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Dr. Schilz, the recommendation for class II PAH
patients made by the ACCP group is of necessity not terribly
specific, since we don’t have an extensive evidence base
to guide us. What is your general approach to these patients?
Do you use endothelin antagonists in these patients? How
do you decide?
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 Robert
Schilz, DO, PhD
Department of Pulmonary and Critical Care Medicine
University Hospitals of Cleveland
Cleveland, Ohio
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The recently published guidelines represent an extremely
careful and extensive review of the current scientific
knowledge relating to the diagnosis and treatment of patients
with PAH. Although data continue to accumulate almost
on a weekly basis, several important questions remain
unanswered.
One such question concerns the recommendations for treatment
of World Health Organization (WHO) class II patients (PAH
patients who have slight limitation of physical activity).
Narrow and specific recommendations based on scientific
evidence are available with regard to patients who are
vasoreactive according to specific guidelines and testing
performed at the time of right-heart catheterization.
These class II patients, assuming they have no contraindications,
can be treated with calcium-channel antagonists as long
as they achieve and maintain excellent functional status
while receiving those agents. Most adult class II patients
probably
will not demonstrate vasoreactivity. Substantial evidence
does not exist to clarify the treatment of such patients.
Scientific evidence supporting any particular treatment
of these patients is lacking for at least two reasons.
One is that previous trials have typically included few
class II patients. The other is that the duration of the
therapeutic trials that have included class II patients
may have been insufficient to detect important long-term
effects in this “functional” patient group.
My current approach to class II patients is to assess
for potential vasoreactivity and treat with calcium-channel
antagonists as defined in the guidelines for the rare
patient demonstrating response. I will consider the use
of warfarin in nonresponders if no contraindications to
its use exist. I believe (as I think many PAH physicians
do) that additional treatment of such patients is important
given what we know
about the progressive nature of PAH. Practically then,
at least four potential agents can be considered. In alphabetical
order, these are bosentan, epoprostenol, sildenafil, and
treprostinil. Outside the United States, aerosolized iloprost
may also be available. Of these, only treprostinil currently
has Food and Drug Administration (FDA) labeling for use
in class II patients.
Issues that I consider in treating WHO class II patients
include:
• Availability of trials and potential for enrollment.
The ACCP guidelines underline the importance of such trials.
• Patient contraindications to therapy (ie, pregnancy
or liver disease may preclude the use of bosentan).
• Insurance concerns. Payment for all regimens is
a reality. Different patients have different plans that
may or may not limit coverage to labeled indications or
certain agents.
• Ability to deliver or monitor therapy. Infusion
therapy with prostacyclin agents, although widely delivered,
may not be appropriate for some patients. Similarly, the
need to reliably monitor liver enzyme values monthly may
not be practical for some.
• Route of administration. Oral administration is
obviously attractive compared with infusion therapies
as far as ease of delivery is concerned.
If all else is equal and the patient is a candidate for
any therapy, I believe that initial monotherapy with bosentan
or perhaps sildenafil is reasonable. Bosentan has an advantage
in terms of being well known, with increased clinical
experience and a well-defined dosing scheme. The use of
sildenafil is less well defined. If oral regimens are
not possible in a patient, I consider infusion therapy
with treprostinil or
epoprostenol.
Regardless of the initial therapy, patients must be followed
closely for efficacy and safety of the regimen. I see
patients approximately every 12 weeks. Exercise testing,
echocardiography, and repeat right-heart catheterization
are important in determining clinical improvement, stabilization,
or deterioration. In patients whose condition improves,
therapy is continued. Patients who deteriorate should
be
considered for alternate or additional therapy. Patients
whose condition remains unchanged present another dilemma
in clinical practice. The good news is that they have
not changed, and the bad news might be that they have
not changed. If a patient whose condition is unchanged
has significant functional limitations that are troublesome
or has substantially elevated pulmonary pressures, I tend
to favor more or alternate therapy.
I want to underline the concept that robust scientific
literature does not exist to support these approaches.
At least two trials may give us more information to guide
therapy in this setting. First, the EARLY trial, a current
trial of bosentan in just such patient populations, may
provide some of the important information that currently
is lacking with regard to the use of this agent in WHO
class II patients. In addition, though not a trial specifically
for class II patients, a large, multicenter trial recently
evaluated the use of sildenafil in patients with PAH and
preliminary results suggest benefit. Results were announced
at the annual American College of Chest Physicians meeting
in October. In addition, the STRIDE II trial is evaluating
sitaxsentan and bosentan and includes not just class III
and IV patients but also class II.
A question beyond our current search defining therapies
for WHO class II patients with PAH is what the optimal
initial and subsequent therapy might be. This will not
be answered in either of these trials, since direct comparisons
with other available agents will not be performed. I remain
extremely optimistic, given the continued advances in
the treatment of PAH. However, many important questions
remain and will require our continued commitment to answer.
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