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Epoprostenol therapy has revolutionized the treatment
of pulmonary arterial hypertension (PAH).1-3 Patients
realized an improvement in quality of life, hemodynamics,
and survival and this therapy has offered hope to patients
with advanced disease.1,4 However, these attributes must
be balanced against the complicated nature of the intravenous
delivery system. Infections may range in severity from
local exit-site infections easily treated with oral antibiotics
to life-threaten-ing 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 pneumoth-orax, deep venous thrombosis, and paradoxical
embolus. Additionally, the patient’s life is radically
changed by the need to mix the medication on a daily basis,
store the medication under refrigerated conditions, and
carry a mechanical pump. The success of epoprostenol coupled
with the limitations of the delivery system has provided
the impetus to develop prostacyclin analogs with alternative
routes of delivery. This article will focus on the analogs
beraprost and treprostinil (the analog iloprost is discussed
in another article in this issue).
Beraprost
Beraprost sodium is an orally administered prostacyclin
ana-log. When taken with food the half-life is approximately
3 to 3 1 /2 hours, requiring dosing four times daily.
Enthusiasm for the treatment of PAH with beraprost arose
from the initial experience in Japan and subsequent experience
in Europe.
In 1999 Nagaya and colleagues reported the benefit of
beraprost on survival in patients with primary pulmonary
hypertension (PPH).5 They followed 58 consecutive patients
with PPH between 1981 and 1997. The 34 patients diag-nosed
before December 1992 were treated with conventional therapy
alone, and the 24 patients diagnosed after January 1993
were treated with beraprost in addition to conventional
therapy. Oral beraprost was initiated at a rate of 60
mcg per day and increased by increments of 60 mcg per
day over 1 to 2 weeks to the highest tolerated dosage.
Survival was estimat-ed from the date of initial diagnosis
until the conclusion of the study in November 1998. Of
the 34 patients in the con-ventional therapy group, 27
patients died of cardiopulmonary causes after a mean follow-up
of 44 ± 45 months. In con-trast, only 4 of the patients
in the beraprost group died of cardiopulmonary causes
during a mean follow-up of 30 ± 20 months. Kaplan-Meier
survival curves demonstrated the 1-, 2-, and 3-year survival
rates in the beraprost group to be 96%, 86%, and 76%,
respectively, compared with 77%, 47%, and 44%, respectively,
in the conventional therapy group, differences that were
statistically significant.
A subgroup of 15 patients treated with beraprost under-went
repeat cardiac catheterization after receiving therapy
for a mean of 53 days. There was a reduction in mean pulmonary
artery pressure of 13% and in total pulmonary resistance
of 25% as well as an increase of 17% in cardiac output.
Sixty-seven percent of the patients treated with beraprost
demon-strated an improvement in New York Heart Association
(NYHA) Functional Class. Although these results suggested
an improvement in survival with beraprost therapy, several
limita-tions of the study bear mention. These include
the small size of the cohort and retrospective analysis.
Other medical thera-pies were not controlled and there
was a significant difference in the use of calcium channel
blockers and digitalis between the conventional therapy
group and the beraprost group. The mean follow-up was
substantially longer in the conventional therapy group
than in the beraprost group. Additionally, a larger proportion
of the patients in the beraprost group went on to treatment
with intravenous epoprostenol.
More recently Vissa and colleagues reported their results
of long-term treatment of PAH with beraprost.6 They studied
13 patients, 9 with PPH, 3 with thromboembolic pulmonary
hypertension, and 1 with PAH related to congenital heart
dis-ease. The mean daily dose of beraprost was 116 ± 24
mcg after the first month of treatment and 193 ± 74 mcg
at the end of 12 months. One patient died at 40 days of
treatment and 1 patient was lost to follow-up. Twelve-month
follow-up data were achieved in 11 patients. Patients
demonstrated an improvement in NYHA Functional Class from
3.4 ± 0.7 at baseline to 2.9 ± 0.7 at the end of 1 month
(P < .016). No further improvement was noted after a full
year of therapy. The 6-minute walk distance increased
by 63 ± 47 meters from a baseline distance of 213 ± 64
meters. This improvement was noted at 1 month and was
maintained over the 12-month period. This prospective
uncontrolled trial suggest-ed that beraprost improved
symptoms and exercise capacity in patients with PAH.
The only prospective, double blind, placebo-controlled,
randomized study of beraprost in the study of PAH has
recent-ly been completed in Europe.7 Galie and colleagues
studied 130 patients with PAH, including PPH and PAH associated
with collagen vascular disease, congenital heart disease,
por-tal hypertension, and human immunodeficiency virus
infec-tion. Patients were randomized to receive the maximal
toler-ated dose of beraprost or placebo for 12 weeks.
The primary end point of distance walked in 6 minutes
improved by 25.1 meters (P = .036) in the active treatment
group. They also noted an improvement in symptoms as measured
by the Borg dyspnea index, which decreased by 0.94 in
the beraprost group (P = .009). Subgroup analysis demonstrated
that patients with PPH realized the greatest improvement,
with a mean change in 6-minute walk distance of 46.1 meters.
