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Dr. Frost, the ACCP recommendations discuss at
length the data on treatment with epoprostenol for PAH
but don’t address the issue of its potential safe discontinuation
in favor of oral therapy. You have recently published
in this area; could you brief us on your patient selection
and general approach to this?
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Adaani Frost, MD
Professor of Medicine
Baylor College of Medicine
Director, Pulmonary Hypertension Service
Methodist Hospital
Houston, Texas
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I will explain the rationale behind the decision to
try to transition patients from epoprostenol to bosentan,
and how we achieved this transition. The benefits of epoprostenol
therapy are well known and clearly stated in the ACCP
guidelines. When epoprostenol therapy was introduced for
the treatment of PAH, it was for most patients the only
therapeutic option. However, while life-saving, it is
not innocuous. Complications of therapy include diarrhea,
nausea, headache, flushing, leg pain, jaw pain, a reduced
quality of life, hospitalizations, morbidity, and occasionally
mortality (due to drug interruption and infection).
The development and release of the oral endothelin receptor
antagonist bosentan has changed first-line therapy in
many patients with PAH. Many patients currently receiving
epoprostenol would have received this drug as their first
line of therapy if it had been available at the time of
their original diagnosis. That is, stable class II or
III patients do not normally require epoprostenol, and
since bosentan has been extensively evaluated in such
patients with PAH, it appeared reasonable to consider
such patients for this drug with cautious weaning from
epoprostenol. Needless to say, it was a question raised
by many PAH patients. The next question was which patients
to transition and how to accomplish this.
Our approach to this process (it may differ at different
centers) is as follows: We considered patients who had
achieved sustained benefit with epoprostenol and had
improved to WHO functional class II (or early III). Patients
who were unstable either acutely or chronically were not
considered for transition. It was also extremely important
that the patients understood that a trial of epoprostenol
cessation was all about making them feel better, that
is, about having equivalent functional capacity but less
risk and inconvenience. Any worsening of symptoms or deterioration
in function was to mean that the transition was to be
aborted immediately, and epoprostenol therapy was to be
resumed or increased. As this was an unexplored area,
the patients were also advised that should they deteriorate
it was possible they would not immediately return to their
pretransition functional state, even if epoprostenol was
resumed. Not unexpectedly, many epoprostenol patients
still wanted to try to achieve the transition.
Pulmonologists and cardiologists treating patients with
PAH routinely use noninvasive criteria (symptoms, World
Health Organization functional class, 6-minute walk tests,
and echocardiography) to evaluate patients, to assess
their response to therapy, and to govern titration of
epoprostenol. It therefore seemed reasonable to use these
same noninvasive parameters to follow patients as they
came off one medicine while starting another.
The bosentan studies suggest that improvement in functional
parameters appears to be achieved after one month of initial-dose
therapy (62.5 mg q12h) followed by one month of full-dose
therapy (125 mg q12h) with little further improvement
reported afterward. A potential risk of starting bosentan
in patients receiving Flolan would theoretically be an
increase in epoprostenol-associated symptoms. Patients
were monitored in the hospital during the initial weaning
process and this was completed on an outpatient basis.
At one month, the standard increase in bosentan from 62.5
mg q12h to 125 mg q12h was undertaken in an outpatient
monitored setting. Patients were then given individual
instructions to gradually decrease their
epoprostenol dosage and it was weaned completely over
one month. If their symptoms, examination, echocardiogram,
and walk test remained stable during this down-titration
and observation period, the infusion catheter was removed
and they were followed closely thereafter.
Approximately half of the 23 patients (11) were successfully
transitioned to bosentan therapy, although two patients
subsequently developed liver function abnormalities necessitating
drug cessation (one resumed epoprostenol, one patient
transitioned to sitaxsentan). Most of the patients who
successfully stopped their epoprostenol have remained
on oral therapy now for over one year. To permit 40% of
patients previously committed to continuous intravenous
infusion therapy to replace it with a pill, while not
perfect, is a tremendous boost to their quality of life.
It is important to emphasize that these transitions are
best carried out by centers experienced at using these
drugs. Longterm follow-up will determine whether or not
patients will be able to remain off epoprostenol.
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