OBJECTIVES: The purpose of this study was to assess the safety and efficacy of the oral prostacyclin analogue beraprost sodium during a 12-month double-blind, randomized, placebo-controlled trial in patients with pulmonary arterial hypertension (PAH). BACKGROUND: Pulmonary arterial hypertension is a progressive disease that ultimately causes right heart failure and death. Despite the risks from its delivery system, continuous intravenous epoprostenol remains the most efficacious treatment currently available. METHODS: A total of 116 patients with World Health Organization (WHO) functional class II or III primary pulmonary hypertension or PAH related to either collagen vascular diseases or congenital systemic to pulmonary shunts were enrolled. Patients were randomized to receive the maximal tolerated dose of beraprost sodium (median dose 120 microg four times a day) or placebo for 12 months. The primary end point was disease progression; i.e., death, transplantation, epoprostenol rescue, or >25% decrease in peak oxygen consumption (VO(2)). Secondary end points included exercise capacity assessed by 6-min walk test and peak VO(2), Borg dyspnea score, hemodynamics, symptoms of PAH, and quality of life. RESULTS: Patients treated with beraprost exhibited less evidence of disease progression at six months (p = 0.002), but this effect was not evident at either shorter or longer follow-up intervals. Similarly, beraprost-treated patients had improved 6-min walk distance at 3 months by 22 m from baseline and at 6 months by 31 m (p = 0.010 and 0.016, respectively) compared with placebo, but not at either 9 or 12 months. Drug-related adverse events were common and were related to the disease and/or expected prostacyclin adverse events. CONCLUSIONS: These data suggest that beneficial effects may occur during early phases of treatment with beraprost in WHO functional class II or III patients but that this effect attenuates with time.

We compared the efficacy and safety of three doses of beraprost sodium, an epoprostenol analogue, with placebo in the treatment of intermittent claudication (Fontaine's stage II). One hundred sixty-four patients were randomized to receive either placebo, 20 micrograms beraprost sodium (BPS60 group), 40 micrograms beraprost sodium (BPS120 group), or 60 micrograms beraprost sodium (BPS180 group) three times daily administered orally in a double-blind manner for 12 weeks. Treadmill exercise tests were performed twice during an initial selection phase (D-28 and D0) at week 10 (at trough beraprost concentration) and week 12 (at peak beraprost concentration) of the treatment phase. At week 10, all groups showed an increase in pain-free walking distance, and this distance was greatest in the BPS60 and BPS120 groups (p = 0.055). At week 12, a similar pattern was observed, and the difference was significant between the groups (p = 0.023). The most frequent adverse events reported were gastrointestinal disorders, headaches, skin disorders, and flushes. Patients who received either 60 or 120 micrograms of beraprost sodium daily had an increased pain-free walking distance. Further studies are required to investigate why the highest dose used (180 micrograms daily) showed lower efficacy. Having both vasodilating and antiplatelet properties and being able to increase pain-free walking distance in the short term, beraprost sodium is a promising drug for the treatment of intermittent claudication.

BACKGROUND: Pulmonary vascular changes which occur early in the course of chronic obstructive pulmonary disease (COPD) are prevalent manifestation and later cause pulmonary hypertension, which is a bad prognostic factor in COPD. Beraprost sodium (BPS), an orally active prostacyclin analogue, has been shown to improve survival in patients with primary pulmonary hypertension. This study investigated the effect of BPS in the patients with COPD. METHODS: This is a double-blind randomized placebo-controlled, two center clinical trial. Twenty one consecutive patients with COPD were enrolled from June 2003 to June 2004 (patients treated with BPS for 3 months, BPS group, n=11; those with placebo, placebo group, n=10). The baseline demographic, pulmonary function and hemodynamic data were not significantly different between two groups. RESULTS: On echocardiographic examination, trans tricuspid valve pressure gradient has decreased significantly after 3 months with beraprost in the BPS group [17.7(+/-11.4) to 8.2(+/-8.9) mm Hg, p-value<0.05], while there was no significant change in the control group. Six-minute walking distance has decreased in the control group and increased in the BPS group, but there was no statistical significance. CONCLUSION: In patients with COPD oral administration of BPS reduced the pulmonary arterial pressure. The clinical significance of this finding, that is improving symptoms and natural course of the disease, needs further study.

