Lewis J. Rubin, MD |
Pulmonary Hypertension
Roundtable
Inside the New Era in Treatment: Three
Experts Analyze the Growing Spectrum of Therapy
and Future Strategies
Three physicians addressed key concerns in the
treatment of pulmonary hypertension in a discussion
that ranged from special considerations in tailoring
therapy to the role of new agents dramatically
changing the algorithm for managing this disease.
The roundtable discussion was moderated by Lewis
J. Rubin, MD, Professor of Medicine, Univer-sity
of California, San Diego, School of Medicine,
and included Robyn Barst, MD, Professor of Pedi-atrics,
Columbia University College of Physicians and
Surgeons, New York, New York, and Nazzareno Galiè
MD, Professor at the Postgraduate School of Cardiology,
University of Bologna, Italy.
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Robyn Barst, MD |
Nazzareno Galiè, MD |
Dr Rubin: The treatment
of pulmonary hypertension has evolved dramatically over
the past decade and in particular is evolving remarkably
at present. It is creating opportunities for us to better
treat our patients and to treat our patients more easily,
but it is also raising many challenges for us and our
colleagues who care for these patients. It might be useful
to address some of the common questions and challenges
that are coming up with new treat-ments. Maybe we should
start by addressing the first new treatment that has now
become available, which is the oral endothelin blocker
bosentan that is now FDA approved and the common question
that I think we are all asked is who should we treat with
bosentan, and secondly, who should be treating patients
with bosentan?
Dr Barst: As background
we should consider a con-sensus
for a treatment algorithm for pulmonary arterial hypertension,
prior to the availability of endothelin receptor antagonists
and prostacyclin analogues.
Dr Rubin: That’s great.
Why don’t you start with that?
Dr Barst: I remember being
at a symposium where my task was to talk solely about
endothelin-receptor antagonists such as bosentan and at
the end of the meeting everyone assumed that’s where
you should start and there was no role for calcium channel
blockers or some of the other standard therapies that
we have used (prior to the availability of endothelin-receptor
antagonists or other novel thera-peutic agents). We are
talking about patients who have pulmonary arterial hypertension,
not just pri-mary pulmonary hypertension. At a symposium
sponsored by the World Health Organization (WHO) in 1998,
there was a reclassification of patients who have pulmonary
hypertension: experts from around the world agreed on
a new diagnostic classi-fication. If we focus upon the
initial part of this classification, we decided that many
patients could be classified as having “pulmonary
arterial hyper-tension” because very often they were
similar from a clinical standpoint as well as with respect
to their pulmonary histopathology. This included patients
who have primary pulmonary hypertension, sporadic and
familial, as well as pulmonary arterial hypertension associated
with collagen ascular disorders, congenital systemic to
pulmonary shunts, HIV, portal hypertension, and appetite
suppressants. So when we are talking about therapeutic
options for these patients, we are considering that many
of the therapeutic options that we’ve learned the
most about from treating patients with primary pulmonary
hypertension may also be efficacious for these other forms
of pulmonary arterial hyper-tension, although our experience
is much less. As Dr Rubin has said, there have recently
been dramatic improvements in treatment options for patients
with primary pulmonary hypertension, but if we want to
review briefly how we have gotten to this point, which
we are very excited about, and what the future holds,
we should first review the treatment options available
prior to the availability of the novel therapeutic options
we will be discussing. There really weren’t any options
until the late 1970s. With the introduction of vasodilators
to treat systemic hypertension, we began looking at vasodilators
to treat pulmonary arterial hypertension as well. These
efforts focused primarily on calcium channel blockers
in the early 1980s, and they have been demonstrated to
be efficacious in patients who respond with acute short-acting
vasodilator testing, eg, inhaled nitric oxide, intravenous
prostacyclin, or intra-venous adenosine. If we see a very
significant fall in the pul-monary artery pressure with
acute testing, these patients are very likely to also
have that same response when they are treated with long-term
calcium channel blockade therapy, such as amlodipine or
nifedipine. The proportion of patients with primary pulmonary
hypertension who demonstrate this response is probably
only about 20%, and in our experience, the proportion
of those patients who continue to do exceed-ingly well
on calcium channel blockers over 5 to 10 years decreases
