Effects of Beraprost Sodium, an Oral Prostacyclin Analogue, in Patients

View metadata, citation and similar papers at core.ac.uk brought to you by CORE

provided by Elsevier - Publisher Connector

Journal of the American College of Cardiology Vol. 39, No. 9, 2002 © 2002 by the American College of Cardiology Foundation ISSN 0735-1097/02/$22.00 Published by Elsevier Science Inc. PII S0735-1097(02)01786-2 Pulmonary Hypertension Effects of Beraprost Sodium, an Oral Prostacyclin Analogue, in Patients With Pulmonary Arterial Hypertension: A Randomized, Double-Blind, Placebo-Controlled Trial Nazzareno Galie`, MD,* Marc Humbert, MD,† Jean-Luc Vachie´ry, MD,‡ Carmine Dario Vizza, MD,§ Meinhard Kneussl, MD,࿣ Alessandra Manes, MD,* Olivier Sitbon, MD,† Adam Torbicki, MD,¶ Marion Delcroix, MD,# Robert Naeije, MD,‡ Marius Hoeper, MD,** Ari Chaouat, MD,†† Sophie Morand, MD,‡‡ Bruno Besse, MD,‡‡ Gerald Simonneau, MD,† for the Arterial Pulmonary Hypertension and Beraprost European Trial (ALPHABET) Study Group Bologna, Italy; Clamart, Strasbourg and Paris, France; Brussels and Leuven, Belgium; Rome, Italy; Vienna, Austria; Warsaw, Poland; and Hannover, Germany

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 ␮g 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 ϭ 0.036). The difference in the mean change of Borg dyspnea index was Ϫ0.94 (95% CI: Ϫ1.63 to Ϫ0.24, p ϭ 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 ϭ 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. (J Am Coll Cardiol 2002;39:1496–502) © 2002 by the American College of Cardiology Foundation

Pulmonary arterial hypertension (PAH) is defined, accord- and pulmonary hypertension associated with various condi- ing to the 1998 World Health Organization classification tions such as collagen vascular diseases (5), congenital (1), as a group of diseases characterized by a progressive systemic-to-pulmonary shunts (6), portal hypertension (7) increase of pulmonary vascular resistance leading to right and human immunodeficiency virus (HIV) infection (8). All ventricular failure and death (2,3). Pulmonary arterial hy- these conditions share virtually identical obstructive patho- pertension includes primary pulmonary hypertension (2,4) logic changes of the pulmonary microcirculation (9). Pros- tacyclin is an endogenous substance produced by vascular From the *Institute of Cardiology, University of Bologna, Bologna, Italy; †Division of Pulmonary and Critical Care Medicine, Antoine Bećle`re Hospital, Clamart, endothelium that has vasodilating, antiplatelet aggregation Paris-Sud University, Clamart, France; ‡Departement de Cardiologie et Laboratoire and antiproliferative effects (10–12). A dysregulation of de Physiologie, Hoˆpital Erasme, Universite´ Libre de Bruxelles, Brussels, Belgium; prostacyclin metabolic pathways has been demonstrated in §Department of Cardiology, University of Roma “La Sapienza,” Rome, Italy; ࿣Allgemeines Krankenhaus der Stadt Wien, University of Vienna, Vienna, Austria; patients with PAH (13) and in experimental models of ¶Department of Chest Medicine, National Institute of Tuberculosis and Lung pulmonary hypertension (14,15). Recently, therapy with Disease, Warsaw, Poland; #Department of Pneumology, Gasthuisberg University continuous intravenous prostacyclin (epoprostenol) has been Hospital, Leuven, Belgium; **Abteilung Pneumologie, Medizinische Hochschule Hannover, Hannover, Germany; ††Service de Pneumologie, Centre Hospitalier shown to improve symptoms and prognosis in New York Hautepierre, Strasbourg, France; ‡‡Laboratoire Aventis, Paris, France. Supported by Heart Association (NYHA) functional class III and IV a grant from Laboratoire Aventis, Paris, France. Manuscript received November 6, 2001; revised manuscript received January 28, patients with different types of PAH (16–20). However, 2002, accepted February 6, 2002. epoprostenol requires permanent intravenous catheters and JACC Vol. 39, No. 9, 2002 Galie` et al. 1497 May 1, 2002:1496–502 Beraprost Sodium in Pulmonary Hypertension

