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Dr Steen: That has certainly
been our experience. But we have to remember that previously
the diagnoses have been made so late that the only time
the diagnosis was made really was when patients had right-heart
failure and clear-cut classic clinical pulmonary hypertension.
Without treatment, even to survive two years for many
patients was just unheard of. With the use of prostacyclin,
my patients have had a much better survival rate and quality
of life, even when the diagnosis is not made until the
patient has right-heart failure.
Dr McLaughlin: One of the
problems that the scleroderma population sometimes has
with prostacyclin is difficulty mixing. Because many of
them have severe Raynaud’s and digital ulcers and sometimes
even amputa-tions, this can be problematic. That is one
of the reasons why the subcutaneous prostacyclin ana-logue,
treprostinil, which has recently been FDA-approved, may
be useful in those patients. The scleroderma patients
were included in the double-blind placebo-controlled randomized
study of sub-cutaneous treprostinil and indeed benefited.
Sometimes, however, that drug is difficult to use because
of pain at the infusion site. Jim, you men-tioned that
there were three FDA-approved drugs. The third one is
an oral therapy, bosentan. Would you like to comment on
your experience with that so far? And perhaps even how
the advent of an oral therapy has changed practice patterns
that lead to earlier screening and diagnosis?
Dr Seibold: There is no
question that the logistical convenience of an oral therapy
really revolutionizes the clinical approach. Prostacyclin
is expensive, it is relatively cumber-some, it has more
than a certain level of day-to-day adverse effects that
impact the quality of life. I agree with you that the
administration of treprostinil in the whole scheme of
things will be more convenient for scleroderma patients
and they will be a little bit better able to handle that.
Dr Badesch: The other important
thing to point out is that the mechanism of action  of
bosentan is considerably different from that of prostacyclin.
Endothelin levels may be increased in some patients with
scleroderma, and using an endothelin receptor antagonist
in that situation may make particular sense, beyond even
what you might expect in patients with pulmonary hypertension.
So, it is particularly attractive on a theoretical basis
to block endothelin in patients with scleroderma and scleroderma-related
pulmonary hypertension. In a randomized and placebo-controlled
study involving over 200 patients with primary pulmonary
hypertension and pulmonary hypertension occurring in association
with collagen vascular disease, bosentan-treated patients
demonstrated better activity tolerance, as assessed by
the 6-minute walk test, than patients receiving placebo.
The drug seems to be relatively well tolerated although
it is important to mention the side effects that have
been seen to date. It can cause an elevation in liver
function tests and this mandates following liver function
tests on a regular basis. In fact, the FDA has mandated
testing at least monthly. The drug has the potential to
be teratogenic and therefore contraception is very important.
It may cause male infertility and young male patients
should be informed of that prior to beginning the treatment.
And finally, it can cause some mild anemia and at times
some fluid retention.
Dr McLaughlin: Those are
important points. Dave, would you like to speculate on
the results in the scleroderma subpopula-tion BREATHE-1
trial, compared with the scleroderma popula-tion in your
trial? Granted, it was a much smaller number in the BREATHE-1
trial, but they didn’t seem to obtain as much benefit
in terms of exercise tolerance over the 16 weeks of that
trial as the scleroderma patients treated with intravenous
epoprostenol did in your trial. Any thoughts on that?
Dr Badesch: The data suggest
that in the study of intravenous prostacyclin in patients
with scleroder-ma- associated pulmonary hypertension,
there was both an improvement in the treatment group and
a decline in the control group that accounted for the
difference between study groups. In the BREATHE-1 study,
when looking at the subgroup of patients with scleroderma-associated
pulmonary hypertension, it appears as though bosentan
may have contributed to the maintenance of stability while
patients in the placebo arm continued to deteriorate.
Now as you’ve mentioned, whether or not we can take away
much of a message from that is a little in doubt because
the relatively small number of patients with scleroderma
included in the BREATHE-1 study. Whether or not bosentan
can contribute to the same amount of symptomatic improvement
or improvement in exer-cise capacity as prostacyclin in
this population I think is still just little bit up in
the air.
Dr McLaughlin: So, the drug
has been commercially available for 7 or 8 months. Jim,
Ginny, would you like to share your experience with it
so far?
Dr Seibold: We were somewhat
concerned when we saw the failure to improve in the scleroderma
subset that was incorpo-rated in the BREATHE-1 study,
but suspect from our clinical use of the drug that that
was an artifact of the relatively small sample size. We
have about 65 scleroderma patients who are receiving bosentan
currently. A large percentage of those patients, somewhere
in the 80% range, have substantial, measurable, clinical
improvement and improved exercise capacity. So we believe
that more widespread use of the drug will validate that
there is a positive clinical benefit from bosentan therapy.
Dr McLaughlin: That is an
important point. The scleroderma population made up a
very small percentage of these included in the BREATHE-1
trial and a much larger experience such as yours, Jim,
is very important to delineate how effective this therapy
is in this subpopulation.
Dr Badesch: I think it is
important as we look toward the future to mention that
we might begin to combine some of these different therapies
in patients with pulmonary hyperten-sion due to scleroderma
and perhaps we will be using some form of prostacyclin
preparation in combination with an endothelin receptor
antagonist, a phosphodiesterase inhibitor, and perhaps
oral L-arginine or a nitric oxide donor. Multi-modality
therapy that mimics the way we treat systemic hyper-tension
or cancer might have a greater likelihood of a positive
effect in patients with pulmonary hypertension due to
scleroderma. It is important to note that my comments
in this regard are speculative, and not yet supported
by clinical studies.
