CLINICAL STUDIES
Effect of orally active prostacyclin analogue on survival of outpatients with primary pulmonary hypertension
Noritoshi Nagaya, MD*,
Masaaki Uematsu, MD, PhD ,
Yoshiaki Okano, MD ,
Toru Satoh, MD, PhD*,
Shingo Kyotani, MD, PhD*,
Fumio Sakamaki, MD, PhD*,
Norifumi Nakanishi, MD, PhD*,
Kunio Miyatake, MD, PhD, FACC* and
Takeyoshi Kunieda, MD, PhD
* Division of Cardiology, Department of Medicine, National Cardiovascular Center, Osaka, Japan
Cardiovascular Division, Osaka Police Hospital, Osaka, Japan
Department of Clinical Laboratory Medicine, Kyoto University Hospital, Kyoto, Japan
Department of Medicine, Ise Keio Hospital, Keio University, Mie, Japan
Manuscript received May 28, 1998;
revised manuscript received May 4, 1999,
accepted June 11, 1999.
Reprint requests and correspondence: Noritoshi Nagaya, MD, Division of Cardiology, Department of Medicine, National Cardiovascular Center, 5-7-1 Fujishirodai, Suita, Osaka 565, Japan
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Abstract
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OBJECTIVES
This study sought to investigate the effect of beraprost sodium (BPS), an orally active prostacyclin analogue, on the survival of outpatients with primary pulmonary hypertension (PPH).
BACKGROUND
Continuous intravenous administration of epoprostenol (prostacyclin) has been shown to improve survival in PPH. However, the effect of oral BPS on survival in PPH remains unknown.
METHODS
Fifty-eight consecutive patients with PPH who could be discharged after the first diagnostic catheterization for PPH were retrospectively divided into two groups: patients treated with BPS (BPS group, n = 24) and those without BPS (conventional group, n = 34). The baseline demographic and hemodynamic data did not significantly differ between the two.
RESULTS
Twenty-seven patients died of cardiopulmonary causes in the conventional group during a mean follow-up period of 44 ± 45 months. In contrast, only 4 patients died of cardiopulmonary causes in the BPS group during a mean follow-up period of 30 ± 20 months. In a subsample (n = 15) of patients in the BPS group, mean pulmonary arterial pressure and total pulmonary resistance significantly decreased, respectively, by 13% and 25% during a mean follow-up period of 53 days. Among the variables previously known to be associated with the mortality in PPH, the absence of BPS therapy and the reduced cardiac output were independently related to the mortality by a multivariate Cox proportional hazards regression analysis (both p < 0.05). The Kaplan-Meier survival curves demonstrated that the one-, two- and three-year survival rates for the BPS group were 96%, 86% and 76%, respectively, as compared with 77%, 47% and 44%, respectively, in the conventional group (log-rank test, p < 0.05).
CONCLUSIONS
The oral administration of BPS may have beneficial effects on the survival of outpatients with PPH as compared with conventional therapy alone.
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Abbreviations and Acronyms
| | BPS | = beraprost sodium | | PPH | = primary pulmonary hypertension |
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Primary pulmonary hypertension (PPH) is a rare, but life-threatening disease characterized by progressive pulmonary hypertension, ultimately producing right ventricular failure and death (1). Although a variety of vasodilators have been proposed as a potential therapy for PPH over the past 30 years (2-6), there have been conflicting results with these vasodilators, and some patients ultimately require heart-lung or lung transplantation (7–9). Recently, continuous intravenous infusion of epoprostenol (prostacyclin) has been introduced as a treatment for advanced PPH (10,11). Long-term therapy with epoprostenol markedly lowered pulmonary vascular resistance in patients with PPH (12,13). A prospective, randomized study has shown sustained clinical benefits of epoprostenol and improved long-term survival in patients who received this agent (14). This treatment, however, requires a continuous intravenous infusion device, hence being more uncomfortable and expensive than taking oral medications.