to approximately 75% of the original responders. For the
patients who could not be treated with a calcium channel
blocker in the 1980s, several studies were begun using
chronic intravenous prostacyclin, or epoprostenol, ini-tially
with the thinking that these patients would not respond
significantly, but we wanted to try to use chronic intravenous
epoprostenol as a bridge to transplantation. In the late
1980s, at least 40% of patients were dying awaiting heart-lung
or lung transplantation so we started using intravenous
epoprostenol as a bridge. Surprisingly, we saw a number
of patients markedly improve clinically and hemodynamically
as well as having improved survival, which led to epoprostenol
being the first FDA approved therapy for the treatment
of pri-mary pulmonary hypertension in 1995. Why epoprostenol
sig-nificantly improved a number of patients when they
had no acute response remains unclear, but recent research
focusing on an antiproliferative effect of epoprostenol
in addition to its vasodilator and antiaggregatory effects
may be why epoprostenol works chronically. That takes
us up to what Dr Rubin began discussing. So, up until
this point our options for primary pulmonary hypertension
patients were chronic oral calcium channel blockade in
approximately 20% of patients, and the remaining 80% were
started on epoprostenol. The results with the other types
of patients we talked about, par-ticularly patients with
collagen vascular disease and congeni-tal heart disease,
show a much less efficacious response with calcium channel
blockers.
Dr Galiè: Regarding
“background” therapy, I would like to mention
oral anticoagulant therapy that has been used in patients
with pulmonary arterial hypertension since the 1980s.
Even if the evidence of efficacy of oral anticoagulant
therapy is based on retrospective and uncontrolled studies,
this form of treatment is largely utilized by clinicians.
In all the controlled clinical trials on new treatments
in pulmonary arterial hypertension, more than two thirds
of patients were receiving anticoagulant treatment.
Dr Rubin: To summarize very
briefly, the calcium channel blockers were advanced in
their time, but only for a limited number of patients,
and as Dr. Barst pointed out, the acute responsiveness
doesn’t guarantee chronic responsiveness in calcium blockers.
For the nonre-sponders, the development of intravenous
prostacy-clin was a dramatic advance, but even with that,
the long-term outlook remained limited for many patients.
Long-term responsiveness to prostacyclin certainly does
occur, but the mode of delivery, the complexity of the
drug, and the side effects have really been limiting factors.
And finally, transplan-tation, typically lung transplantation,
has been an option for a select few patients who have
failed to respond to medical therapy, but the availability
of organs has really been limited. Long-term complications
after transplanta-tion, typically chronic rejection and
opportunistic infections have hampered its long-term efficacy
in many patients. All that has prompted efforts to develop
new therapies or modify existing therapies into modalities
that are easier to deliver and more efficacious. There
have been several studies of late that have demonstrated
encouraging positive findings. The most recent one is
the development of endothelin-receptor antago-nists for
the treatment of pulmonary hypertension. Endothelin is
a vasoconstrictor and mitogen that is produced by the
vas-cular endothelium and is produced in excess in the
pulmonary vascular endothelium of patients with pulmonary
hyperten-sion. There are now drugs that are blockers of
the endothelin receptor that have been studied in patients
with pulmonary hypertension. There are two types of endothelin
receptors: endothelin A or ETA and endothelin B or ETB
receptors. The first drug that has been extensively studied
and now FDA approved in pulmonary hypertension is the
nonselective ETA and ETB receptor blocker bosentan (Tracleer).
It is an orally active drug that has been demonstrated
in two randomized placebo-controlled, double-blind trials
to produce improve-ment in a variety of parameters of
clinical significance in pul-monary hypertension, pulmonary
artery hypertension, although it has been primarily studied,
thus far, in patients with either primary pulmonary hypertension
or pulmonary hypertension associated with connective tissue
diseases. This has now opened up the opportunity to treat
patients with an orally active drug even if they are not
vasoreactive, even if they can-not be treated with calcium
channel blockers. There are ongo-ing studies now using
more selective endothelin receptor blockers, ETA receptor
blockers, in particular, to see whether selectivity confers
preferential effects compared with nonse-lective blockade.
But this also creates questions. And among the questions
that have to be addressed are which patients should be
treated with endothelin-receptor blockers, at this point,
and when?
