Journal of the American College of Cardiology
`© 2004 by the American College of Cardiology Foundation
`Published by Elsevier Inc.
`
`Vol. 43, No. 12 Suppl S
`ISSN 0735-1097/04/$30.00
`doi:10.1016/j.jacc.2004.02.036
`
`Prostanoid Therapy for
`Pulmonary Arterial Hypertension
`David B. Badesch, MD,* Vallerie V. McLaughlin, MD,† Marion Delcroix, MD,‡
`Carmine Dario Vizza, MD,§ Horst Olschewski, MD,㛳 Olivier Sitbon, MD,¶ Robyn J. Barst, MD#
`Denver, Colorado; Ann Arbor, Michigan; Leuven, Belgium; Rome, Italy; Giessen, Germany; Clamart, France;
`and New York, New York
`
`Prostanoids have played a prominent role in the treatment of pulmonary arterial hypertension
`(PAH). Several compounds and methods of administration have been studied: chronic
`intravenously infused epoprostenol, chronic subcutaneously infused treprostinil,
`inhaled
`iloprost, and oral beraprost. Chronic intravenous epoprostenol therapy has had a substantial
`impact on the clinical management of patients with severe PAH. It improves exercise
`capacity, hemodynamics, and survival in patients with idiopathic pulmonary arterial hyper-
`tension (IPAH). It also improves exercise capacity and hemodynamics in patients with PAH
`occurring in association with scleroderma. The complexity of epoprostenol therapy (chronic
`indwelling catheters, reconstitution of the drug, operation of the infusion pump, and others)
`has led to attempts to develop other prostanoids with simpler modes of delivery. Treprostinil,
`a stable prostacyclin analogue with a half-life of 3 h, has been developed for subcutaneous
`delivery. It has beneficial effects on exercise and hemodynamics, which depend somewhat on
`the dose achieved. This, in turn, is determined by the patient’s ability to tolerate the drug’s
`side effects, including pain and erythema at the infusion site. Inhaled iloprost therapy may
`provide selectivity of the hemodynamic effects to the lung vasculature, thus avoiding systemic
`side effects. In a randomized and controlled trial, iloprost resulted in improvement in a
`combined end point incorporating the New York Heart Association functional class, 6-min
`walk test, and deterioration or death. Beraprost is the first orally active prostacyclin analogue.
`In the first of two randomized controlled trials, beraprost increased exercise capacity in
`patients with IPAH, with no significant changes in subjects with associated conditions.
`Hemodynamics did not change significantly, and no difference in survival was detected
`between the two treatment groups. The second study showed that beraprost-treated patients
`had less disease progression at six months and confirmed the results of the previous trial.
`However, this improvement was no longer present at 9 or 12 months. In conclusion, though
`treatment with prostanoids is complicated by their generally short half-lives and complicated
`drug delivery systems, they continue to play an important role in the treatment of
`PAH.
`(J Am Coll Cardiol 2004;43:56S–61S) © 2004 by the American College of
`Cardiology Foundation
`
`A metabolite of arachidonic acid, prostacyclin is endog-
`enously produced by vascular endothelium. It is a potent
`vasodilator in both the pulmonary and systemic circulations,
`and has antiplatelet aggregatory activity. A relative defi-
`ciency of prostacyclin may contribute to the pathogenesis of
`pulmonary arterial hypertension (PAH). Clinical studies
`have explored the possibility that chronic therapy with
`exogenous prostacyclin analogues might be of long-term
`benefit in patients with moderately severe to severe PAH.
`To date, the following compounds and methods of admin-
`istration have been studied: chronic intravenously infused
`epoprostenol, chronic subcutaneously infused treprostinil,
`inhaled iloprost, and oral beraprost. This report summarizes
`the rationale for therapy utilizing each of these prostanoids,
`and it provides currently available evidence supporting the
`use of each in the treatment of PAH.
