Effect of Orally Active Prostacyclin Analogue on Survival in Patients With Chronic Thromboembolic Pulmonary Hypertension Without Major Vessel Obstruction

doi:10.1378/chest.123.5.1583

Chest

Volume 123, Issue 5, May 2003, Pages 1583-1588

https://doi.org/10.1378/chest.123.5.1583 Get rights and content

Objectives:

This study investigated whether treatment with beraprost sodium (BPS), an orally active prostacyclin analog, improves hemodynamics and survival in patients with peripheral-vessel chronic thromboembolic pulmonary hypertension (CTEPH), for which there is no surgical option.

Background:

Oral administration of BPS has been shown to improve the hemodynamics and prognosis in patients with primary pulmonary hypertension; however, whether BPS has beneficial effects in CTEPH remains unknown.

Methods:

Forty-three patients with peripheral-vessel CTEPH were classified into two groups: patients treated with BPS (BPS group, n = 20) and those without BPS (conventional group, n = 23). Baseline demographic and hemodynamic data did not significantly differ between the two groups.

Results:

BPS therapy improved New York Heart Association functional class in 10 patients (50%) and significantly decreased total pulmonary resistance from 18 ± 6 to 15 ± 8 Wood units (p < 0.05) [mean ± SD]. Sixteen patients died of cardiopulmonary causes in the conventional group during a mean follow-up period of 58 ± 45 months. In contrast, only three patients died of cardiopulmonary causes in the BPS group during a mean follow-up period of 44 ± 30 months. The absence of BPS therapy, elevated total pulmonary resistance, heart rate, and age were independently related to the mortality by Cox proportional hazard analysis. The 1-year, 3-year, and 5-year survival rates for the BPS group were 100%, 85%, and 76%, respectively, compared to 87%, 60%, and 46% in the conventional group.

Conclusions:

This preliminary study suggests that oral administration of BPS may improve hemodynamics and survival in patients with peripheral-vessel CTEPH, for which there is no surgical option.

Section snippets

Study Subjects

We studied 43 patients (16 men and 27 women; mean ± SD age, 54 ± 13 years) with peripheral-vessel CTEPH that was not suitable for surgical pulmonary thromboendarterectomy. The diagnosis of CTEPH was made on the basis of the previously reported procedure.¹⁴ In brief, patients with clinical symptoms suggesting CTEPH underwent ventilation/perfusion lung scanning to detect pulmonary perfusion defects. The diagnosis was confirmed by pulmonary angiography.¹⁵ When characteristic angiographic findings

Results

During a follow-up period of 2 ± 1 month, NYHA functional class significantly improved in 10 patients (50%), worsened in 1 patient (5%), and was unchanged in 9 patients (45%) in the BPS group (Fig 1). However, no significant change in NYHA functional class was observed in the conventional group.

BPS significantly lowered mean pulmonary arterial pressure by 11% (55 ± 15 to 49 ± 16 mm Hg, p < 0.05; Fig 2) and total pulmonary resistance by 18% (18 ± 6 to 15 ± 8 Wood units, p < 0.05) during a

Discussion

In the present study, we demonstrated the following: (1) oral administration of BPS improved NYHA functional class and decreased total pulmonary resistance in patients with peripheral-vessel CTEPH, for which no surgical option exists; (2) the absence of BPS therapy was significantly related to mortality in such patients; and (3) the Kaplan-Meier survival curves demonstrated that the BPS group had a significantly higher survival rate than the conventional group.

IV infusion of epoprostenol

Conclusions

This study suggest that oral administration of BPS may improve NYHA functional class, hemodynamics, and long-term prognosis in patients with peripheral-vessel CTEPH, for which no surgical option exists. Thus, BPS may be a new therapeutic approach to the treatment of inoperable CTEPH.

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Cited by (85)