They noted no statistically significant differences in
cardiopulmonary hemodynamics or NYHA Functional Class.
The median dosage of beraprost in the study was 80 mcg
four times per day.
The most common side effects of beraprost reported in
these studies were headache, flushing, jaw pain, diarrhea,
leg pain, and nausea. Side effects can be minimized when
the drug is taken with a meal. Beraprost is currently
available in Japan and may become available in Europe.
A placebo-controlled trial with beraprost in the United
States was terminated prematurely and this drug will not
likely become commercially available in the United States.
Presumably the early termination was because of a lack
of efficacy estimation by the Data and Safety Monitoring
Board.
Treprostinil
Treprostinil is a prostacyclin analog with a half-life
of 3 hours when administered subcutaneously. The drug
is stable at room temperature. Animal studies suggest
that the hemodynamic effects of treprostinil are similar
to those of epoprostenol.8,9 To test this hypothesis in
humans, we studied 14 patients with PPH acutely with intravenous
epoprostenol and then intravenous treprostinil.10 Both
drugs had similar effects on hemodynamics. There was no
difference in reduction in pul-monary vascular resistance
(22% with epoprostenol versus 20% with treprostinil).
To then test the alternative subcutaneous delivery method,
we compared the effects of intravenous and subcutaneous
treprostinil in 25 patients with PPH. In the intravenous
treprostinil and subcutaneous treprostinil groups there
was a 6% and 13% decline in mean pulmonary artery pressure
and a 23% and 28% decline in pulmonary vascular resistance
respectively.
Having demonstrated that the drug favorably affects car-diopulmonary
hemodynamics when given subcutaneously acutely, we embarked
on an 8-week, placebo controlled, 2:1, randomized trial
of subcutaneous treprostinil. Twenty-six patients with
PPH were enrolled. Two patients in the treprostinil group
did not complete the study because of intolerable side
effects. The remaining 15 patients randomized to active
drug were receiving a mean dosage of 13.0 ± 3.1 ng/kg/min
of treprostinil, and the 9 patients randomized to placebo
were receiving 38.9 ± 6.7 ng/kg/min at the end of the
8-week period. There was an improvement of 37 ± 17 meters
in the 6-minute walk distance in patients receiving the
active thera-py (from 373 meters to 411 meters) compared
with a 6 ± 28 meter reduction in those receiving placebo
(from 384 meters to 379 meters), which was not statistically
significant. There was a favorable, but again not statistically
significant trend in hemodynamics, with a 20% reduction
in pulmonary vascular resistance index over the 8-week
period in the group receiving active treprostinil. Adverse
events, including headache, diar-rhea, flushing, jaw pain,
and foot pain, were as common in the treprostinil-treated
as in the epoprostenol-treated group. An unexpected adverse
effect was pain at the site of the sub-cutaneous infusion.
This pain was occasionally severe, was often associated
with erythema, and occurred in nearly all the patients
undergoing active therapy. This proof-of-concept trial
demonstrated that this novel subcutaneous agent could
be given safely and effectively on an outpatient basis
and paved the way for a larger pivotal trial.
Subsequently, the largest placebo-controlled randomized
study involving PAH patients was an international trial
assessing the efficacy of subcutaneously delivered treprostinil
in patients with PAH, either primary or associated with
collagen vascular disease or congenital systemic-to-pulmonary
shunts.11 Patients were enrolled between November 1998
and October 1999 in 24 centers in North America and 16
centers in Europe, Australia, and Israel. Four hundred-seventy
patients were randomly assigned to receive either continuous
subcutaneous infusion of treprostinil plus conventional
thera-py or continuous infusion of placebo (vehicle solution
without treprostinil) plus conventional therapy. Because
of the infusion- site pain and reaction noted in the proof-of-concept
trial, the dosing strategy called for lower doses at initiation
and a maximal allowable dose at the end of 12 weeks of
22.5 ng/kg/min. The primary end point of this trial was
exercise capacity as measured by the 6-minute walk distance,
which improved in the treprostinil group and was unchanged
with placebo. The median between treatment group difference
was 16 meters (P = .006). This effect on exercise tolerance
appeared to be dose-related. The patients in the lowest
two quartiles of dosing experienced little improvement
in 6-minute walk distance, and patients in the highest
quartile of dosing (greater than 13.8 ng/kg/min) demonstrated
a mean improve-ment of 36 meters (Figure 1). Secondary
end points, includ-ing the dyspnea fatigue rating and
the Borg dyspnea scale, confirmed an improvement with
treprostinil therapy. Treprostinil also demonstrated a
significant improvement in the hemodynamic parameters
of mean right atrial pressure, mean pulmonary artery pressure,
cardiac index, pulmonary vascular resistance, and mixed
venous oxygen saturation (Table 1). Common side effects
included headache, diarrhea, nausea, rash, and jaw pain.
Side effects related to the infu-sion site were common.
Eighty-five percent of patients experi-enced infusion
site pain and 83% had erythema or induration at the infusion
site. Eight percent of the patients in the active treatment
group were withdrawn from the study because of site pain.
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