Aiko Ogawa

Background: The New International Chronic Thromboembolic Pulmonary Hypertension (CTEPH) Registry, conducted between 2015 and 2019, revealed the significant impact of pulmonary endarterectomy (PEA) and balloon pulmonary angioplasty (BPA) on the long-term survival of CTEPH patients. The objective of the current pre-specified analysis was to evaluate the effect of medical treatment, including the approved oral guanylate cyclase stimulator (sGC) riociguat, in patients with or without mechanical intervention. Methods: 1009 newly diagnosed patients were included in the study, with recruitment conducted at 34 centres across 20 countries. At the outset of the registry, sGC was available in 85% of the countries involved. Results: 52% of all patients included were treated with pulmonary hypertension (PH) drugs. The proportion of patients receiving PH drugs was 38% among the 605 patients who underwent PEA, 78% among the 185 patients who underwent BPA and 76% among the 219 remaining patients who did not undergo PEA or BPA. In the “BPA” and “no PEA/BPA” groups, the 3-year survival was superior in patients who received sGC in comparison with other PH drugs. Cox regression confirmed that sGC treatment was associated with reduced mortality in the global cohort, in the BPA group and in the “no PEA/BPA” group. Conclusion: This international CTEPH registry suggests that, although an increasing proportion of patients with CTEPH benefited from mechanical treatment, medical treatment with sGC may be associated with a survival advantage in patients undergoing BPA or no intervention. These observations confirm the results of previous randomised controlled trials in a real-world setting.

BACKGROUND: The European Chronic Thromboembolic Pulmonary Hypertension (CTEPH) registry, conducted between 2007 and 2012, reported the major impact of pulmonary endarterectomy (PEA) on the long-term survival of patients with CTEPH. Since then, 2 additional treatments for inoperable CTEPH have become available: balloon pulmonary angioplasty (BPA), and an approved oral drug therapy with the guanylate cyclase stimulator riociguat. The current registry aimed to evaluate the effect of these new therapeutic approaches in a worldwide context. METHODS: Participation in this international global registry included 34 centers in 20 countries. Between February 2015 and September 2016, 1009 newly diagnosed, consecutive patients were included and followed until September 2019. RESULTS: Overall, 605 patients (60%) underwent PEA and 185 (18%) underwent BPA; 76% of the 219 remaining patients not receiving mechanical intervention (ie, neither PEA nor BPA) were treated with pulmonary hypertension drugs. Of patients undergoing PEA and BPA, 38% and 78% also received drugs for pulmonary hypertension, respectively. Median age at diagnosis was higher in the BPA and No PEA/BPA groups than in the PEA group: 66 and 69, respectively, versus 60 years. Pulmonary vascular resistance (PVR) was similar in all groups, with an average of 643 dynes.s.cm ⁻⁵ . During the observation period (>3 years; ≤5.6 years), death was reported in 7%, 11%, and 27% of patients treated by PEA and BPA, and those receiving no mechanical intervention ( P P =0.756). In Cox regression, reduced mortality was associated with: PEA and BPA in the global cohort; history of venous thromboembolism and lower PVR in the PEA group; lower right atrial pressure in the BPA group; and use of pulmonary hypertension drugs, oxygen therapy, and lower right atrial pressure, as well as functional class in the group receiving no mechanical intervention. CONCLUSIONS: This second international CTEPH registry reveals important improvement in patient survival since the introduction of BPA and an approved drug for pulmonary hypertension. The type of anticoagulation regimen did not influence survival. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02656238.

Background: Pulmonary endarterectomy (PEA), pulmonary arterial hypertension (PAH) therapy and balloon pulmonary angioplasty (BPA) are currently accepted therapies for chronic thromboembolic pulmonary hypertension (CTEPH). This international CTEPH Registry identifies clinical characteristics of patients, diagnostic algorithms and treatment decisions in a global context.Methods: 1010 newly diagnosed consecutive patients were included in the registry between February 2015 and September 2016. Diagnosis was confirmed by right heart catheterisation, ventilation–perfusion lung scan, computerised pulmonary angiography and/or invasive pulmonary angiography after at least 3 months on anticoagulation.Results: Overall, 649 patients (64.3%) were considered for PEA, 193 (19.1%) for BPA, 20 (2.0%) for both PEA and BPA, and 148 (14.7%) for PAH therapy only. Reasons for PEA inoperability were technical inaccessibility (n=235), comorbidities (n=63) and patient refusal (n=44). In Europe and America and other countries (AAO), 72% of patients were deemed suitable for PEA, whereas in Japan, 70% of patients were offered BPA as first choice. Sex was evenly balanced, except in Japan where 75% of patients were female. A history of acute pulmonary embolism was reported for 65.6% of patients. At least one PAH therapy was initiated in 35.8% of patients (26.2% of PEA candidates, 54.5% of BPA candidates and 54.1% of those not eligible for either PEA or BPA). At the time of analysis, 39 patients (3.9%) had died of pulmonary hypertension-related causes (3.5% after PEA and 1.8% after BPA).Conclusions: The registry revealed noticeable differences in patient characteristics (rates of pulmonary embolism and sex) and therapeutic approaches in Japan compared with Europe and AAO.

The right ventricle (RV) is more sensitive to an increase in afterload than the left ventricle (LV), and RV afterload during exercise increases more easily than LV afterload. Pulmonary arterial hypertension (PAH)-specific therapy has improved pulmonary hemodynamics at rest; however, the pulmonary hemodynamic response to exercise is still abnormal in most patients with PAH. In these patients, RV afterload during exercise could be higher, resulting in a greater increase in RV wall stress. Recently, an increasing number of studies have indicated the short-term efficacy of exercise training. However, considering the potential risk of promoting myocardial maladaptive remodeling, even low-intensity repetitive exercise training could lead to long-term clinical deterioration. Further studies investigating the long-term effects on the RV and pulmonary vasculature are warranted. Although the indications for exercise training for patients with PAH have been expanding, exercise training may be associated with various risks. Training programs along with risk stratification based on the pulmonary hemodynamic response to exercise may enhance the safety of patients with PAH.

Pulmonary arterial hypertension (PAH)-specific combination therapy improves pulmonary haemodynamics at rest in patients with PAH; nevertheless, exertional dyspnoea remains. We investigated pulmonary haemodynamic response to exercise, and the relationship to ventilatory efficiency and hypoxaemia in patients with PAH treated with combination therapy. 32 clinically stable patients with PAH undergoing combination therapy underwent cardiopulmonary exercise testing with right heart catheterisation. Haemodynamic impairment was moderate to severe before treatment. However, after treatment it was significantly improved, and the mean pulmonary arterial pressure (mPAP) at rest was −1). It significantly correlated with both the minute ventilation/carbon dioxide output slope (r=0.51, p<0.01) and peripheral arterial oxygen saturation/workload slope (r=−0.41, p=0.02). In addition, the mPAP/CO slope correlated significantly with mPAP at rest (r=0.73, p<0.01) and TPR at rest (r=0.64, p<0.01). Even after pulmonary haemodynamics at rest was significantly improved in PAH patients with PAH-specific combination therapy, the mPAP/CO slope was steep and the steep mPAP/CO slope related to decreased ventilatory efficiency and the severity of hypoxaemia. The mPAP/CO slope was steeper in patients with higher mPAP and TPR at rest.