Chronic Thromboembolic Pulmonary Hypertension
2018, Heart Failure Clinics
Citation Excerpt :
Data regarding the use of prostacyclin therapies to treat CTEPH are more limited. In a small retrospective study of 43 patients with peripheral vessel CTEPH, improvements in PVR and in New York Heart Association (NYHA) functional class were seen in 20 patients treated with oral beraprost but not in 23 patients give conventional therapy including anticoagulants and diuretics alone.73 In the conventional therapy group 16 out of 23 patients died during a mean follow-up period of 58 ± 45 months, whereas only 3 out of 20 patients in the beraprost group died during a mean follow-up of 44 ± 30 months.
Medical Therapy Versus Balloon Angioplasty for CTEPH: A Systematic Review and Meta-Analysis
2018, Heart Lung and Circulation
Citation Excerpt :
Only one RCT which evaluated riociguat required independent adjudication of inoperability of disease as an eligibility criteria. Regarding uncontrolled observational studies of medical therapy, a total of 333 patients from 12 studies evaluated the effects of bosentan (n = 5) [24–28], sildenafil (n = 2) [29,30], beraprost (n = 1) [31], riociguat (n = 1) [32], intravenous epoprostenol (n = 2) [33,34], and subcutaneous treprostenil (n = 1) [35]. NYHA functional class III represented the majority of patients and prior PEA ranged from 0 to 32% of patients.
A significant number of chronic thromboembolic pulmonary hypertension (CTEPH) patients will have an inoperable disease. Medical therapy and balloon pulmonary angioplasty (BPA) have provided alternate therapeutic options for patients with inoperable CTEPH, although there are a limited number of published studies examining the outcomes. Thus, our study aims to evaluate and compare the efficacy of medical therapy and BPA in patients with inoperable CTEPH.
An electronic search of six databases was performed and the search results were screened against established criteria for inclusion into this study. Data was extracted and meta-analytical techniques were used to analyse the data.
Pooled data from RCTs revealed that medical therapy, compared with a placebo, was associated with a significant improvement of at least one functional class (p = 0.038). With regards to pulmonary haemodynamics, medical therapy also resulted in a significant reduction in both mean pulmonary arterial pressure (mPAP) (p = 0.002) and pulmonary vascular resistance (PVR) (p < 0.001). From the included observational studies, the 6-minute walk distance (6MWD) significantly increased following medical therapy by an average of 22.8% (p < 0.001). The pooled improvement in 6MWD was found to be significantly higher in the BPA group when compared to medical therapy for CTEPH (p = 0.001). Pooled data from available observational studies of medical therapy or BPA all demonstrated significant improvements in mPAP and PVR for pre versus post intervention comparisons. The improvement in mPAP (p = 0.002) and PVR (p = 0.002) were significantly greater for BPA intervention when compared to medical therapy.
High-quality evidence supports the use of targeted medical therapy in improving haemodynamics in patients with inoperable CTEPH. There is only moderate-quality evidence from observational studies supporting the efficacy of BPA in improving both haemodynamics and exercise capacity. Further RCTs and prospective observational studies comparing medical therapy and BPA in patients with inoperable CTEPH are required.
Use of outcome measures in pulmonary hypertension clinical trials
2015, American Heart Journal
To evaluate the use of surrogate measures in pulmonary hypertension (PH) clinical trials and how it relates to clinical practice.
Studies of pulmonary arterial hypertension (PAH) employ a variety of surrogate measures in addition to clinical events because of a small patient population, participant burden, and costs. The use of these measures in PH drug trials is poorly defined.
We searched PubMed/MEDLINE/Embase for randomized or prospective cohort PAH clinical treatment trials from 1985 to 2013. Extracted data included intervention, trial duration, study design, patient characteristics, and primary and secondary outcome measures. To compare with clinical practice, we assessed the use of surrogate measures in a clinical sample of patients on PH medications at Duke University Medical Center between 2003 and 2014.
Between 1985 and 2013, 126 PAH trials were identified and analyzed. Surrogate measures served as primary endpoints in 119 trials (94.0%). Inclusion of invasive hemodynamics decreased over time (78.6%, 75.0%, 52.2%; P for trend = .02), while functional testing (7.1%, 60.0%, 81.5%; P for trend < .0001) and functional status or quality of life (0%, 47.6%, 62.8%; P for trend < .0001) increased in PAH trials over the same time periods. Echocardiography data were reported as a primary or secondary outcome in 32 trials (25.4%) with increased use from 1985-1994 to 1995-2004 (7.1% vs 35.0%, P = .04), but the trend did not continue to 2005-2013 (25.0%). In comparison, among 450 patients on PAH therapies at our institution between 2003 and 2013, clinical assessments regularly incorporated serial echocardiography and 6-minute walk distance tests (92% and 95% of patients, respectively) and repeat measurement of invasive hemodynamics (46% of patients).
The majority of PAH trials have utilized surrogate measures as primary endpoints. The use of these surrogate endpoints has evolved significantly over time with increasing use of patient-centered endpoints and decreasing or stable use of imaging and invasive measures. In contrast, imaging and invasive measures are commonly used in contemporary clinical practice. Further research is needed to validate and standardize currently used measures.
Pulmonary Thromboembolism
2015, Murray and Nadel's Textbook of Respiratory Medicine: Volume 1,2, Sixth Edition
Long-term advanced therapy with bosentan improves symptoms and prevents deterioration of inoperable chronic thromboembolic pulmonary hypertension
2014, Life Sciences
Citation Excerpt :