20 ␮g or matching placebo four times a day each week. In Abbreviations and Acronyms case of intolerable side effects, the dose was reduced to that CI ϭ confidence interval of the previous week, and this was considered as the HIV ϭ human immunodeficiency virus maximal tolerated dose. Therefore, the up-titration was ϭ PAH pulmonary arterial hypertension based on side effects and not on clinical efficacy, in order to NYHA ϭ New York Heart Association administer the highest tolerated dose. The maximal dose allowed in the study was 120 ␮g four times a day at week 6. The maximal tolerated dose was kept constant during the portable pumps and is associated with several side effects maintenance period between week 7 and week 12. Side and potentially serious complications. For these reasons, effects limiting dose increase were moderate to severe alternatives to intravenous prostacyclin have been sought, flushing, headache and diarrhea and usually occurred 1 to and this has led to analogues, which can be administered 2 h after single-dose intake. All patients were enrolled in an subcutaneously (treprostinol), by inhalation (iloprost) or open-label study with beraprost sodium after the comple- orally (beraprost sodium) (21). tion of the randomized study. Beraprost sodium is the first chemically stable and orally Outcome measures. Patients were evaluated at baseline, active prostacyclin analogue (22). In experimental studies, week 6 and week 12. The primary efficacy parameter was beraprost sodium has been shown to exert a protective effect exercise capacity measured by the distance a patient could on the development of monocrotaline-induced pulmonary walk in 6 min (6-min walk test) at week 12. The 6-min walk hypertension (23). Uncontrolled and retrospective experi- test was performed after standardized procedures (26) 2 to ences in patients with primary pulmonary hypertension have 4 h after drug intake. preliminarily shown that long-term oral treatment with Secondary measures of efficacy included the Borg dyspnea beraprost sodium improves hemodynamics (24) and prog- index (27) assessed immediately after completion of the nosis (25). 6-min walk test and cardiopulmonary hemodynamics mea- We report on the results of a randomized, double-blind, sured by right heart catheterization at baseline and week 12. placebo-controlled, multicenter study designed to deter- Cardiac index (l/min/m2) was computed as cardiac output mine the effects of 12-week oral administration of beraprost divided by body surface area; pulmonary vascular resistance sodium on exercise capacity, symptoms and cardiopulmo- index (U/m2) was calculated using standard formula: mean nary hemodynamics in NYHA class II and III patients with pulmonary artery pressureϪpulmonary capillary wedge PAH. pressure/cardiac index. Secondary measures of efficacy also METHODS included the NYHA functional class and the reduction in all-cause mortality or hospitalization for worsening of Patients selection. Patients eligible for this study were symptoms related to pulmonary hypertension. Safety was males or females over 8 years of age with PAH (1) in assessed by adverse event recording and laboratory assess- NYHA functional classes II and III, including primary ment. pulmonary hypertension, pulmonary hypertension associ- Statistical analysis. The sample size was estimated under ated with collagen vascular disease, congenital systemic-to- the assumptions of a two-sided alpha probability of 0.05, an pulmonary shunts, portal hypertension and HIV infection. 