To study the effectiveness for the treatment of intermittent claudication (IC) of three drugs with antiplatelet effects, cilostazol, beraprost sodium, and prostaglandin E(1) (PGE(1)), by using a systemic review of literature and a meta-analysis. A search was undertaken for studies reported between 1966-2002 in the MEDLINE database, and references in published articles and reviews were obtained. Data for maximum walking distance (MWD), pain-free walking distance (PFWD), and adverse clinical events were extracted from the articles that met the inclusion criteria. The pooled estimates of the weighted mean differences (WMD) of MWD and PFWD for cilostazol were 52.19 m [95% confidence interval (CI) 32.08, 72.31] and 39.75 m [95% CI 23.39, 56.10], and those for PGE(1) were 100.27 m [95% CI 15.76, 184.78] and 55.73 [95% CI 21.54, 89.92], respectively. These differences were statistically significant between the test drugs and placebo. However there was no statistical significance difference between beraprost sodium and placebo, even though there was one study that showed a tendency for improvement in walking distance. The total rate of adverse clinical events in cilostazol and beraprost sodium was higher than that for placebo, while there was no statistical significant difference between PGE(1) and placebo, although PGE(1) had a higher tendency for adverse clinical events. The literature evaluation results and the meta-analysis suggest that these two drugs (cilostazol and PGE(1)) can be considered to be effective drugs for the treatment of IC. Due to current availability of only a few clinical reports, further studies are needed to clarify the efficacy of beraprost sodium in the treatment of IC.

BACKGROUND: Beraprost sodium (BPS) is a new stable, orally active prostaglandin I(2) analogue with antiplatelet and vasodilating properties. We report the results of a phase III clinical trial of BPS in patients with intermittent claudication. METHODS AND RESULTS: Patients (n=549) with a pain-free walking distance of between 50 and 300 m were entered into a 4-week single-blind placebo run-in phase. Patients whose pain-free walking distance had changed by <25% were then randomized to receive either BPS (40 microg TID, n=209) or placebo (n=213) in a double-blind manner for 6 months. Pain-free and maximum walking distances were measured on the occasion of treadmill exercise tests performed at baseline and 1.5, 3, 4.5, and 6 months after randomization. Success was defined as an improvement of >50% in pain-free walking distance at month 6 and in > or =1 earlier treadmill exercise test in the absence of critical cardiovascular events. Success was observed more frequently in the BPS group (43.5%) than in the placebo group (33.3%, P=0.036). Pain-free walking distances increased by 81.5% and 52.5%, respectively, in the BPS and placebo groups (P=0.001) and maximum walking distances by 60.1% and 35.0%, respectively (P=0.004). The incidence of critical cardiovascular events was 4.8% in the BPS group and 8.9% in the placebo group. CONCLUSIONS: These results show that BPS is an effective symptomatic treatment of patients with intermittent claudication. The beneficial effects of BPS on critical cardiovascular events should be confirmed in appropriate clinical trials.

CRD SUMMARY: This review assessed cilostazol, beraprost sodium and prostaglandin E1 (PGE1) for treating intermittent claudication to improve walking distance. The authors concluded that cilostazol and PGE1 are effective, but further studies ofberaprost sodium are needed. A narrow literature search limits the reliability of these conclusions.

