Professional Documents
Culture Documents
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
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 Béclère 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, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium; prostacyclin metabolic pathways has been demonstrated in
§Department of Cardiology, University of Roma “La Sapienza,” Rome, Italy;
㛳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
Hospital, Leuven, Belgium; **Abteilung Pneumologie, Medizinische Hochschule
continuous intravenous prostacyclin (epoprostenol) has been
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 Galiè et al. 1497
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 ⫽
0.036) and in PPH patients (p ⫽ 0.035). No statistically significant changes were observed in APH patients (p ⫽ 0.676). Numbers at the tops of the bars ⫽
exact mean rates; lines ⫽ standard error of the mean. N ⫽ the number of patients in each group.
366 ⫾ 100 m to 366 ⫾ 120 m. The difference in mean Borg dyspnea index was ⫺1.46 (95% CI: ⫺2.63 to ⫺0.28)
distance walked adjusted by baseline values (Fig. 2) was in favor of beraprost sodium (p ⫽ 0.013) and in the
5.1 m (95% CI: ⫺19.5 to 29.6) in favor of beraprost sodium associated forms of pulmonary hypertension sub-group was
(p ⫽ 0.676). ⫺0.45 (95% CI: ⫺1.31 to 0.40) in favor of beraprost
Signs and symptoms. Borg dyspnea index improved (de- sodium (p ⫽ 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 ⫾ 2.4 m to 3.0 ⫾ 2.4 m and worsened (increased) in the beraprost sodium and 10 patients (15%) of the placebo
placebo group from 3.5 ⫾ 2.5 m to 3.9 ⫾ 2.8 m. The group showed improved NYHA functional class (p ⫽
difference in mean Borg dyspnea index adjusted by baseline 0.190).
values (Fig. 3) was ⫺0.94 (95% CI: ⫺1.63 to ⫺0.24) in During the 12-week study period, four patients (6%) in
favor of beraprost sodium (p ⫽ 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 ⫽
0.009) and in PPH patients (p ⫽ 0.013). No statistically significant changes were observed in APH patients (p ⫽ 0.935). Numbers at the tops of the bars ⫽
exact mean rates; lines ⫽ standard error of the mean. N ⫽ the number of patients in each group.
1500 Galiè et al. JACC Vol. 39, No. 9, 2002
Beraprost Sodium in Pulmonary Hypertension May 1, 2002:1496–502
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 ⫾ 36 g four times a day vs. 96 ⫾ 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, Hôpital 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, Universität zu Berlin, Germany.
forms, whereas the placebo-treated patients with primary
pulmonary hypertension showed a significant decrease of Reprint requests and correspondence: Dr. Nazzareno Galiè,
exercise capacity (Fig. 2). Istituto di Cardiologia, Università di Bologna, via Massarenti, 9,
Symptoms and outcome. In the overall population, the 40138-Bologna, Italy. E-mail: n.galie@bo.nettuno.it.
improvement in the 6-min walking distance was associated
with a concomitant significant improvement in the percep-
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