80%-power, an expected treatment difference for the change A baseline 6-min walking distance between 50 and 500 m, from baseline in 6-min walk test of 40 m and an SD of a mean pulmonary artery pressure Ͼ25 mm Hg and a 70 m. Under these conditions, the study’s 1:1 randomization pulmonary capillary wedge pressure Ͻ15 mm Hg were required a sample size of at least 50 evaluable patients in required for inclusion. Patients were excluded if they had each group. Assuming a 10% drop-out rate, planned recruit- received long-term treatment with other prostacyclin ana- ment was for a total of 110 patients (55 per group). logues within one month of enrolment. The study was Analysis were performed in the intent-to-treat popula- conducted in accordance with good clinical practices, the tion that included all patients who were randomized, re- current version of the declaration of Helsinki and with local ceived at least one dose of study treatment and who also had regulations. The local ethics review committee approved the a valid assessment of the primary end point (change from protocol, and written informed consent was obtained from baseline in exercise capacity after 12 weeks of treatment) all patients. after applying the imputation rules for missing data. Study design. This study was designed as a prospective, In the event that no data were available at week 12 for the double-blind, randomized, placebo-controlled, 12-week primary or secondary efficacy variable, the week 6 values or, trial conducted in 13 centers in Europe. The first six weeks if lacking, the baseline values were carried forward and used of the study were considered as a titration period in which as values at week 12 (last observation carried forward). Two the dose of beraprost sodium was increased weekly until the additional methods for missing data imputation were pro- maximal tolerated dose was achieved. Patients received one spectively planned for the primary efficacy variable to ensure tablet (20 ␮g) of beraprost sodium or matching placebo four robustness of the results: the “left censored data” and “worst times a day for the first week, and the dose was increased by quartile” methods. 1498 Galie` et al. JACC Vol. 39, No. 9, 2002 Beraprost Sodium in Pulmonary Hypertension May 1, 2002:1496–502

Table 1. Demographic and Hemodynamic Characteristics at Baseline, According to Treatment Group* Beraprost Placebo (65 ؍ n) (65 ؍ Characteristic (n Age, yrs 45.8 Ϯ 16.3 45.1 Ϯ 14.4 Gender, no. (%) Male 23 (35.4) 27 (41.5) Female 42 (64.6) 38 (58.5) Etiology, no. (%) Primary pulmonary hypertension 35 (53.9) 28 (43.1) Pulmonary hypertension associated with: Congenital cardiac shunt 9 (13.8) 15 (23.1) Portal hypertension 12 (18.5) 9 (13.8) Collagen vascular diseases 5 (7.7) 8 (12.3) HIV infection 4 (6.2) 5 (7.7) NYHA functional class, no. (%) II 31 (47.7) 33 (50.8) Figure 1. Change in 6-min walking distance from baseline to week 6 and week 12 in the placebo and beraprost groups. Values are expressed as mean III 34 (52.3) 32 (49.2) Ϯ ϭ 6-min walk distance, m 362 Ϯ 94 383 Ϯ 93 standard error. p 0.036 for no difference between treatment groups with analysis of covariance at week 12. Borg dyspnea score, Borg scale 3.6 Ϯ 2.4 3.5 Ϯ 2.4 Hemodynamic parameters Right atrial pressure, mm Hg 8 Ϯ 59Ϯ 6 walked at the 6-min walk test or in severity of pulmonary Mean pulmonary artery pressure, 58 Ϯ 21 61 Ϯ 15 hemodynamics. In the beraprost sodium group, there was a mm Hg nonsignificant trend toward a higher prevalence of patients Cardiac index, l/min/m2 2.4 Ϯ 0.7 2.4 Ϯ 0.7 with primary pulmonary hypertension as well as a trend Ϯ Ϯ Pulmonary vascular resistance 22.7 12.8 23.9 10.8 toward a lower mean distance walked at baseline. index, U/m2 Treatment at inclusion, no. (%) Exercise capacity. The distance walked in 6 min improved Anticoagulants 49 (75.4) 46 (70.8) in the beraprost sodium group from 362 Ϯ 94mto377Ϯ Diuretics 33 (50.8) 36 (55.4) 106 m at week 6 and to 377 Ϯ 113 m at week 12. The Calcium channel blockers 17 (26.2) 