`
`From the *University of Colorado Health Sciences Center, Denver, Colorado;
`†University of Michigan, Ann Arbor, Michigan; ‡University Hospital Gasthuisberg,
`Leuven, Belgium; §University of Roma “La Sapienza,” Rome, Italy; 㛳University
`Hospital, Justus-Liebig-University, Giessen, Germany; ¶Hoˆpital Antoine Be´cle`re,
`Clamart, France; and #Columbia University College of Physicians and Surgeons,
`New York, New York.
`Manuscript received November 26, 2003; accepted February 3, 2004.
`
`EPOPROSTENOL
`
`Rationale. Christman et al. (1) reported a deficiency of
`prostacyclin and an excess of thromboxane in patients with
`PAH. Tuder et al. (2) showed decreased expression of
`prostacyclin synthase in lungs from patients with severe
`PAH. Exogenously administered prostanoid analogues
`might help to overcome the adverse effects of decreased
`endogenously produced prostacyclin. Epoprostenol has a
`very short half-life in the bloodstream, requiring constant
`intravenous (IV) administration.
`Treatment. In a multicenter, randomized, controlled trial
`in 81 patients with severe idiopathic pulmonary arterial
`hypertension (IPAH, formerly known as primary pulmo-
`nary hypertension or PPH), continuously intravenously
`infused epoprostenol plus conventional therapy (oral vaso-
`dilators, anticoagulation, others) was compared to conven-
`tional therapy alone. The epoprostenol-treated group dem-
`onstrated improved survival and exercise tolerance,
`increased cardiac output, and decreased pulmonary vascular
`resistance (3). The beneficial effects of epoprostenol therapy
`are often sustained. Barst et al. (4) reported long-term
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`June 16, 2004:56S–61S
`
`Badesch et al.
`Prostanoid Therapy for PAH
`
`57S
`
`Abbreviations and Acronyms
`IPAH ⫽ idiopathic pulmonary arterial hypertension
`⫽ intravenous
`IV
`⫽ nitric oxide
`NO
`NYHA ⫽ New York Heart Association
`PAH ⫽ pulmonary arterial hypertension
`PPH ⫽ primary pulmonary hypertension
`
`benefit in a small group of patients from centers involved in
`the earliest clinical use of epoprostenol. Shapiro et al. (5)
`and McLaughlin et al. (6) have described sustained benefit
`in larger numbers of patients. McLaughlin et al. (7) more
`recently reported experience with long-term epoprostenol
`therapy in 162 consecutive patients with IPAH followed for
`a mean of 36.3 months (median, 31 months) (Fig. 1). Data
`followed included functional class, exercise tolerance, and
`hemodynamics. Observed survival with epoprostenol ther-
`apy at one, two, and three years was 87.8%, 76.3%, and
`62.8%, respectively, and was significantly greater than the
`expected survival of 58.9%, 46.3%, and 35.4%, respectively,
`based on historical data. Baseline predictors of survival
`included exercise tolerance, functional class, right atrial
`pressure, and vasodilator response to adenosine. Predictors
`of survival after the first year of therapy included functional
`class and improvement in exercise tolerance, cardiac index,
`and mean pulmonary artery pressure.
`Sitbon et al. (8) evaluated the factors associated with
`long-term survival in patients with PPH/IPAH treated with
`continuous epoprostenol infusion. A total of 178 patients in
`New York Heart Association (NYHA) functional class III
`
`Figure 1. McLauglin et al. (7) reported 162 consecutive patients diagnosed
`with primary pulmonary hypertension and treated with epoprostenol who
`were followed for a mean of 36.3 months (median, 31 months). Observed
`survival (diamonds) with epoprostenol therapy at one, two, and three years
`was 87.8%, 76.3%, and 62.8%, respectively, and was significantly greater
`than the expected survival (squares) of 58.9%, 46.3%, and 35.4%, respec-
`tively, based on historical data. Baseline predictors of survival included
`exercise tolerance, functional class, right atrial pressure, and vasodilator
`response to adenosine. Predictors of survival after the first year of therapy
`included functional class and improvement in exercise tolerance, cardiac
`index, and mean pulmonary artery pressure. Reprinted with permission
`from Circulation (Lippincott Williams & Wilkins).
