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One on One Interview
Seeking a Consensus on PH: Challenges Left by the Venice
Symposium
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The Venice Symposium was a unique assemblage
of physicians and scientists representing a variety
of disciplines ranging from pulmonary medicine to
cardiology, rheumatology, pathology, genetics, molecular
biology, and surgery, all with a common interest in
pulmonary vascular disease. The state-of-the-art overviews
provided not only a perspective of where we are and
how we got there, but also glimpses into the future
of new and exciting directions in basic and translational
research. The opportunity for basic investigators,
clinical researchers, and representatives from industry
to interact and explore new avenues to pursue will
undoubtedly lead to fruitful collaborations and innovative
approaches to the understanding, and ultimately the
cure, of hypertensive pulmonary vascular disease.
It is remarkable that, despite the attendance by several
hundred individuals, a consensus on major issues was
reached, including the adoption of a revised nomenclature.
- Lewis Rubin, MD, University of California at San
Diego. |
Commentary on the Venice
Meeting, featuring an interview of Nazzareno Galič, MD,
one of the organizers of the Third World Symposium on
Pulmonary Hypertension. Victor Tapson, MD, is Editor-in-Chief
of Advances in Pulmonary Hypertension.
Dr Tapson: Nazzareno, would you give
us an overview of this meeting and how you would compare
it with other sessions?
Dr Galič: This meeting was a challenge
because we tried to combine the concepts of the Evian
meeting based on task force discussions with more conventional
scientific presentations in front of a larger audience.
It was a challenge because the plenary presentations to
a wide audience were really prepared during the task force
meeting. This was difficult because the time allowed was
not infinite and we forced competitive scientists with
different ideas to reach a consensus on “hot” topics and
to have this consensus written and definite before the
plenary presentation. The real success was this: we forced
and we obtained this consensus between the task force
members because during the plenary presentation only attending
people asked additional questions. There was not additional
discussion among the task force members. This means that
the consensus was reached.
Dr Tapson: Did you think there were
any big surprises or controversies with the meeting that
were difficult to resolve?
Dr Galič: I don’t think so. There were
challenges because in some task forces—for example, genetics,
we put together people who were “scientifically” competing
among themselves for the last 3 or 4 years. This has been
important because they had consensus to collaborate, to
define some common research strategies for the future.
This was another success. Another surprise was the consensus
we reached on the treatment algorithm. I thought it would
have been very difficult to get a consensus between people
in Europe and the United States because the approved drugs
and experiences are somewhat different. Nevertheless,
we reached a good compromise in the treatment algorithm.
Dr Tapson: Despite initial differences,
it’s impressive to make those agreements when practices
can be quite different. There are certain obvious things
like the use of inhaled prostacyclin, iloprost in some
countries. Were there any international differences that
were really significant in terms of diagnosis and treatment?
Dr Galič: The main difference is that
in the United States subcutaneous prostacyclin (treprostinil)
is approved whereas this is not approved in Europe. And
in contrast, iloprost is already approved in Europe. It
was adopted as “off-label” use in some German-speaking
countries. Now we have the official approval of the EMEA
(European Agency for Evaluation of Medicinal Products)
that will become fully operative in a few months. In the
United States you have the availability of subcutaneous
treprostinil that we have utilized only in patients enrolled
in clinical trials. The lack of availability of treprostinil
in the clinical setting limits our experience with the
use of this drug. This is the main difference. Otherwise,
epoprostenol is approved in most European countries, as
is bosentan.
Dr Tapson: Did you get a sense from
the task force on pathology and pathobiology that there
is any one disease mechanism that people seem to agree
is the most important or that there is any trend in priorities
of the most important mechanism?
Dr Galič: No, we didn’t find a particular
mechanism that can be considered more important than any
other. We have the problem related to the endothelial
dysfunction, to all the changes in the NO, prostacyclin,
or endothelin pathways. We have the serotonin hypothesis.
This is coming back because of the genetics. Serotonin
transport can explain some differences in the development
of pulmonary hypertension in subgroups such as those with
HIV or people with portal pulmonary hypertension. I think
also the TGF-beta pathway has been studied a lot because
of the mutations found on that type of receptor. But I
haven’t found a pathway that has been more explored than
any other.
Dr Tapson: So the concept of combination
therapy is still going to be important in the future?
Dr Galič: Yes, this is the rationale
for the combination therapy. It is linked to the multiple
changes in the different pathways. The concept of combination
therapies is quite complex because you combine drugs but
you also can combine side effects. We cannot forget that
all the drugs we are using in pulmonary hypertension are
also systemic vasodilators. So you combine many systemic
vasodilators and this combination may be detrimental for
blood pressure. In any case, this is a problem that can
be addressed by an appropriate dosing and timing strategy.
Dr Tapson: Along the lines of treatment,
one of the tough topics for me has been the timing of
transplantation. Do you think we came to any more consensus?
Dr Galič: This is another challenge
that is linked to the length of the waiting list. If we
could rely on a definite mean time for the waiting list
(for example 6 months) we could wait until the patient’s
condition has deteriorated to the level at which the expected
survival is approximately 6 months. But this is not the
case. You know that the waiting list is usually longer
than 12 months and up to 18 to 24 months. This is why
it is difficult to include in a treatment algorithm the
lung transplantation intervention. How can you decide
to put a patient on a waiting list 18 to 24 months before
the transplantation? Anything can happen in 18 to 24 months.
Despite this, the long-term experience with Flolan published
recently by Vallerie McLaughlin (Chicago) and by Olivier
Sitbon (Paris) showed that the people who have not shown
an adequate hemodynamic or exercise capacity improvement
after 3 to 4 months of therapy need to be listed for lung
transplantation. For example, if the patient cannot walk
more than 350 meters, he or she should be considered for
listing for lung transplantation because this is a negative
prognostic factor. This is probably what we will implement
in the future. Maximized medical treatment, including
combination therapy. If you cannot obtain a good hemodynamic
profile and an exercise capacity above a defined level,
they are likely candidates who should be listed.
Dr Tapson: Let’s backtrack for a second.
In terms of genetics, do you have a sense of who should
be tested for BMPR-2 mutations? Do you test families or
do you have a sense of what we should do?
Dr Galič: I don’t think we have a consensus
about this. It’s still a matter of research. Genetics
is still a research tool, not something you can use in
clinical practice. Even if you identify a mutation in
family members who do not have pulmonary hypertension,
you do not know if they will ever develop pulmonary hypertension.
And in any case, if you tested such patients who are otherwise
healthy and you reported to them that they have the mutation
you can completely change their lives. For scientific
and ethical reasons, we believe that genetic testing does
not currently play a role in clinical practice for pulmonary
hypertension.
Dr Tapson: That seems to be the consensus
of most. It sounds like most people think we should be
careful about how we’re using genetic testing at this
point. It was a fantastic meeting. What does the future
hold?
Dr Galič: We look forward to the proceedings
being published. We will not have another meeting for
some time. It’s like the Olympics. We need to wait maybe
another 4 years.
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