11 (16.9) distance walked increased in the placebo group from 383 Ϯ Digoxin 12 (18.5) 13 (20.0) 93 m to 388 Ϯ 111 m at week 6 and decreased to 374 Ϯ *Values with a Ϯ symbol are the mean Ϯ SD. 121 m at week 12. The difference in mean distance walked HIV ϭ human immunodeficiency virus; NYHA ϭ New York Heart Association. (beraprost sodium group Ϫ placebo group) at week 12 adjusted by baseline values was 25.1 m (95% confidence The significance levels of the difference between treat- interval [CI]: 1.8 to 48.3) in favor of beraprost sodium (p ϭ ment groups for the 6-min walk test were evaluated with 0.036) (Fig. 1). The significance of the improvement in analysis of covariance (ANCOVA) (i.e., analysis of variance exercise capacity with beraprost sodium was confirmed if the adjusted by baseline values, using the change from baseline missing walking distance was replaced utilizing left censored to week 12 for each patient [SAS, version 8, Cary, North data (p ϭ 0.048) and worst quartile (p ϭ 0.046) methods. Carolina]). This test was performed at 5% two-tail level. The significance was confirmed also in the per-protocol The changes from baseline to week 12 of Borg dyspnea (standard) population (p ϭ 0.041). index and hemodynamic parameters were compared be- Because the clinical hypothesis of an interaction between tween treatment groups with ANCOVA. Changes from treatment effect and the two sub-groups of patients with baseline to week 12 in NYHA classification (ordinal scale) primary pulmonary hypertension and associated forms of were analyzed using Mantel-Haenszel method. Values with pulmonary hypertension was suggested by an interaction a Ϯ symbol are the mean Ϯ SD. All the reported p values test (p ϭ 0.073 last observation carried forward, p ϭ 0.036 were two-tailed. left-censored, p ϭ 0.044 worst quartile methods), a sub- RESULTS group analysis was performed (post-hoc analysis). In the sub-group of patients with primary pulmonary hyperten- One hundred thirty patients were included in the study sion, the distance walked in 6 min improved at week 12 in (65 beraprost/65 placebo). At the end of 12 weeks, mean the beraprost sodium group from 357 Ϯ 95mto380Ϯ dose of drug was 80 Ϯ 35 ␮g four times a day (median ϭ 117 m and decreased in the placebo group from 406 Ϯ 79 m 80 ␮g four times a day) in the beraprost sodium group, and to 383 Ϯ 125 m. The difference in mean distance walked the hypothetical dose in the placebo group was 111 Ϯ 22 ␮g adjusted by baseline values (Fig. 2) was 46.1 m (95% CI: 3.0 four times a day. to 89.3) in favor of beraprost sodium (p ϭ 0.035). In the Baseline characteristics. Baseline demographic, clinical sub-group of patients with associated forms of pulmonary and hemodynamic characteristics of the two groups are hypertension, the distance walked in 6 min increased at shown in Table 1. The groups did not differ significantly in week 12 in the beraprost sodium group from 367 Ϯ 94mto etiology of PAH, in NYHA functional class, in distance 373 Ϯ 110 m and was unchanged in the placebo group from JACC Vol. 39, No. 9, 2002 Galie` et al. 1499 May 1, 2002:1496–502 Beraprost Sodium in Pulmonary Hypertension

Figure 2. Mean change from baseline in results of the 6-min walk test at week 12 in all patients (ALL), in patients with primary pulmonary hypertension (PPH) and in patients with associated forms of pulmonary hypertension (APH). Analysis of covariance adjusted by baseline values showed that the mean distance walked in 6 min increased in patients who received beraprost (solid bars) compared with patients who received placebo (open bars) in ALL (p ϭ 0.036) and in PPH patients (p ϭ 0.035). No statistically signiﬁcant changes were observed in APH patients (p ϭ 0.676). Numbers at the tops of the bars ϭ exact mean rates; lines ϭ standard error of the mean. N ϭ the number of patients in each group.