`
`or IV were treated with epoprostenol. Survival rates at one,
`two, three, and five years were 85%, 70%, 63%, and 55%,
`respectively. Baseline variables associated with a poor out-
`come were a history of right-sided heart failure, NYHA
`functional class IV, 6-min walk test ⱕ250 m (median
`value), right atrial pressure ⱖ12 mm Hg, and, paradoxically,
`mean pulmonary artery pressure ⱕ65 mm Hg. Multivariate
`analysis, including both baseline variables and those mea-
`sured after three months on epoprostenol, demonstrated
`that a history of right-sided heart failure, persistence of
`NYHA functional class III or IV at three months, and the
`absence of a decline in total pulmonary resistance of ⱖ30%,
`relative to baseline, were associated with poor survival. The
`investigators concluded that survival of patients with IPAH
`treated with epoprostenol depends both on severity of
`disease at baseline and the response to three months of
`therapy.
`A multicenter, randomized, and controlled study of
`chronic IV epoprostenol in patients with PAH occurring in
`association with the scleroderma spectrum of disease
`showed improvement in exercise capacity and hemodynam-
`ics at 12 weeks as compared to the control group (9). Trends
`were seen toward greater improvement in severity of the
`Raynaud phenomenon and fewer new digital ulcers in the
`epoprostenol group. A survival difference between groups
`was not seen in this population over the period of study, but
`the study was not adequately powered to detect such a
`difference.
`Epoprostenol therapy requires continuous IV infusion.
`The drug has a very short half-life (⬍6 min), is unstable at
`acidic PpH, and cannot be taken orally. It is unstable at
`room temperature, and is generally kept cold prior to
`infusion. Patients are usually begun on a low dosage of
`epoprostenol (1 to 2 ng/kg/min), and gradually titrated
`upward in increments of 1 to 2 ng/kg/min, based upon side
`effects and tolerance. Many patients seem to reach a
`“plateau” dose and may not require continued up-titration
`from that point. Whereas this dose may be between 20 and
`40 ng/kg/min for many patients, the dose range is wide,
`with considerable interindividual variability.
`Common side effects of epoprostenol therapy include
`flushing, headache, jaw pain with the first bite of food,
`(which is usually tolerable), diarrhea, nausea, a blotchy
`erythematous rash, and musculoskeletal aches and pain
`(predominantly involving the legs and feet). These side
`effects tend to be dose dependent, and they often respond to
`a cautious reduction in dose. Abrupt or inadvertent inter-
`ruption of the epoprostenol infusion should be avoided, as
`this may lead to a rebound worsening of pulmonary hyper-
`tension with symptomatic deterioration and perhaps even
`death. Complications of chronic IV therapy with epopro-
`stenol include line-related infections (which range from exit
`site reactions, to tunnel infections and cellulitis, to bactere-
`mia or sepsis), catheter-associated venous thrombosis,
`thrombocytopenia, and ascites (although this may also be a
`manifestation of severe disease).
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`Badesch etal.
`Prostanoid Therapy for PAH
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`JACC Vol. 43, No. 12 Suppl S
`June 16, 2004:56S–61S
`
`Chronic IV epoprostenol therapy has had a substantial
`impact on the treatment of patients with moderately severe
`to severe PAH. It has been best studied in patients with
`IPAH and PAH occurring in association with the sclero-
`derma spectrum of disease. Because of the complexity of
`epoprostenol therapy (chronic indwelling catheters, recon-
`stitution of the drug, operation of the infusion pump, and so
`forth), and the relative rarity of severe PAH, strong con-
`sideration should be given to referral to centers of excel-
`lence.
`
`TREPROSTINIL
`
`Rationale. Although epoprostenol is effective therapy for
`PAH, the nature of the delivery system has a number of
`potential complications, which range in severity from local
`exit site infections easily treated with oral antibiotics to
`life-threatening sepsis. Because of the short half-life of
`epoprostenol, interruptions in therapy related to catheter
`displacement or pump malfunction may be life-threatening.