Dr Barst: These are very important questions and I’d
like to reiterate what Dr. Rubin said at the opening of
the discussion and that is, who should treat these patients
and where should they be treated? One of our concerns
is that with the availabil-ity of several of these novel
therapeutic agents, in particular the ease of therapy,
eg, oral therapy, more and more physi-cians have the opportunity
to treat patients with pulmonary arterial hypertension
without having to send them to centers that have significant
experience and expertise in the treatment of pulmonary
arterial hypertension patients. In the past, when patients
were in need of chronic intravenous epoprostenol, or Flolan,
most patients were sent to centers because of the need
for nurses to teach the fami-lies and the patients how
to take care of their Flolan, their central venous lines,
and mixing and delivering of the drug therapy. One concern
that I think many of us have is that not uncommonly patients
are referred to us with the diagnosis of primary pulmonary
hypertension, and, in fact, they have another etiology
for their pulmonary hypertension, hyperten-sion, and the
therapy, assuming the diagnosis is primary pul-monary
hypertension, may be the wrong therapy for that patient.
A classic example of this is patients who are pre-sumed
to have primary pulmonary hypertension and upon fur-ther
evaluation turn out to have chronic thromboembolic dis-ease
as the etiology of their pulmonary arterial hypertension,
which is very often amenable to surgery, with excellent
results with thromboendarterectomy. We certainly would
like to treat these patients with surgery if that is indicated,
as opposed to treating them with any of our medical therapies.
As Dr. Rubin said earlier, our therapeutic options have
improved and although the palliative effects of the therapies
have markedly improved over the past decade, we still
are only palliating these patients; we are not curing
them. For example, if a patient truly has chronic thromboembolic
disease, it is not uncommon that these patients can be
“cured” with effective surgery. So we really want to be
very, very careful that we are making the right diagnosis.
The second point is that, not uncommonly, these patients
are presumed to have primary pulmonary hypertension when
they may have subtle findings of left ventricular dysfunction
with pulmonary venous hyper-tension and secondary pulmonary
arterial hypertension. It is a concern to many of us that
if patients are initially evaluated by a physician who
does not have a great deal of experience with pulmonary
arterial hypertension, patients may be misdi-agnosed.
All patients need a thorough evaluation, which includes
a right heart catheterization. The consensus is that patients
absolutely need a right heart catheterization to make
sure that they don’t have some component of left ventricular
dysfunction or elevated pulmonary venous pressure triggering
their pulmonary arterial hypertension. Now that we have
oral agents available, many of us are concerned that if
a patient goes to see his or her physician and is complaining
of dysp-nea on exertion, if an echocardiogram suggests
there may be pulmonary arterial hypertension, the patient
may then be told he/she has primary pulmonary hypertension.
If the patient does not have primary pulmonary hypertension,
we are doing him/her a terrible disservice. Even though
some clinicians may say that since we now have an agent
such as bosentan, which can be given orally twice a day,
if the echo suggests pul-monary hypertension, let’s just
try bosentan, I believe this is doing the patient a disservice,
and we should try to strongly recommend that we think
this is inappropriate and we want to avoid it. With regard
to the questions that Dr Rubin raised about whom we should
treat with bosentan, we are in a very exciting time, but
that means that we have a lot of unknowns. Whether patients
who are very reactive and responsive and to date have
been treated efficaciously with calcium channel blockers
would respond as well or better if they were on an enhdothelin-receptor
antagonist is unknown. Would such patients respond better
if they were on a combination? There are many questions
that these advances have opened up for us, and I think
it behooves us to carefully evaluate who should be treated
with which therapies. And hopefully, with many of the
physicians who treat pulmonary arterial hypertension patients,
we will be able to do further clinical trials evaluating
what combination therapies may be better for subsets of
selected patients versus other subsets. I believe many
of us feel that even when we try to use the most homogeneous
group of patients (for clinical trials), eg, patients
with primary pulmonary hypertension, there are subsets
within that disease. I suspect that we will find that,
for example, selective ETA receptor antagonists may be
more efficacious for a certain subset as opposed to a
dual endothelin-receptor antagonist for other subsets.