366 Ϯ 100 m to 366 Ϯ 120 m. The difference in mean Borg dyspnea index was Ϫ1.46 (95% CI: Ϫ2.63 to Ϫ0.28) distance walked adjusted by baseline values (Fig. 2) was in favor of beraprost sodium (p ϭ 0.013) and in the 5.1 m (95% CI: Ϫ19.5 to 29.6) in favor of beraprost sodium associated forms of pulmonary hypertension sub-group was (p ϭ 0.676). Ϫ0.45 (95% CI: Ϫ1.31 to 0.40) in favor of beraprost Signs and symptoms. Borg dyspnea index improved (de- sodium (p ϭ 0.283). creased) at week 12 in the beraprost sodium group from At the end of 12 weeks, 16 patients (25%) treated with 3.6 Ϯ 2.4 m to 3.0 Ϯ 2.4 m and worsened (increased) in the beraprost sodium and 10 patients (15%) of the placebo placebo group from 3.5 Ϯ 2.5 m to 3.9 Ϯ 2.8 m. The group showed improved NYHA functional class (p ϭ difference in mean Borg dyspnea index adjusted by baseline 0.190). values (Fig. 3) was Ϫ0.94 (95% CI: Ϫ1.63 to Ϫ0.24) in During the 12-week study period, four patients (6%) in favor of beraprost sodium (p ϭ 0.009). In the primary the beraprost sodium group and three (5%) patients in the pulmonary hypertension sub-group, the difference in mean placebo group either died or were hospitalized for worsening

Figure 3. Mean change in Borg dyspnea index from baseline to week 12 in all patients (ALL), in patients with primary pulmonary hypertension (PPH) and in patients with associated forms of pulmonary hypertension (APH). Analysis of covariance adjusted by baseline values showed that Borg dyspnea index improved (decreased) in patients who received beraprost (solid bars) and worsened (increased) in the placebo group (open bars) over 12 weeks in ALL (p ϭ 0.009) and in PPH patients (p ϭ 0.013). No statistically signiﬁcant changes were observed in APH patients (p ϭ 0.935). Numbers at the tops of the bars ϭ exact mean rates; lines ϭ standard error of the mean. N ϭ the number of patients in each group. 1500 Galie` et al. JACC Vol. 39, No. 9, 2002 Beraprost Sodium in Pulmonary Hypertension May 1, 2002:1496–502

Table 2. Changes From Baseline in Cardiopulmonary DISCUSSION Hemodynamic Measurements Exercise capacity. This double-blind, placebo-controlled, Change From Baseline p 12-week study demonstrated that the oral prostacyclin Variables Beraprost Placebo Value* analogue beraprost sodium improves exercise capacity and Right atrial pressure (mm Hg) 0 Ϯ 11Ϯ 0 0.219 symptoms in patients with PAH. As in other trials per- Systolic pulmonary artery Ϫ2 Ϯ 22Ϯ 2 0.058 formed in this patient population, the primary end point of pressure (mm Hg) this study was the 6-min walking distance that has been Ϫ Ϯ Ϯ Mean pulmonary artery 1 111 0.216 shown to be an independent predictor of mortality (16,28). pressure (mm Hg) Cardiac index (l/min/m2) 0.2 Ϯ 0.08 0.0 Ϯ 0.08 0.192 In our study the robustness of the 6-min walk test results Pulmonary vascular resistance Ϫ1.3 Ϯ 0.83 0.3 Ϯ 0.83 0.188 were confirmed by different statistical analysis. So far, index (U/m2) therapeutic trials in PAH have included more severely Values are given as mean Ϯ standard error of the mean. compromised subjects in NYHA functional class III or IV *Analysis of covariance. (16,18). For the first time, our study has included a larger proportion (49% of overall population) of less severe pa- of symptoms related to pulmonary hypertension. Two tients in NYHA functional class II (Table 1). Interestingly, patients died, one in the beraprost sodium group due to no significant interaction was observed between NYHA progressive right heart failure and one in the placebo group functional class and treatment effect, suggesting that the due to septic shock. favorable effects of beraprost sodium were similar in both Cardiopulmonary hemodynamics. The changes in hemo- NYHA functional class II and III patients. dynamic measures from baseline to week 12 are shown in Sub-group analysis. Sub-group analysis has shown that Table 2. The beraprost and placebo treated patients had the improvement in the 6-min walk test was achieved only small variations of hemodynamic parameters, and no statis- in patients with primary pulmonary hypertension, while no tically significant changes were detected. statistically significant changes were observed in the associ- Safety and tolerability. Selected