`Rare adverse events associated with the delivery system
`include pneumothorax, deep venous thrombosis, and para-
`doxical embolus. The efficacy of epoprostenol, coupled with
`the limitations of the delivery system, has led to the
`development of prostacyclin analogues with alternative
`routes of delivery. Treprostinil, a stable prostacyclin ana-
`logue with a half-life of 3 h, has been developed for
`subcutaneous delivery.
`Treatment. In 14 patients with IPAH, treatment acutely
`with IV epoprostenol and IV treprostinil had similar hemo-
`dynamic effects (10). To test the alternative subcutaneous
`delivery method, the effects of IV treprostinil and subcuta-
`neous treprostinil were compared in 25 patients with IPAH.
`Acute hemodynamic effects were similar. An eight-week,
`placebo-controlled, 2:1 randomized trial of subcutaneous
`treprostinil was subsequently performed in 26 patients with
`IPAH. An improvement of 37 ⫾ 17 m in the 6-min walk
`distance occurred in patients receiving the active therapy
`(from 373 m to 411 m), compared to a 6 ⫾ 28-m reduction
`in those receiving placebo (379 m vs. 384 m), a nonstatis-
`tically significant trend. There was a favorable, but not
`statistically significant, trend in hemodynamics, with a 20%
`reduction in pulmonary vascular resistance index over the
`eight-week period in the group receiving active treprostinil.
`Adverse events including headache, diarrhea, flushing, jaw
`pain, and foot pain were common in the treprostinil group,
`similar to what had been previously reported with epopro-
`stenol. Pain (occasionally severe), erythema, and induration
`at the site of the subcutaneous infusion occurred frequently.
`A large international, placebo-controlled, randomized
`study was conducted assessing the efficacy of chronic sub-
`cutaneously delivered treprostinil in patients with IPAH or
`PAH occurring in association with collagen vascular disease
`or congenital systemic-to-pulmonary shunts (11). Four
`hundred-seventy patients enrolled between November 1998
`and October 1999 in 24 centers in North America and 16
`
`centers in Europe, Australia, and Israel were randomly
`assigned to receive either continuous subcutaneously infused
`treprostinil plus conventional therapy or continuous infu-
`sion of placebo plus conventional therapy. Owing to the
`infusion-site pain and reaction that occurred in the proof-
`of-concept trial, the dosing strategy called for lower doses at
`initiation, with a maximal allowable dose at the end of 12
`weeks of 22.5 ng/kg/min. The primary end point was
`exercise capacity as measured by the 6-min walk distance,
`which improved in the treprostinil group and was un-
`changed with placebo. The median difference between
`treatment groups was 16 m (p ⫽ 0.006), and the effect on
`exercise tolerance appeared to be dose related. The patients
`in the lowest two dosing quartiles experienced little im-
`provement in the 6-min walk distance, whereas patients in
`the highest quartile in terms of dose (⬎13.8 ng/kg/min)
`demonstrated an improvement of 36 m. Treprostinil ther-
`apy was also associated with a significant improvement in
`mean right atrial pressure, mean pulmonary artery pressure,
`cardiac index, pulmonary vascular resistance, and mixed
`venous oxygen saturation. Common side effects included
`headache, diarrhea, nausea, rash, jaw pain, and infusion-site
`pain. Of the patients, 85% complained of pain at the
`infusion site, and 83% had erythema or induration at the
`infusion site. Although statistically significant,
`improve-
`ment in the 6-min walk distance was relatively modest. The
`reasons for this may be multifactorial. Entry criteria for the
`treprostinil trial were much more broad than for either of
`the epoprostenol trials.
`
`INHALED ILOPROST
`
`Rationale. Inhaled therapy for pulmonary hypertension
`may provide selectivity of the hemodynamic effects to the
`lung vasculature, thus avoiding systemic side effects. Pul-
`monary selective vasodilation has been described for inhaled
`nitric oxide (NO), but this agent has several drawbacks.