RECORD STATUS: None CITATION: Augustovski F, Pichon Riviere A, Alcaraz A, Bardach A, Ferrante D, Garcia Marti S, Glujovsky D, Lopez A, Regueiro A. Prostacyclins (epoprostenol, iloprost, treprostinil and beraprost) for the management of primary pulmonary hypertension and pulmonary hypertension in collagen vascular disease Ciudad de Buenos Aires: Institute for Clinical Effectiveness and Health Policy (IECS) 2005

RECORD STATUS: None CITATION: Pichon-Riviere A, Augustovski F, Garcia Marti S, Bardach A, Galante J, Lopez A, Regueiro A, Glujovsky D, Aruj P, Calcagno J, Linetzky B. Prostacyclins (epoprostenol, iloprost, treprostinil and beraprost) for the management of primary pulmonary hypertension and pulmonary hypertension in collagen vascular disease Buenos Aires: Institute for Clinical Effectiveness and Health Policy (IECS). Informe de Respuesta Rapida No.166 . 2009

OBJECTIVES: In the current study, we hypothesized that beraprost would: 1) improve treadmill exercise performance and quality of life; and 2) decrease rates of ischemic events in patients with intermittent claudication. BACKGROUND: Previous trials with beraprost sodium, an orally active prostaglandin I(2) analogue, in the treatment of claudication in patients with peripheral arterial disease (PAD) have been inconsistent. METHODS: Patients with intermittent claudication (n = 897) were randomized to receive either 40 microg three times a day of beraprost with meals (n = 385) or placebo (n = 377) in a double-blinded manner for one year. The primary efficacy parameter was treadmill-measured maximum walking distance, as assessed at three and six months after randomization. Secondary efficacy parameters included treadmill-measured pain-free walking distance and change in quality of life. RESULTS: There was no significant improvement in maximum walking distance in the beraprost group (16.7%) as compared with the placebo group (14.6%, p = NS). Administration of beraprost did not improve the pain-free walking distance (p = NS between treatment groups), and there was no improvement in the quality-of-life measures between the treatment groups. The incidence of critical cardiovascular events was 7.3% in the beraprost group and 11.4% in the placebo group (p = NS). There was a significant reduction in the combination of cardiovascular death and myocardial infarction in the beraprost group (p = 0.01). CONCLUSIONS: Despite previous investigations suggesting efficacy, these results indicate that beraprost is not an effective treatment to improve symptoms of intermittent claudication in patients with PAD. The potential benefit of beraprost on critical cardiovascular events would require confirmation in a larger prospective investigation.

OBJECTIVES: The purpose of this study was to assess the efficacy and safety of beraprost sodium, an orally active prostacyclin analogue, in New York Heart Association (NYHA) functional class II and III patients with pulmonary arterial hypertension (PAH). BACKGROUND: Pulmonary arterial hypertension is a life-threatening disease for which continuous intravenous infusion of prostacyclin has been proven effective. However, this treatment is associated with serious complications arising from the complex delivery system. METHODS: In this double-blind, placebo-controlled study, 130 patients with PAH were randomized to the maximal tolerated dose of beraprost (median dose 80 microg four times a day) or to placebo for 12 weeks. The primary end point was the change in exercise capacity assessed by the 6-min walk test. Secondary end points included changes in Borg dyspnea index, cardiopulmonary hemodynamics and NYHA functional class. RESULTS: Patients treated with beraprost improved exercise capacity and symptoms. The difference between treatment groups in the mean change of 6-min walking distance at week 12 was 25.1 m (95% confidence interval [CI]: 1.8 to 48.3, p = 0.036). The difference in the mean change of Borg dyspnea index was -0.94 (95% CI: -1.63 to -0.24, p = 0.009). In the sub-group of patients with primary pulmonary hypertension, the difference in the mean change of 6-min walking distance was 46.1 m (95% CI: 3.0 to 89.3, p = 0.035). Cardiopulmonary hemodynamics and NYHA functional class had no statistically significant changes. Drug-related adverse events were common in the titration phase and decreased in the maintenance period. CONCLUSIONS: Beraprost improves exercise capacity and symptoms in NYHA functional class II and III patients with PAH and, in particular, in those with primary pulmonary hypertension.