adverse events attributed ated forms group (Fig. 2). The treatment effect observed in to the underlying disease or to the treatment are shown in NYHA class II and III patients with primary pulmonary Table 3. Disease-related events had similar incidence in hypertension was 45 m. In a previous study with intravenous patients receiving beraprost and in those receiving placebo. epoprostenol, carried out in a more severe patient popula- Drug-related adverse events like headache, flushing, jaw tion (NYHA functional class III and IV), the treatment pain and diarrhea were more common in patients treated effect was 47 m (16). with beraprost sodium and occurred mostly during the The absence of significant improvement of exercise ca- six-week titration period. The incidence was markedly pacity in associated forms of pulmonary hypertension could reduced in the maintenance period. be attributed to different causes. Firstly, in this trial the Six patients (9%) in the beraprost sodium group and two group of associated forms was heterogeneous including 36% patients (3%) in the placebo group withdrew prematurely of patients with congenital systemic-to-pulmonary shunts, from the study because of adverse events. No clinically 32% with portal hypertension, 19% with collagen vascular adverse changes in hematologic or biochemical variables disease and 13% with HIV infection. Analysis of the effects were seen in the beraprost sodium group. Liver transami- on each individual sub-group is prevented by the small nases increased by more than 0.6 times the upper normal sample size. So far, a single controlled clinical study has limits in four (6%) patients in the placebo group as com- demonstrated a positive effect of epoprostenol on exercise pared with none in the beraprost sodium group. capacity in patients with pulmonary hypertension associated

Table 3. Incidence of Selected Adverse Events According to the Study Period (65 ؍ Placebo (n (65 ؍ Beraprost (n Titration Maintenance Titration Maintenance Event (Week 1–6) (Week 7–12) (Week 1–6) (Week 7–12) Disease-related, no. (%) Dizziness 5 (7.7) 0 (0.0) 5 (7.7) 2 (3.1) Syncope 0 (0.0) 0 (0.0) 0 (0.0) 1 (1.5) Right heart failure 1 (1.5) 2 (3.1) 3 (4.6) 3 (4.6) Treatment-related, no. (%) Headache 44 (67.7) 11 (16.9) 11 (16.9) 1 (1.5) Flushing 35 (53.8) 9 (13.8) 8 (12.3) 3 (4.6) Jaw pain 18 (27.7) 3 (4.6) 1 (1.5) 0 (0.0) Diarrhea 17 (26.2) 2 (3.1) 4 (6.2) 1 (1.5) Leg pain 14 (21.5) 3 (4.6) 4 (6.2) 1 (1.5) Nausea 13 (20.0) 4 (6.2) 3 (4.6) 2 (3.1) JACC Vol. 39, No. 9, 2002 Galie` et al. 1501 May 1, 2002:1496–502 Beraprost Sodium in Pulmonary Hypertension with scleroderma (18). Treatment with prostanoids of all renal or hematologic side effects. Adverse events commonly the other forms of associated pulmonary hypertension have observed with all prostacyclin analogues (headache, flush- been evaluated in uncontrolled studies (17), and the favor- ing, jaw pain, diarrhea and nausea) were frequent during the able effects require further confirmations. Secondly, the titration period when the highest possible doses were tested, doses of beraprost sodium were substantially lower in while the tolerability of the drug was much better in the patients with associated forms of pulmonary hypertension maintenance phase. than in patients with primary pulmonary hypertension Conclusions. Oral beraprost sodium therapy is effective in (62 Ϯ 36 ␮g four times a day vs. 96 Ϯ 35 ␮g four times a improving functional capacity and symptoms in NYHA day, respectively). Dose increase was usually limited by functional class II and III patients with PAH and, in symptoms like headache, flushing and diarrhea, and it is particular, in those with primary pulmonary hypertension. possible that patients with associated conditions are more The benefit/risk ratio of beraprost sodium appears to be predisposed to these side effects. In fact, patients with portal satisfactory. However, further studies are needed to define hypertension, HIV infection and collagen vascular disease the long-term effect of this treatment on morbidity and have a multi-organ involvement that could interfere with mortality of patients with PAH. beraprost sodium tolerability. It is unclear from our data if the higher