`Most importantly, there are no data demonstrating im-
`proved survival during therapy with inhaled NO, and this
`agent possesses less vasodilative potency than do prostanoids
`in IPAH patients (12,13). In contrast, prostacyclin (epopro-
`stenol) has been shown to improve survival, exercise capac-
`ity, and hemodynamics in patients with severe IPAH
`(3,4,6), and the continuous IV infusion of this drug has been
`approved for therapy in certain groups of patients in the
`U.S. and several European countries.
`Treatment. Iloprost is a prostacyclin analogue and has the
`same biologic profile as the natural substance with respect to
`prostaglandin receptor binding and cellular effects (14). Its
`effects and its side effects are similar to those seen during
`epoprostenol infusion (15). In contrast, the chemical stabil-
`ity of iloprost is considerably better. Where epoprostenol
`has to be freshly dissolved, continuously cooled, and pro-
`tected from light to provide full activity, iloprost is stable at
`room temperature, at pH 7.4, and normal light. Epopro-
`stenol has a half-life of ⬍6 min, whereas iloprost has a
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`Badesch et al.
`Prostanoid Therapy for PAH
`
`59S
`
`serum half-life of 20 to 25 min (16). Iloprost has been
`approved for the treatment of PAH in New Zealand, and
`was recently approved for the treatment of IPAH in
`Europe. Although epoprostenol is available in the United
`States and Europe, iloprost is not approved in the U.S.
`Owing to the fact that the intra-acinar pulmonary arteries
`are tightly surrounded by alveolar surfaces, it is possible to
`vasodilate these vessels by means of alveolar deposition of a
`prostanoid. For long-term therapy, repetitive inhalations of
`iloprost are administered six to nine times daily. Each
`inhalation requires 10 to 15 min. With alternative devices it
`is possible to reduce the inhalation time to about 4 min (17)
`and to avoid any noise by use of ultrasound energy for
`nebulization.
`In patients with severe PAH, inhalation of aerosolized
`iloprost resulted in a substantial decrease in pulmonary
`artery pressure and resistance, concomitant with an increase
`in cardiac output, in the absence of significant systemic
`artery pressure drop and ventilation–perfusion mismatch
`(18,19). In severe lung fibrosis, an increase of the pulmonary
`shunt blood flow may limit the use of IV epoprostenol (19),
`whereas inhaled iloprost can safely be administered. In
`uncontrolled studies, inhaled iloprost was effective in de-
`compensated right heart failure (20) and showed favorable
`long-term hemodynamic improvement (21).
`A large randomized, double-blind, placebo-controlled
`European multicenter study with inhaled iloprost (Aerosol-
`ized Iloprost Randomized, AIR [22]) involved a total of 203
`patients in NYHA functional class III or class IV with
`IPAH or PAH occurring in association with appetite-
`suppressant use, collagen vascular disease, or nonoperable
`thromboembolic disease. In both the iloprost and placebo
`groups, approximately 50% suffered from IPAH, and about
`60% were in NYHA functional class III and 40% in NYHA
`functional class IV. The primary end point of the study,
`defined as an improvement in NYHA functional class
`combined with at least 10% improvement in the 6-min
`walking test, and no deterioration or death (combined
`clinical end point), was reached by 3.4 ⫻ more patients in
`the iloprost versus the placebo group (16.8% vs. 4.9%; p ⫽
`0.007). This effect was achieved with a mean inhaled dose of
`0.37 ng/kg/min. In the 6-min walk test, the treatment effect
`was 36.4 m in favor of iloprost (p ⬍ 0.01). Hemodynamics
`significantly deteriorated in the placebo group, whereas in
`the iloprost group preinhalation values were unchanged
`compared to baseline, and postinhalation values were sig-
`nificantly improved. Importantly, the number of patients
`remaining on study medication, a measure corresponding to
`event-free survival, was significantly higher in the iloprost
`than in the placebo group. Over three months of therapy,
`there was no indication of tachyphylaxis. In the iloprost
`group, one patient (1.0%) died during the double-blind
`study period versus four patients (4.0%) in the placebo
`group. Overall, the therapy was well tolerated. Cough
`occurred more frequently in the iloprost compared to the
`placebo group (38.6% vs. 25.5%) as well as headache (29.7%
`
`vs. 19.6%) and flushing (26.7% vs. 8.8%). These adverse
`events were mild and mostly transient. Syncope occurring in
`the iloprost group was more often rated as serious than in
`the placebo group, but was not commonly associated with
`clinical deterioration.