Dr McLaughlin: I agree with
that, David, and certainly combination therapy is where
we are going. The scleroderma patients were included in
the BREATHE-2 trial, which looks at the combination of
bosentan and prostacyclin in patients with severe pulmonary
hypertension. Scleroderma patients are also being included
in other clinical trails, specifically with the PDE5 inhibitor
sildenafil and selective endothelin receptor antagonists.
Dave, you also mentioned L-arginine; there is an international
trial looking at L-arginine supplementation in patients
with pulmonary arterial hypertension that also includes
the scleroderma spectrum of diseases.
Dr Seibold: It should be
emphasized that there is a level of scientific enthusiasm/optimism
about the specificity of all these drugs in the scleroderma
vascular lesion. We all recognize that scleroderma starts
with vascular injury frequently expressing as dysfunctional
vascular change, ie, Raynaud’s phenomenon, but the endothelial
injury is important very early on. One consequence is
diminished nitric oxide production. A second consequence
is diminished prostacyclin synthase activity and lower
prostacyclin levels. A third and potentially very important
tissue response is increased endothelial production of
endothelin, which has vasoconstrictive effects and a variety
of proliferative and proinflammatory effects that may
perpetuate and worsen the structural vascular injury.
So all of these agents that are being discussed, from
L-arginine through prostacyclin delivery systems through
endothelin antagonists may have some level of specifically
addressing a key pathophysiologic derangement of scleroderma.
Dr McLaughlin: We focus
so much on the existence of pul-monary arterial hypertension
in the scleroderma spectrum of diseases. Are there other
rheumatologic diseases that are associated with pulmonary
hypertension? I have seen patients with some different
rheumatologic diseases, lupus, even just Sjögren’s syndrome,
or polymyositis, present with pulmonary hypertension.
Is that rare, or is that something rheumatolo-gists should
keep their eye out for?
Dr Steen: Well, certainly
they are significantly less common than in scleroderma,
but I think in the lupus population and the mixed connective
disease population it is becoming more and more of a problem.
In the other diseases, Sjögren’s and myositis and even
rheumatoid arthritis, pulmonary hyperten-sion is well
documented and we have all had these patients, but the
frequency is much less.
Dr McLaughlin: Dave, have
you treated a number of patients with pulmonary hypertension
and interstitial lung disease? Clearly that population
exists. One thing we always worry about is the potential
for a worsening in V-Q mismatch, and then sometimes we
just tend to treat them for their pulmonary hypertension
because there is nothing else to do. I have treat-ed a
number of patients like that that and I can’t say that
I have seen anyone develop worsening hypoxemia because
of the V-Q mismatch. How about yourself?
Dr Badesch: Initially, we
excluded patients with more than mild interstitial lung
disease from the prostacyclin study, because of the concern
that we would worsen ventilation perfusion mismatching.
I have continued to be relatively cautious in my approach
to those patients, but, as I am sure other centers have
done, we have broadened the group of patients we will
try to treat aggressively with prostacyclin and now bosentan.
I agree with you that the worsening of ventilation perfusion
mismatching is probably not as much of a problem as we
expected it might be early on. I would add that in the
population with both interstitial lung disease and pulmonary
hypertension, the early consideration of the possibility
of lung transplantation is an important aspect of their
care. Some of these patients may not prove to be good
candidates for lung transplantation because of esophageal
dysmotility and reflux and the risk of aspiration, but
in the group of patients with both pulmonary hypertension
and interstitial lung disease, it may be particularly
important to consider the possibility of lung transplantation
early on. What do you think, Jim, do you end up referring
those patients for a transplant evaluation?
Dr Seibold: Dave, I really
agree, but I can’t find a program that will accept my
patients. The problem is that somewhere between 85% and
90% of these patients have esophageal dysmotility. So
there are very few centers in the United States that are
doing single lung transplantation in scleroderma at all,
and there is a long list of centers that have automatically
excluded scleroderma from consideration.
Dr McLaughlin: Would anyone
like to make any closing remarks before we finish up?
Dr Badesch: I am pleased
to see that patients with scleroderma-related pulmonary
hypertension are being included in most of the studies
now. And as Jim mentioned earlier, the level of en-thusiasm
for treating these patients has increased over time. I
hope that we will continue to work collaboratively on
clinical trials and toward improving the timely diagnosis
of pulmonary hypertension and prompt initiation of appropriate
therapy.
Dr Steen: I hope that in
future studies we look for patients who have what I’d
term pre-pulmonary hypertension, or are borderline, or
at high risk, or whatever you want to call them, and see
whether by very early aggressive treatment we might totally
prevent or allay or delay the dangerous deadly consequences
of this.
Dr Seibold: I would just
like to express my appreciation and admiration to the
group of collegial, high-quality investigators in cardiology
and pulmonary medicine who have pushed the field of management
options in pulmonary hypertension so far and so fast,
and have made available so many different options for
patients with scleroderma. It has been an astounding several
years of productivity.
Dr McLaughlin: The one thing
I want to emphasize from our discussion is that recognizing
these patients is critical. We now have something that
we can do for them. Early detection of pulmonary arterial
hypertension in the scleroderma popula-tion might allow
us to really have an impact on this devastating disease.
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