/m2, p = 0.01). Patients with severe disease tended to undergo pre-treatment before BPA; however, patient survival did not differ across pretreatment types. De-escalation of medical therapy after BPA can affect cardiac index. Therefore, de-escalation or continuation of medical therapy should be carefully considered even after mean PAP normalizes after BPA.

Advances in chronic thromboembolic pulmonary hypertension (CTEPH) treatment have improved prognosis, shifting focus towards symptom management. This study aimed to identify factors influencing the World Health Organization functional class (WHO-FC) in CTEPH patients. The CTEPH AC registry is a prospective, multicenter database from 35 Japanese institutions, analyzing data from August 2018 to July 2023. We examined factors associated with achieving WHO-FC I and WHO-FC changes over time in 1,270 patients. Significant factors for WHO-FC I achievement included male sex (odds ratio: 1.86, p = 0.019), age (0.98, p = 0.007), pulmonary vasodilator use (0.51, p = 0.001), post-balloon pulmonary angioplasty (BPA) (1.93, p = 0.010), lower mean pulmonary arterial pressure (0.94, p = 0.004), and lower pulmonary vascular resistance (PVR) (0.78, p = 0.006). Multivariate analysis showed that WHO-FC improvement correlated with male sex, baseline PVR, and BPA during follow-up. WHO-FC deterioration was associated with cancer, history of pulmonary endarterectomy and/or BPA at registration, bleeding risks, and thyroid disease or hormone therapy. BPA implementation is closely linked to symptomatic improvement and achieving WHO-FC I, while symptom worsening is often associated with patient-specific, difficult-to-control conditions.

BACKGROUND:Treprostinil has been approved for pulmonary hypertension associated with interstitial lung disease (PH-ILD) in Japan. This report aimed to evaluate long-term effects of inhaled treprostinil in Japanese patients with PH-ILD based on observation over 52 weeks. METHODS:Inhaled treprostinil was administered via a nebulizer from 18 μg (three breaths, four times daily) to 72 μg (12 breaths, four times daily) at minimum 3-day intervals. World Health Organization (WHO) functional class, clinical worsening, adverse events, pulmonary function and ILD-related biomarkers were evaluated throughout the trial. RESULTS:Among 20 patients, 16 and 13 completed the 52-week and 100-week observation periods, respectively. Eleven patients continued on the trial until transitioning to a commercially available product. The reasons of discontinuation in nine patients were adverse events in six patients (including four adverse drug reactions (ADRs)), withdrawal of consent in two patients, and lung transplantation in one patient. The median observation period was 107.5 weeks (interquartile range, 61.4-128.8 weeks) in 20 patients. Among 13 patients observed until week 100, WHO functional class was maintained in 69.2 % (9/13), and improved from class III to class II in 30.8 % (4/13). The main ADRs included cough, malaise, and blood pressure decreased. At the final measurement timepoint in each patient, 70.0 % (14/20) and 83.3 % (15/18) maintained had no absolute decline of forced vital capacity ≥5 % and diffusing capacity for carbon monoxide ≥10 %, respectively. CONCLUSION:Considering its long-term clinical benefits and tolerability, inhaled treprostinil is a promising treatment option for patients with PH-ILD. TRIAL REGISTRATION:Japan Registry of Clinical Trials (jRCT), jRCT2051210016. (first registered: May 7, 2021).

OBJECTIVE:The survival benefit of thrombolysis compared with surgical pulmonary embolectomy for high-risk pulmonary embolism has not been established, although current guidelines advocate thrombolysis as first-line therapy. This study compared the short-term outcomes of surgical pulmonary embolectomy and thrombolysis to determine the optimal treatment for high-risk pulmonary embolism. METHODS:Patients with high-risk pulmonary embolism who underwent surgical pulmonary embolectomy or thrombolysis within 2 days of admission were identified using a nationwide inpatient administrative database in Japan between July 2010 and March 2023. The primary outcome was in-hospital mortality, and secondary outcomes were complications, length of hospital stay, and total hospitalization costs. Outcomes were compared using overlap weighting, with sensitivity analyses conducted using inverse probability of treatment weighting and multivariate logistic regression model. RESULTS:Of the 2813 eligible patients, 526 underwent surgical pulmonary embolectomy, and 2287 underwent thrombolysis. After overlap weighting, surgical pulmonary embolectomy was associated with lower in-hospital mortality (22.2% vs 30.1%, P = .002), more favorable neurological outcomes at discharge (72.5% vs 66.7%, P = .040), and higher total costs ($30,548 vs $13,374, P < .001) than thrombolysis. No significant differences were observed in complications or length of hospital stay between the 2 groups. Sensitivity analyses yielded results consistent with the primary analyses. CONCLUSIONS:These findings suggest potential benefits of surgical pulmonary embolectomy over thrombolysis for high-risk pulmonary embolism. Surgical pulmonary embolectomy may be considered a reasonable reperfusion therapy option for suitable patients. Further research is needed to confirm these findings.