dose of beraprost sodium tolerated by patients Additional Members of the ALPHABET Study Group: with primary pulmonary hypertension may explain the Giulio Boggian, MD, Elena Mazzoni, MD, Federica Pe- better results obtained on 6-min walking distance. Finally, a lino, MD, University of Bologna, Italy; Roberto Badagli- 12-week study may be too short to demonstrate a beneficial acca, MD, University of Roma “La Sapienza,” Italy; Pawel effect of prostanoid therapy in the associated forms group. Kuca, MD, Marcin Kurzyna, MD, National Institute of In fact, patients with pulmonary hypertension associated Lung Disease, Warsaw, Poland; Edda Spiekerkoetter, MD, with systemic-to-pulmonary shunt or to portal hypertension Medizinische Hochschule Hannover, Germany; Christophe (67% of associated forms in this trial) may show a slower Pison, MD, Centre Hospitalier Universitaire, Grenoble, rate of clinical deterioration (29) and a longer preservation France; Francois Chabot, MD, CHU de Nancy, France; of the cardiac output. This evidence is supported in our Benoit Wallaert, MD, Hoˆpital Calmette, Lille, France; study by the absence of a reduction of the 6-min walking Irene Lang, MD, University of Wien, Austria; Christian distance in placebo-treated patients with the associated Opitz, MD, Universita¨t zu Berlin, Germany. forms, whereas the placebo-treated patients with primary pulmonary hypertension showed a significant decrease of Reprint requests and correspondence: Dr. Nazzareno Galie`, exercise capacity (Fig. 2). Istituto di Cardiologia, Universita`di Bologna, via Massarenti, 9, Symptoms and outcome. In the overall population, the 40138-Bologna, Italy. E-mail: [email protected]. improvement in the 6-min walking distance was associated with a concomitant significant improvement in the percep- tion of dyspnea, as assessed by the reduction of Borg REFERENCES dyspnea score (Fig. 3). On the other hand, we observed no 1. Nomenclature Committee. Nomenclature and classification of pulmo- statistically significant improvement of NYHA functional nary hypertension. Rich S, editor. Primary Pulmonary Hypertension: class in patients treated with beraprost, as compared with Executive Summary From the World Symposium—Primary Pulmo- placebo. In addition, the rate of the combined end point of nary Hypertension 1998. 1998:25–7. Geneva: World Health Organi- zation http://www.who.int/ncd/cvd/pph.html. death or hospitalization was low and similar in both 2. Rubin LJ. Primary pulmonary hypertension. N Engl J Med 1997;336: beraprost sodium and placebo groups (6% vs. 5%, respec- 111–7. tively). Possible explanations for these findings include the 3. Galie`N, Manes A, Uguccioni L, et al. Primary pulmonary hyperten- high proportion of NYHA functional class II patients at sion: insights into pathogenesis from epidemiology. Chest 1998;114 3 Suppl:184S–94S. baseline and the short duration of the study that was not 4. D’Alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with specifically designed to detect a difference in these secondary primary pulmonary hypertension: results from a national prospective end points. registry. Ann Intern Med 1991;115:343–9. 5. MacGregor AJ, Canavan R, Knight C, et al. Pulmonary hypertension Cardiopulmonary hemodynamics. Unlike the previous in systemic sclerosis: risk factors for progression and consequences for studies with epoprostenol (18), we did not find statistically survival. Rheumatology 2001;40:453–9. significant improvements in resting hemodynamic variables 6. Brickner ME, Hillis LD, Lange RA. Congenital heart disease in adults (second of two parts). N Engl J Med 2000;342:334–42. even if small favorable trends in the beraprost sodium group 7. Herve´ P, Lebrec D, Brenot F, et al. Pulmonary vascular disorders in were observed. Possible reasons for explaining these differ- portal hypertension. Eur Respir J 1998;11:1153–66. ences include the greater severity of baseline hemodynamic 8. Petitpretz P, Brenot F, Azarian R, et al. Pulmonary hypertension in patients with human immunodeficiency virus infection: comparison changes in earlier epoprostenol trials and the small deteri- with primary pulmonary hypertension. Circulation 1994;89:2722–7. oration we observed in the placebo group. 9. Pietra GG, Edwards WD, Kay JM, et al. Histopathology of primary Safety and tolerability. Despite the high doses of beraprost pulmonary hypertension: a qualitative and quantitative study of pulmonary blood vessels from 58 patients in the National Heart, Lung, sodium used in this study, the safety profile of the drug was and Blood Institute, Primary Pulmonary Hypertension registry. Cir- excellent with neither systemic hypotension nor hepatic, culation 1989;80:1198–206. 1502 Galie` et al. JACC Vol. 39, No. 9, 2002 Beraprost Sodium in Pulmonary Hypertension May 1, 2002:1496–502