Interestingly, histological changes in the non-occluded pulmonary arteries are similar to those seen in pulmonary artery hypertension (PAH), such as medial hypertrophy and the intimal proliferative and fibrotic changes that include plexiform lesions (Galiè and Kim, 2006). As the pathological changes in the pulmonary vasculature appear similar, new pulmonary vasodilating drugs used to treat PAH have also been used in CTEPH: prostanoids (Ono et al., 2003; Cabrol et al., 2007; Skoro-Sajer et al., 2007), endothelin-receptor antagonists (ERAs) (Becattini et al., 2010), and phosphodiesterase type-5 (PDE5) inhibitors (Suntharalingam et al., 2008) are reported to have hemodynamic and clinical benefits, although these have not been established in randomized, placebo-controlled trials. Nonetheless, the prognosis of Japanese patients with CTEPH is improving: it has recently been reported that the 5-year survival rate has risen to 87.3% as a result of the use of PAH-specific therapies by almost two-thirds of patients (Nishimura et al., 2013).
Chronic thromboembolic pulmonary hypertension (CTEPH) is a devastating disease, and treating patients with CTEPH who are not eligible for pulmonary endarterectomy is particularly challenging. Short-term bosentan or phosphodiesterase type-5-inhibitor treatment can greatly improve symptoms and hemodynamics in these patients; however, the long-term benefits of advanced pulmonary vasodilators are not known. We retrospectively investigated the long-term effects of advanced pharmacological therapy in Japanese patients with inoperable CTEPH.
Seven consecutive patients with inoperable CTEPH (five women; mean age, 62.6 ± 6.9 years) treated with bosentan were included. World Health Organization functional class (WHO-FC), hemodynamics, exercise capacity, and plasma B-type natriuretic peptide (BNP) concentration were evaluated at baseline and for more than 2 years. Time to clinical worsening was also examined during long-term follow-up.
WHO-FC improved significantly, from 3.1 ± 0.4 to 2.1 ± 0.4 (p = 0.005). Significant improvement was also seen in pulmonary vascular resistance, which decreased from 786.9 ± 300.0 to 352.2 ± 210.7 dynes s cm^− 5 (p < 0.05). Plasma BNP concentration decreased significantly from 1160.0 ± 971.4 to 305.1 ± 285.9 pg/mL (p < 0.05). No patient required hospitalization during the follow-up period (mean, 896 ± 564 days).
Long-term advanced therapy with bosentan significantly improves symptoms, pulmonary vascular resistance, plasma BNP concentration, and time to clinical worsening in Japanese patients with inoperable CTEPH. We consider bosentan to be an essential treatment for these patients.
Recent progress in the diagnosis and management of chronic thromboembolic pulmonary hypertension
2013, Respiratory Investigation
Citation Excerpt :
In an uncontrolled study in Japan, Ono et al. reported that oral beraprost improved New York Heart Association class in 10 patients (50%) and significantly decreased total pulmonary resistance from 18±6 to 15±8 Wood units (p<0.05). Sixteen patients died of cardiopulmonary causes in the group receiving conventional therapy, while only 3 patients died of cardiopulmonary causes in the group receiving beraprost [61]. The clinical efficacy of modern PAH therapy in CTEPH remains to be demonstrated by an RCT.
Chronic thromboembolic pulmonary hypertension (CTEPH) is a form of pulmonary hypertension caused by non-resolving thromboembolisms of the pulmonary arteries. In Japan, in contrast to Western countries, CTEPH is more prevalent in women. A Japanese multicenter study reported that a form of CTEPH unrelated to deep vein thrombosis is associated with HLA-B⁎5201, suggesting that this form of CTEPH may be associated with vasculopathy. CTEPH can be cured by pulmonary endarterectomy, provided that the thrombi are surgically accessible; thus, early diagnosis is important, and all patients with exertional dyspnea should be evaluated for pulmonary hypertension. Ventilation/perfusion scans provide an excellent non-invasive means to distinguish CTEPH from pulmonary arterial hypertension. Similarly, computed tomographic pulmonary angiograms allow for the detection of thrombi and evaluation of pulmonary hemodynamics in a minimally invasive manner. Importantly, the absence of subpleural perfusion on pulmonary angiograms can suggest the presence of small vessel disease. Small vessel disease might be involved in the pathogenesis of CTEPH, and its detection is essential in preventing operative death. Although no modern therapies for pulmonary arterial hypertension have been approved for treatment of CTEPH, a recent randomized control trial of riociguat in patients with CTEPH demonstrated that riociguat significantly improved 6-min walking distance. Further investigations into treatments that target endothelial dysfunction and hyperproliferative CTEPH cells are needed. Recently, balloon pulmonary angioplasty has emerged as a promising treatment modality in Japan. A specialized medical team, including at least one expert surgeon, should make decisions regarding patients' candidacy for pulmonary endarterectomy and/or balloon pulmonary angioplasty.

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: This work was supported by a Research Grant for Cardiovascular Disease (12C-2) from the Ministry of Health, Labour and Welfare, the Uehara Memorial Foundation, and a grant from the Japan Cardiovascular Research Foundation.

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Chest

Clinical InvestigationsPULMONARY HYPERTENSIONEffect of Orally Active Prostacyclin Analogue on Survival in Patients With Chronic Thromboembolic Pulmonary Hypertension Without Major Vessel Obstruction

Objectives:

Background:

Methods:

Results:

Conclusions:

Section snippets

Study Subjects

Results

Discussion

Conclusions

J Thorac Cardiovasc Surg

Chest

J Am Coll Cardiol

J Am Coll Cardiol

Lancet

J Am Coll Cardiol

Prog Cardiovasc Dis

Chest

Chest

Chronic major vessel thrombo-embolic pulmonary hypertension

Circulation

Clinical Investigations
PULMONARY HYPERTENSION
Effect of Orally Active Prostacyclin Analogue on Survival in Patients With Chronic Thromboembolic Pulmonary Hypertension Without Major Vessel Obstruction