Dr Galiè: I agree with the
concept that if a treatment is easy to administer it can
be more often given without a correct indication. For
example, we are aware that not more that 20% of pulmonary
hypertension patients are “responders” to acute vasoreactivity
testing and have the indication for chronic calci-um channel
blockers treatment. Nevertheless, the percentage of patients
on this form of oral therapy as assessed in recent trials
is about 50%. We need to consider that the therapy of
patients with pulmonary arterial hypertension requires
a com-plex strategy that starts from correct diagnosis
and appropriate prescriptions and continues in the monitoring
of treatment effects and side effects. I strongly believe
that this strategy is better accomplished if the patient
is followed up in special-ized centers with experience
in all the resources now avail-able, from the simpler
to the more complex ones.
Dr Rubin: At this point,
which patients would you start treat-ing with an endothelin-receptor
blocker?
Dr Barst: With the initial
evaluation, if a patient has a dramat-ic response to acute
vasodilator testing, I think the standard of therapy is
that we start that patient on a chronic calcium channel
blocker. What defines a “response” remains contro-versial.
The definition of a significant response depends upon
the percentage decrease in mean pulmonary arterial pressure
as well as the absolute pressure that the mean pulmonary
arterial pressure falls to. We usually start chronic calcium
channel blockade if patients have a very reactive response
with short-acting vasodilator testing, as well as with
acute testing with calcium channel blockers. We also routinely
repeat a right heart catheterization one year after starting
a patient’s treatment, and if we have a patient who started
receiving chronic calcium channel blockade, even if they
sig-nificantly improved clinically, if we do not see a
significant improvement in pulmonary hemodynamics at repeat
study, we would go down the treatment algorithm to see
what we could add to that patient’s medical regimen. And
I think, certainly, when we have an oral agent available,
such as bosentan, it is worth considering as opposed to
adding Flolan to their calcium channel blockade therapy.
Dr Galiè: Are you talking
about pediatric patients or adult patients?
Dr Barst: Most of what I
am talking about is with respect to adult patients.
Dr Rubin: Dr Galie, how
would you approach therapy in a patient who is not vasoreactive
acutely?
Dr Galiè: The problem is
availability here in Europe of the endothelin receptor
antagonist bosentan. Hopefully, it will be available late
in spring. It is now available in France, as an-ticipated
treatment, and in Italy for selected patients.
Dr Rubin: Let us make the
assumption that you have several medications available,
which would include an endothelin antagonist and would
also include the oral prostacyclin analogue, beraprost,
which you have studied, and also the aerosolized prostacyclin
analogue iloprost, and also include the subcutaneous analogue,
trepostinil. Readers should recog-nize that the availability
of these agents is somewhat variable from country to country.
In the US bosentan is available, prostacyclin intravenously
is available, trepostinil is still under FDA review, and
beraprost and iloprost as of right now are not available.
In Europe things are a little different. Let’s say that
you have all of those available and you have obviously
exten-sive familiarity with the experience thus far with
those drugs. Where do you go?
Dr Galiè: Of course, in
class IV patients, I would use epoprostenol because of
the rapidity and reliability of this form of treatment.
In class III, the most relevant patient popu-lation, I
think I would first try one of the two orally available
drugs, the endothelin-receptor antagonist bosentan or
the prostacyclin analogue beraprost. The advantage of
bosentan is that the administration is only twice a day,
compared with four times a day for beraprost. Actually,
I have seen favorable results with both drugs and I would
try one of the two. I would discuss with the patient the
side effects of the two drugs, and possible personal preferences.
Some individual clinical char-acteristics could be of
help: in a patient with a tendency to have head-ache,
I would exclude beraprost, and in a patient with moderate
liver function abnormalities, I would avoid bosentan as
the first choice. We need more time to define the effect
of these two treatments over the long term; this is very
important information we still lack. In case of intolerable
side effects with these oral compounds, a minimally invasive
alter-native is the subcutaneous infusion of trepostinil
by means of small portable pumps. I have observed favorable
results with this treatment, even though some patients
may have local pain at the infusion site that can prevent
its use. A suitable option is also represented by inhaled
iloprost which is available in some European countries.
The data of several uncontrolled experiences and of the
randomized AIR study confirm efficacy of this treatment
in class III and IV patients. Compliance to inhaled iloprost
can be influenced by the number of required inhalations
which ranges from a minimum of six up to 12 a day.
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