`An open-label multicenter study of the two-year effects of
`inhaled iloprost in pulmonary hypertension with an initial
`three-month controlled randomized phase was performed
`in Germany. Inhaled iloprost treatment was administered
`for up to two years to 63 patients (40 with IPAH and 23
`with PAH occurring in association with underlying disor-
`ders). The median daily aerosolized dose was 100 ␮g (total
`inhaled dose ⬇24 ␮g) divided into six inhalations. At study
`entry, 66.6% of patients were in NYHA functional class III
`or class IV, and 33.4% in functional class II. During the
`two-year study period, five IPAH patients were switched to
`alternative therapy (mostly IV iloprost) but remained in the
`study, and 13 patients discontinued the study prematurely (7
`with IPAH; 6 with other forms of PAH). After two years,
`37 patients received inhaled iloprost treatment (25 with
`IPAH; 12 with other forms of PAH). During the course of
`the study, eight patients died: three IPAH and five with
`other forms of PAH. Two of these patients died before
`receiving inhaled iloprost treatment. The survival rate ac-
`cording to Kaplan-Meier analysis was 0.850 for all patients
`and 0.914 (95% confidence interval: 0.81; ⬇1) for IPAH
`patients for the two-year study period, including the ran-
`domized phase. For IPAH patients, the predicted survival
`rate according to D’Alonzo et al. (23) was 0.631, which
`corresponds to ⬇14.8 deaths. In contrast, only three IPAH
`patients died. This suggests that survival on inhaled iloprost
`treatment is substantially higher than expected.
`In addition to treatment of IPAH, the pulmonary selec-
`tivity of inhaled iloprost provides the opportunity to apply
`prostanoids to patients who are prone to decrease in
`systemic arterial pressure, as in portopulmonary hyperten-
`sion, and in emergency situations. The intrapulmonary
`selectivity also allows prostanoid application to patients who
`are prone to intrapulmonary right to left shunt, like hepa-
`topulmonary syndrome and lung fibrosis (19).
`Inhaled iloprost may provide an alternative to the use of
`IV epoprostenol. When the clinical effects of
`inhaled
`iloprost and IV epoprostenol are compared, inhaled iloprost
`has some advantages but also certain drawbacks. Most
`importantly, the inhalation provides potent pulmonary va-
`sodilation with little systemic side effects and no risk of
`catheter complications. Additionally, it allows therapy in
`patients with pre-existent ventilation-perfusion mismatch
`and in those who are prone to develop such a mismatch
`during systemic prostanoid application. The most important
`drawback is the fact that the hemodynamic effect of inhaled
`iloprost plateaus within 30 to 90 min, and that six to nine
`inhalations per day are needed to achieve satisfactory clinical
`results. Inhaled iloprost is currently approved in Europe for
`functional class III IPAH. Long-term survival data are
`needed.
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`BERAPROST
`
`Rationale. Beraprost is the first orally active prostacyclin
`analogue (24). It is rapidly absorbed during fasting, peak
`concentration is reached after 30 min, and the elimination
`half-life is 35 to 40 min after oral administration (25). In the
`monocrotaline-induced pulmonary hypertension model,
`beraprost has been shown to have a protective effect on the
`development of pulmonary hypertension lesions (26). High
`doses of beraprost appear to have inotropic and chrono-
`tropic effects in the isolated guinea pig myocardium (27).