The basic treatment for chronic thromboembolic pulmonary hypertension (CTEPH) includes lifelong anticoagulant therapy and pulmonary endarterectomy; moreover, balloon pulmonary angioplasty (BPA) and vasodilators are also known to be effective. Surgery is the standard treatment for localized lung cancer. However, no established treatment guidelines exist for cases of coexisting CTEPH and lung cancer. The patient was a 55-year-old woman who experienced dyspnea on exertion. She was diagnosed with non-small cell lung cancer, and surgery was scheduled; however, she was also diagnosed with CTEPH during preoperative examinations. She was referred to our hospital, where right heart catheterization revealed a mean pulmonary artery pressure (mPAP) of 39 mmHg. We prioritized the treatment of CTEPH, starting oral riociguat followed by BPA three times. The mPAP decreased to 27 mmHg. Then, right upper lobectomy and lymph node dissection were performed. After surgery, there was no significant worsening of right heart failure, and no recurrence of the lung cancer. This case report presents a method for managing both CTEPH and primary lung cancer. The essence was the intensification of CTEPH treatment in anticipation of lobectomy.

Background:Invasive treatments for chronic thromboembolic pulmonary hypertension (CTEPH) include pulmonary endarterectomy (PEA) and balloon pulmonary angioplasty (BPA). Both PEA and BPA demonstrate significant benefits for symptom relief, hemodynamic improvement, and overall patient outcomes. However, evidence of their efficacy in older adults remains limited. This study aimed to evaluate treatment efficacy-including exercise tolerance, hemodynamics, functional status-and clinical outcomes in CTEPH patients aged ≥70 years who underwent PEA or BPA. Methods:Among 1,527 patients in the CTEPH AntiCoagulants Registry, we selected those aged 70 years or older, including 25 who underwent PEA during follow-up and 210 who received BPA. We evaluated the World Health Organization functional class (WHO FC), a measure of subjective symptoms, along with exercise capacity, hemodynamic parameters, and clinical outcomes. Results:At baseline, BPA patients were older (P = 0.003) and tended to have lower body weight (P = 0.069) than those undergoing PEA. At a median follow-up of ∼2 years, BPA significantly improved six-minute walk distance and cardiac index, and reduced mean pulmonary artery pressure and pulmonary vascular resistance, with effects comparable to PEA after adjusting for age, sex, and body mass index (all adjusted P > 0.10). However, improvement in WHO FC was more frequent with BPA and became significant after covariate adjustment (adjusted P = 0.035). Adverse event rates were infrequent and similar between the two groups (all P > 0.10). Conclusions:In adults aged ≥ 70 years with CTEPH, BPA improved hemodynamics, exercise capacity, and outcomes comparable to PEA, but with greater WHO FC improvement. Further randomized trials in older adults are warranted. Clinical trial registration number:UMIN Clinical Trials Registry (identifier UMIN 000033784).