10. Moncada S, Gryglewski R, Bunting S, Vane JR. An enzyme isolated 20. Aguilar RV, Farber HW. Epoprostenol (prostacyclin) therapy in from arteries transforms prostaglandin endoperoxides to an unstable HIV-associated pulmonary hypertension. Am J Respir Crit Care Med substance that inhibits platelet aggregation. Nature 1976;263:663–5. 2000;162:1846–50. 11. Gryglewski RJ. Interactions between endothelial mediators. Pharma- 21. Galie`N. Do we need controlled clinical trials in pulmonary arterial col Toxicol 1995;77:1–9. hypertension? Eur Respir J 2001;17:1–3. 12. Jones DA, Benjamin CW, Linseman DA. Activation of thromboxane 22. Nishio S, Kurumatani H. Pharmacological and clinical properties of and prostacyclin receptors elicits opposing effects on vascular smooth beraprost sodium, orally active prostacyclin analogue. Nippon muscle cell growth and mitogen-activated protein kinase signaling Yakurigaku Zasshi 2001;117:123–30. cascades. Mol Pharmacol 1995;48:890–6. 23. Miyata M, Ueno Y, Sekine H, et al. Protective effect of beraprost 13. Christman BW, McPherson CD, Newman JH, et al. An imbalance sodium, a stable prostacyclin analogue, in development of between the excretion of thromboxane and prostacyclin metabolites in monocrotaline-induced pulmonary hypertension. J Cardiovasc Phar- pulmonary hypertension. N Engl J Med 1992;327:70–5. 14. Tuder RM, Cool CD, Geraci MW, et al. Prostacyclin synthase macol 1996;27:20–6. expression is decreased in lungs from patients with severe pulmonary 24. Okano Y, Yoshioka T, Shimouchi A, Satoh T, Kunieda T. Orally hypertension. Am J Respir Crit Care Med 1999;159:1925–32. active prostacyclin analogue in primary pulmonary hypertension. Lan- 15. Badesch DB, Orton EC, Zapp LM, et al. Decreased arterial wall cet 1997;349:1365. prostaglandin production in neonatal calves with severe chronic pul- 25. Nagaya N, Uematsu M, Okano Y, et al. Effect of orally active monary hypertension. Am J Respir Cell Mol Biol 1989;1:489–98. prostacyclin analogue on survival of outpatients with primary pulmo- 16. Barst RJ, Rubin LJ, Long WA, et al. A comparison of continuous nary hypertension. J Am Coll Cardiol 1999;34:1188–92. intravenous epoprostenol (prostacyclin) with conventional therapy for 26. Guyatt GH, Sullivan MJ, Thompson PJ, et al. The 6-minute walk: a primary pulmonary hypertension: the Primary Pulmonary Hyperten- new measure of exercise capacity in patients with chronic failure. Can sion study group. N Engl J Med 1996;334:296–302. Med Assoc J 1985;132:919–23. 17. Rosenzweig EB, Kerstein D, Barst RJ. Long-term prostacyclin for 27. Borg GA. Psychophysical bases of perceived exertion. Med Sci Sports pulmonary hypertension with associated congenital heart defects. Exerc 1982;14:377–81. Circulation 1999;99:1858–65. 28. Miyamoto S, Nagaya N, Satoh T, et al. Clinical correlates and 18. Badesch DB, Tapson VF, McGoon MD, et al. Continuous intrave- prognostic signiﬁcance of six-minute walk test in patients with primary nous epoprostenol for pulmonary hypertension due to the scleroderma pulmonary hypertension: comparison with cardiopulmonary exercise spectrum of disease: a randomized, controlled trial. Ann Intern Med testing. Am J Respir Crit Care Med 2000;161:487–92. 2000;132:425–34. 29. Hopkins WE, Ochoa LL, Richardson GW, Trulock EP. Comparison 19. McLaughlin VV, Genthner DE, Panella MM, Hess DM, Rich S. of the hemodynamics and survival of adults with severe primary Compassionate use of continuous prostacyclin in the management of secondary pulmonary hypertension: a case series. Ann Intern Med pulmonary hypertension or Eisenmenger syndrome. J Heart Lung 1999;130:740–3. Transplant 1996;15:100–5.