Beraprost sodium (BPS) is a newly developed prostacyclin analogue with a stable structure because of its cyclopentabenzofuranyl skeleton (15). Unlike epoprostenol, BPS permits oral ingestion because of its long-lasting activities (16). Like epoprostenol, BPS produces strong vasodilation and inhibition of platelet aggregation (17). Recently, we have shown that long-term therapy with BPS reduces pulmonary vascular resistance in patients with PPH (18). However, whether oral BPS improves long-term survival in PPH remains unknown. Thus, in this study, we sought to investigate the effect of BPS on the survival of outpatients who could be discharged after the first diagnostic catheterization for PPH.
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Methods
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Study subjects.
We enrolled 58 consecutive patients who could be discharged after the first diagnostic catheterization for PPH between June 1981 and August 1997. PPH was defined as pulmonary hypertension unexplained by any secondary cause, based on the criteria of National Institutes of Health registry on PPH (1). The 24 patients diagnosed between January 1993 and August 1997 were treated with BPS in addition to conventional therapy, serving as a BPS group. The other 34 patients diagnosed before December 1992 were treated with conventional therapy alone: calcium antagonists, nitrates, digitalis and diuretics, serving as a conventional group. Calcium antagonists were used in patients who showed a more than 20% decrease in total pulmonary resistance by short-term oral administration of nifedipine (20 mg). This study was designed to maintain BPS therapy at the highest dose tolerated. Oral administration of BPS was begun at a rate of 60 µg/day and was increased by increments of 60 µg/day over one to two weeks until the highest dose tolerated (range = 60 to 180 µg/day). The daily dose was split into three or four times. Within one week of the administration of BPS, several side effects occurred in 10 patients (42%): flushing in 4 patients; headache in 2; flushing and headache in 2; arthralgia in 1; diarrhea and nausea in 1. When the adverse effects of BPS occurred, either the dose of BPS was reduced or the same daily dose was given by splitting. All patients in the BPS group eventually tolerated at least 60 µg/day of BPS. Additional therapy for PPH and right ventricular failure, such as anticoagulation, digitalis and diuretics, was prescribed by attending physicians ad libitum.
Hemodynamic studies.
Baseline hemodynamic variables including mean pulmonary arterial pressure, mean right atrial pressure, pulmonary capillary wedge pressure and mean systemic arterial pressure were measured at end expiration in all patients by right heart catheterization. Cardiac output was measured by Fick’s method (19). Total pulmonary resistance was calculated by dividing mean pulmonary arterial pressure by cardiac output. Hemodynamic measurements were repeated in a subsample (n = 15) of study patients after a mean follow-up period of 53 days in order to assess the long-term hemodynamic effects of BPS.
Survival estimates.
Survival was estimated from the date of initial diagnosis to November 30, 1998, or the death of the patient. Patients who received the continuous intravenous infusion of epoprostenol or transplantation and those who died of noncardiac causes were judged at that time point. Four patients in the conventional group to whom BPS was later prescribed by attending physicians were also judged at that time point.
Statistical analysis.
All data were expressed as mean values ± SD. Comparisons between two groups were made by the Fisher exact test or the unpaired Student t test. Hemodynamic effects of BPS therapy were analyzed with the paired Student t test. To determine whether BPS therapy had independent prognostic significance, the following seven variables were entered into a multivariate Cox proportional hazards regression analysis: mean pulmonary arterial pressure, cardiac output, mean right atrial pressure, arterial oxygen pressure, mixed venous oxygen saturation, absence of anticoagulation and absence of BPS therapy. Survival curves according to the presence or absence of BPS therapy were derived using the Kaplan-Meier method and compared using log-rank tests. A p value <0.05 was considered statistically significant.
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Results
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Demographic, hemodynamic and pulmonary function data at baseline did not significantly differ between the BPS group and the conventional group (Table 1). There was no difference in the frequency of using anticoagulant agents, nitrates, diuretics and home oxygen therapy between the groups, except that digitalis and calcium antagonists were more frequently used in the conventional group than in the BPS group.
Of the 34 patients in the conventional group, 27 patients died of cardiopulmonary causes, 1 died of a traffic accident, 1 had lung transplantation and 1 patient received continuous intravenous infusion of epoprostenol during a mean follow-up period of 44 ± 45 months. In contrast, of the 24 patients in the BPS group, only 4 patients died of cardiopulmonary causes and 4 patients received continuous intravenous infusion of epoprostenol during a mean follow-up period of 30 ± 20 months.