BACKGROUND:The contact between the aorta, main pulmonary artery (MPA), main pulmonary vein, vena cava (VC), and esophagus affects segmentation of the aorta and MPA in non-contrast-enhanced computed tomography (NCE-CT) images. PURPOSE:A two-stage stacked U-Net and localization of the aorta and MPA were developed for the segmentation of the aorta and MPA in NCE-CT images. METHODS:Normal-dose NCE-CT images of 24 subjects with chronic thromboembolic pulmonary hypertension (CTEPH) and low-dose NCE-CT images of 100 subjects without CTEPH were used in this study. The aorta is in contact with the ascending aorta (AA) and MPA, the AA with the VC, the aortic arch (AR) with the VC and esophagus, and the descending aorta (DA) with the esophagus. These contact surfaces were manually annotated. The contact surfaces were quantified using the contact surface ratio (CSR). Segmentation of the aorta and MPA in NCE-CT images was performed by localization of the aorta and MPA and a two-stage stacked U-Net. Localization was performed by extracting and processing the trachea and main bronchus. The first stage of the stacked U-Net consisted of a 2D U-Net, 2D U-Net with a pre-trained VGG-16 encoder, and 2D attention U-Net. The second stage consisted of a 3D U-Net with four input channels: the CT volume and three segmentation results of the first stage. The model was trained and tested using 10-fold cross-validation. Segmentation of the entire volume was evaluated using the Dice similarity coefficient (DSC). Segmentation of the contact area was also assessed using the mean surface distance (MSD). The statistical analysis of the evaluation underwent a multi-comparison correction. CTEPH and non-CTEPH cases were classified based on the vessel diameters measured from the segmented MPA. RESULTS:For the noncontact surfaces of AA, the MSD of stacked U-Net was 0.31 ± 0.10 mm (p < 0.05) and 0.32 ± 0.13 mm (p < 0.05) for non-CTEPH and CTEPH cases, respectively. For contact surfaces with a CSR of 0.4 or greater in AA, the MSD was 0.52 ± 0.23 mm (p < 0.05), and 0.68 ± 0.29 mm (p > 0.05) for non-CTEPH and CTEPH cases, respectively. MSDs were lower than those of 2D and 3D U-Nets for contact and noncontact surfaces; moreover, MSDs increased slightly with larger CSRs. However, the stacked U-Net achieved MSDs of approximately 1 pixel for a wide contact surface. The area under the receiver operating characteristic curve for CTEPH and non-CTEPH classification using the right main pulmonary artery (RMPA) diameter was 0.97 (95% confidence interval [CI]: 0.94-1.00). CONCLUSIONS:Segmentation of the aorta and MPA on NCE-CT images were affected by vascular and esophageal contact. The application of stacked U-Net and localization techniques for non-CTEPH and CTEPH cases mitigated the impact of contact, suggesting its potential for diagnosing CTEPH.

Background: Quality indicators (QIs) are used to standardize care and improve outcomes in patients with pulmonary arterial hypertension (PAH). It is important that QIs are validated within specific healthcare contexts. Therefore, this study aimed to validate QIs for PAH management in Japan using a modified Delphi consensus method. Methods: QI candidates were identified from published European QIs and clinical practice guidelines. An expert panel of 11 PAH specialists from diverse Japanese institutions anonymously rated the 36 initial QI candidates in two rounds using a nine-point appropriateness scale. Results: In the first round, 35 QIs received a median score of ≥7 points. A panel discussion was held between rounds to address the single low-scored QI, biomarker modifications, and invasive examinations, resulting in 36 modified QIs. In the second round, all modified QIs received median scores of ≥7 points and were judged to be valid as the final Japanese set of QIs. Conclusions: The findings of this study validated a set of QIs for PAH management tailored to the Japanese healthcare context. These QIs can be used to standardize care, identify areas for improvement, and ultimately enhance outcomes for Japanese patients with PAH.