`Beraprost has also been studied in peripheral vascular
`diseases such as intermittent claudication (28), Raynaud
`phenomenon, and digital necrosis in systemic sclerosis (29),
`with variable results.
`Treatment. Beraprost has been used to treat PAH since
`1995 in Japan; several small open uncontrolled studies have
`reported beneficial hemodynamic effects with beraprost in
`patients with IPAH (24,30). Functional class also improved
`in the majority of the patients after a mean of two months,
`and pulmonary vascular resistance was reduced by 26% (24,
`30). Nagaya et al. (31), in a retrospective open uncontrolled
`study, reported improved survival
`in 24 IPAH patients
`treated with beraprost compared to a similar group of 34
`patients on conventional therapy. The three-year survival
`rate was 76% in the beraprost group and 44% in the
`conventional-therapy group.
`Two randomized, double-blind, placebo-controlled trials
`of beraprost in PAH have been performed. The first was a
`12-week double-blind, randomized, placebo-controlled trial
`performed in 130 NYHA functional class II and class III
`patients with PAH of various etiologies (IPAH, and PAH
`associated with collagen vascular diseases, congenital
`systemic-to-pulmonary shunts, portal hypertension, or hu-
`man immunodeficiency virus infection) (32). At a median
`dose of 80 ␮g administered orally four times daily, beraprost
`increased exercise capacity assessed by the 6-min walk test:
`treatment effect was 25 m in the overall population, and
`45 m in the IPAH patients, with no significant changes in
`the exercise capacity of subjects with the associated condi-
`tions. Hemodynamics had no statistically significant
`changes, and no difference in survival was detected between
`the two treatment groups. Side effects related to systemic
`vasodilation were frequent, mainly in the initial titration
`period.
`A second trial evaluated the effects of beraprost therapy
`for PAH in 116 NYHA functional class II and class III
`patients. This study was 12 months in duration, double-
`blind, randomized, and placebo-controlled (33). It showed
`that the beraprost-treated patients had less disease progres-
`sion at six months and confirmed the results of the previous
`trial (32): improved 6-min walk distance at three months
`(⫹22 m from baseline) and six months (⫹31 m), as
`compared to placebo. However, this improvement was no
`longer present at 9 or 12 months (33). No significant
`changes occurred in hemodynamics or survival at month 12
`
`JACC Vol. 43, No. 12 Suppl S
`June 16, 2004:56S–61S
`
`versus baseline. It is possible that the beneficial effects of
`beraprost may attenuate with time. Beraprost is approved
`for treatment of PAH in Japan, and is currently under
`evaluation by the European Agency for the Evaluation of
`Medicinal Products (EMEA).
`
`SUMMARY
`
`Chronic IV epoprostenol therapy has had a substantial
`impact on the clinical management of patients with severe
`PAH. The complexity of epoprostenol therapy has led to
`attempts to develop other prostanoids with simpler modes
`of delivery. Subcutaneous treprostinil, inhaled iloprost, and
`oral beraprost have all been studied, and they have various
`relative advantages and disadvantages. In conclusion, al-
`though treatment with prostanoids is complicated by their
`generally short half-lives and complicated drug-delivery
`systems, they continue to play an important role in the
`treatment of PAH. Together with the other major classes of
`therapeutic agents currently utilized or under investigation
`for the treatment of PAH (including anticoagulants, sup-
`plemental oxygen, calcium channel antagonists, endothelin
`receptor antagonists, phosphodiesterase inhibitors, and NO
`or NO donors), prostanoids remain an important therapeu-
`tic option.
`
`Reprint requests and correspondence: Dr. David B. Badesch,
`Divisions of Pulmonary Sciences and Critical Care Medicine, and
`Cardiology, University of Colorado Health Sciences Center, Box
`C-272, 4200 East Ninth Avenue, Denver, Colorado 80262.
`E-mail: David.Badesch@UCHSC.edu.
`
`REFERENCES
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