Long-term therapy with BPS significantly lowered mean pulmonary arterial pressure and total pulmonary resistance by 13% and 25%, respectively (Fig. 1). Cardiac output significantly increased by 17%. There was a slight reduction in mean systemic blood pressure (84 ± 9 to 78 ± 11 mm Hg). New York Heart Association functional class improved in 16 patients (67%), worsened in 2 (8%) and was unchanged in 6 (25%).
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Figure 1 Long-term effects of beraprost sodium on: (A) mean pulmonary arterial pressure (mPAP), (B) cardiac output (CO) and (C) total pulmonary resistance (TPR).
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Among the variables previously known to be associated with the mortality in PPH, i.e., mean pulmonary arterial pressure, cardiac output, mean right atrial pressure, arterial oxygen pressure, mixed venous oxygen saturation and anticoagulation therapy (20–22), the absence of BPS therapy and the reduced cardiac output were independently related to the mortality (Table 2). The Kaplan-Meier survival curves demonstrated that the BPS group had a significantly higher survival rate than the conventional group (log-rank test, p <0.05; Fig. 2). The one-, two- and three-year survival rates for the BPS group were 96%, 86% and 76%, respectively, as compared with 77%, 47% and 44%, respectively, in the conventional group.
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Figure 2 Kaplan-Meier survival curves showing that outpatients treated with beraprost sodium (BPS) have a significantly higher survival rate than those treated with conventional therapy (log-rank test, p < 0.001).
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Discussion
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The mean survival of patients with PPH has been reported to be two to three years after the diagnosis (22). In the present study, however, 80% of outpatients treated with oral BPS survived even after a mean follow-up period of 2.5 years. The absence of BPS therapy and the reduced cardiac output were independently related to mortality by a multivariate Cox proportional hazards regression analysis. The Kaplan-Meier survival curves demonstrated that the BPS group had a significantly higher survival rate than the conventional group. These results suggest that the oral administration of BPS may have beneficial effects on the survival of outpatients with PPH as compared with conventional therapy alone.
Conventional medical approaches for patients with PPH include the treatment with anticoagulants (21) and oral vasodilators (2-6). Rich et al. confirmed the beneficial effects of anticoagulant agents and calcium-channel blockers on survival in PPH (6). Nevertheless, there are some patients refractory to those medical treatments, ultimately requiring heart-lung or lung transplantation (7–9). Recently, continuous intravenous administration of epoprostenol (prostacyclin) has significantly improved survival of patients with PPH as compared with conventional therapy alone (14,23). More recently, long-term therapy with epoprostenol has been shown to markedly lower pulmonary vascular resistance beyond the level of acute vasodilator response to adenosine (12). Based on these studies, the intravenous infusion of prostacyclin has been established as treatment of PPH. However, epoprostenol is quickly metabolized and hence requires continuous intravenous administration. Quality of life and cost effectiveness still remain as important issues to be resolved. Thus, BPS, a prostacyclin analogue, was first developed in Japan (18).
In contrast to epoprostenol, BPS can be orally ingested because of its long-lasting activities (16). In humans, oral administration of BPS has acutely reduced pulmonary hypertension both in responders and in nonresponders to nitric oxide (25). In this study, long-term therapy with BPS significantly lowered mean pulmonary arterial pressure and total pulmonary resistance, although the hemodynamic responses to BPS were relatively small compared with intravenous epoprostenol therapy (10–12). Antiplatelet action as well as vasodilator activity of BPS may contribute to the long-term beneficial effects (17). Oral BPS has inhibited the development of monocrotaline-induced pulmonary hypertension and has reduced medial thickness of the pulmonary artery in rats (24). It is interesting to speculate that long-term treatment with BPS may inhibit vascular remodeling and vascular growth in patients with PPH. Further investigations are necessary regarding the mechanisms responsible for the improvement in the survival by oral BPS.