Background The contemporary outcome of balloon pulmonary angioplasty (BPA) and pulmonary endarterectomy (PEA) in patients with chronic thromboembolic pulmonary hypertension (CTEPH) are unclear. Objectives This study aimed to clarify the characteristics and outcomes of CTEPH patients treated with BPA and PEA in Japan. Methods Among 1,270 participants enrolled between 2018 and 2023 in the CTEPH AC (Chronic Thromboembolic Pulmonary Hypertension Anticoagulant) registry, a Japanese nationwide CTEPH registry, 369 treatment-naive patients (BPA strategy: n = 313; PEA strategy: n = 56) and 690 on-treatment patients (BPA strategy: n = 561; PEA strategy: n = 129) were classified according to the presence of prior reperfusion therapy. Morbidity and mortality events (all-cause death, rescue mechanical reperfusion therapy, and/or initiation of parenteral pulmonary vasodilators), pulmonary hemodynamics, exercise tolerance, and relevant laboratory test results were evaluated. Results The BPA strategy was chosen in older patients than the PEA strategy (mean age, BPA vs PEA: 66.5 ± 12.6 years vs 62.5 ± 11.8 years; P = 0.028). Median follow-up period was 615 (Q1-Q3: 311-997) days in treatment-naive patients and 1,136 (Q1-Q3: 684-1,300) days in on-treatment patients. BPA strategy had as acceptable morbidity and mortality as PEA strategy (5-year morbidity and mortality event rate, BPA vs PEA: 10.2% [95% CI: 5.2%-19.5%] vs 16.1% [95% CI: 4.3%-50.6%] in treatment-naive patients; 9.7% [95% CI: 6.7%-13.8%] vs 6.9% [95% CI: 2.7%-17.3%] in on-treatment patients), with greater improvement of renal function; glomerular filtration rate in propensity score-matched population (difference between change: 4.9 [95% CI: 0.5-9.3] mL/min/1.73 m2; P = 0.030). Conclusions BPA strategy was more frequently chosen in older patients compared with PEA strategy and showed acceptable outcomes for efficacy with greater advantage for improvement in renal function. (Multicenter registry of chronic thromboembolic pulmonary hypertension in Japan; UMIN000033784)

BACKGROUND:The management of chronic thromboembolic pulmonary hypertension (CTEPH) has advanced significantly in recent years, thereby improving patient prognosis. However, the impact of cancer on the outcomes of patients with CTEPH under current treatment remains unclear. This study aimed to investigate the prevalence of cancer in patients with CTEPH and determine how comorbid cancer affects their prognosis and clinical course. METHODS:Data from an ongoing Japanese prospective cohort study were analyzed. Prevalence and primary cancer sites were evaluated. The association of a history of cancer with a composite endpoint, including all-cause death, lung transplantation, and worsening of CTEPH, as well as venous thromboembolism and bleeding events, was assessed. RESULTS:Of the 1,270 patients in the cohort, 134 (10.6%) had a history of cancer, with the most common primary sites being the breast in women and the prostate in men. The incidence of composite outcome and all-cause death was higher in those with a history of cancer (p < 0.001, log-rank test). In the Cox proportional hazard model, age- and sex-adjusted hazard ratios for the composite outcome and all-cause death were 2.69 (95% confidence interval, 1.48-4.89, p = 0.001) and 4.25 (95% confidence interval, 1.98-9.10, p < 0.001), respectively, for patients with a history of cancer. No significant differences in venous thromboembolism and bleeding events were observed between patients with and those without a history of cancer. CONCLUSIONS:A history of cancer, with a prevalence of 10.6%, is an independent risk factor for mortality in patients with CTEPH undergoing the currently recommended treatment.

Background Pulmonary arterial hypertension is a serious medical condition. However, the condition is often misdiagnosed or a rather long delay occurs from symptom onset to diagnosis, associated with decreased 5-year survival. In this study, we developed and tested a deep-learning algorithm to detect pulmonary arterial hypertension using chest X-ray (CXR) images. Methods From the image archive of Chiba University Hospital, 259 CXR images from 145 patients with pulmonary arterial hypertension and 260 CXR images from 260 control patients were identified; of which 418 were used for training and 101 were used for testing. Using the testing dataset for each image, the algorithm outputted a numerical value from 0 to 1 (the probability of the pulmonary arterial hypertension score). The training process employed a binary cross-entropy loss function with stochastic gradient descent optimization (learning rate parameter, α = 0.01). In addition, using the same testing dataset, the algorithm’s ability to identify pulmonary arterial hypertension was compared with that of experienced doctors. Results The area under the curve (AUC) of the receiver operating characteristic curve for the detection ability of the algorithm was 0.988. Using an AUC threshold of 0.69, the sensitivity and specificity of the algorithm were 0.933 and 0.982, respectively. The AUC of the algorithm’s detection ability was superior to that of the doctors. Conclusion The CXR image-derived deep-learning algorithm had superior pulmonary arterial hypertension detection capability compared with that of experienced doctors.