The mortality of patients with PPH have been shown to be associated with those variables of right ventricular function, that is, mean pulmonary arterial pressure, cardiac output and mean right atrial pressure (20,22). Mixed venous oxygen saturation, arterial oxygen pressure and anticoagulation therapy have also been related to the mortality (20,21). In this study, the absence of BPS was independently related to the mortality among the variables previously known to be associated with the mortality in PPH. Furthermore, the Kaplan-Meier survival curves demonstrated that the one-, two- and three-year survival rates for the BPS group were 96%, 86% and 76%, respectively, as compared with 77%, 47% and 44%, respectively, in the conventional group. Although this study population comprised outpatients with PPH who could be discharged after the first diagnostic catheterization, excluding patients with the most severe forms of PPH, the oral administration of BPS may have beneficial effects on the survival of the patients with milder forms of PPH. Given the potential risks and high medical costs of the invasive method, orally active BPS may be worth trying in such patients before the intravenous infusion therapy is considered.
Study limitations.
The patients who could not tolerate any vasodilator therapy due to the hypotension resulting from uncompensated right heart failure and died during the hospitalization were not enrolled in this study. This study may therefore include milder forms of PPH than earlier studies (20,22,23). Thus, effects of oral BPS in most severe forms of PPH remains unknown.
This study was retrospective, and the time point for the enrollment and the follow-up period differed between the BPS group and the conventional group, which might bias the results of this study. In addition, the subsequent therapy, which included calcium channel antagonists and digitalis, was not controlled in this study. These drugs might have an effect on mortality in PPH. Although other demographic, hemodynamic and pulmonary function data at baseline did not significantly differ between the groups, a prospective, randomized and multicenter trial should be planned.
The mean follow-up period of the conventional group in this study exceeded the average survival of PPH previously reported by earlier studies (21,22). Because our study included only outpatients with PPH, who could be discharged after the first diagnostic catheterization, the average survival in our study may be longer than that in the whole patients with PPH.
Long-term hemodynamic effects of BPS were examined only in 15 patients who accepted the repeated right heart catheterization. However, there was no significant difference in baseline total pulmonary resistance (18 ± 6 vs. 17 ± 7 Wood units) or clinical outcome (death number, 4 vs. 1) between the 15 patients and the remaining 9 patients.
Four patients in the BPS group and one patient in the conventional group developed heart failure, eventually receiving continuous intravenous infusion of epoprostenol, and they are still alive. The results would not have been different even if these five had died of cardiopulmonary causes. Further studies are necessary to determine the indications for the intravenous infusion of epoprostenol and for the oral BPS.
Conclusions.
Although retrospective, this study suggests that the oral administration of BPS may have beneficial effects on the survival of outpatients with PPH as compared with conventional therapy alone.
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G. SIMONNEAU, R. J. BARST, N. GALIE, R. NAEIJE, S. RICH, R. C. BOURGE, A. KEOGH, R. OUDIZ, A. FROST, S. D. BLACKBURN, et al.
Continuous Subcutaneous Infusion of Treprostinil, a Prostacyclin Analogue, in Patients with Pulmonary Arterial Hypertension . A Double-blind, Randomized, Placebo-controlled Trial
Am. J. Respir. Crit. Care Med.,
March 15, 2002;
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800 - 804.
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M.M. Hoeper
Pulmonary hypertension in collagen vascular disease
Eur. Respir. J.,
March 1, 2002;
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L. H. Clapp, P. Finney, S. Turcato, S. Tran, L. J. Rubin, and A. Tinker
Differential Effects of Stable Prostacyclin Analogs on Smooth Muscle Proliferation and Cyclic AMP Generation in Human Pulmonary Artery
Am. J. Respir. Cell Mol. Biol.,
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M. R WILKINS and J. WHARTON
Progress in, and future prospects for, the treatment of primary pulmonary hypertension
Heart,
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C D Vizza, S Sciomer, S Morelli, C Lavalle, P Di Marzio, D Padovani, R Badagliacca, A R Vestri, R Naeije, and F Fedele
Long term treatment of pulmonary arterial hypertension with beraprost, an oral prostacyclin analogue
Heart,
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W Budts, N Van Pelt, H Gillyns, M Gewillig, F Van de Werf, and S Janssens
Residual pulmonary vasoreactivity to inhaled nitric oxide in patients with severe obstructive pulmonary hypertension and Eisenmenger syndrome
Heart,
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N. Galiè and A. Torbicki
GENERAL CARDIOLOGY: Pulmonary arterial hypertension: new ideas and perspectives
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