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Dr Bridges: I agree precisely
with every single thing that Dunbar just said. That is
exactly the way I approach patients. I still find it alarming
how many pediatric cardiologists in the community are
starting calcium channel blockade in the clinic after
an echo. That is still a big, common practice and I think
we really need to emphasize that that is not an appropriate
practice. I think the other problem is that there are
occasional patients who have a paradoxical response to
calcium channel blockade. I haven’t seen many, I think
I have seen 3 in the last 10 years, but I have seen 3
patients whose PA pressure went up, whose PVR went up,
and whose cardiac output went down when treat-ed with
calcium channel blockade. These were all patients who
had a very nice response to nitric oxide. Dunbar, have
you seen this?
Dr Ivy: Yes. I would agree.
In patients reactive to acute vasodila-tor testing, we
test the response to calcium channel blockers in the cath
lab. We usually use IV diltiazem instead of nifedipine,
just for ease of administration.
Dr Barst: OK, let’s turn
our attention to the various treatment options. We have
soft retrospective and prospective data in PPH that anticoagulation
prolongs survival in adult patients. We don’t have those
data in children. If we start off saying a very small
percentage will respond favorably to calcium channel blockers,
for those children that is wonderful, but let’s discuss
the other 80 to 90% of patients. Do you want to touch
on anti-coagulation, and then move on to other therapies
with vasodila-tor and perhaps antiproliferative effects?
Dr Bridges: I generally
anticoagulate my patients unless I have a very good reason
not to. And that is regardless of the etiology of their
PH, as long as we are talking about PAH. The only exception
that I make to this is in the case of young toddlers because
of the risk of a bleeding event in association with a
fall, and the difficulty of monitoring their anticoagulation.
I will wait until they are a little older before I anticoagulate
them.
Dr Barst: You are right.
We don’t have data. But I think all of us are seeing patients
who are having significant episodes of hemoptysis. So
I think we need to be careful about “assuming” that we
should use anticoagulation in patients with PAH associ-ated
with congenital heart disease the same way we do with
PPH.
Dr Bridges: Assuming that
they have appropriate levels of anticoagulation, an INR
of 2 to 2 1 /2, do we really think that is a cause of
any of the hemoptysis? Hemoptysis is a part of the disease.
Dr Barst: Yes, absolutely,
but if a child has hemopt-ysis, are you continuing them
on low-dose anticoag-ulation, since we think that the
hemoptysis is part of their underlying disease, or are
you doing something else?
Dr Wessel: We certainly
study patients who are hav-ing acute hemoptysis to investigate
whether there are collaterals that can be identified that
are con-tributing to the symptoms. I think it is a little
bit hard when you actually get there and you start look-ing
at collaterals and deciding which ones to embolize. I’d
like to outline an algorithm for the care that we are
gradually evolving for patients with PPH or perhaps repaired
congenital heart disease where there’s still persistence
of PH. First we test them in the cath lab and look for
vasoreactivity. If they are very good responders we put
them on a calcium channel blocker and eval-uate them closely
over the next few months to see if there is a sustained
reduction in pulmonary artery pressure. If they’re not
dramatic responders, then we go to the other therapies.
I think there is a reasonable basis now for discussing
the use of con-tinuous IV prostacyclin that could be offered
to the child. If there were a reason not to use a central
venous line and con-tinuous IV epoprostenol, then we would
consider some of the other alternatives. The next option
usually is other FDA-approved therapies for certain kinds
of adult PH disease. Bosentan is an example but our experience
is mixed and pre-liminary. Beyond that we get into more
investigational therapy and we have offered families inhaled
nitric oxide for long-term administration or I think we
may see emerging the opportunity to use phosphodiesterase
inhibitors in outpatients. Most of these patients who
are not in the infant or toddler group we anticoagulate.
We may modify that in Eisenmenger patients with hemoptysis.
Dr Barst: Are we helping
these patients with these treatments, particularly Eisenmenger
patients who have an 80% 5-year sur-vival and a 40% 25-year
survival without treatment? Are there subgroups that we
need to evaluate to determine the overall risk-benefit
considerations for these various treatments versus no
treatment?
Dr Wessel: As everyone knows,
the majority of advances in the treatment of PH in adults
have been a result of properly designed clinical trials.
We do not have placebo-controlled tri-als to guide our
therapy in patients with Eisenmenger syn-drome. We extrapolate
in part from adult PPH work and studies by Dr Barst. So
I would say that we don’t know if we are help-ing. It
would be crucial, especially in most pediatric diseases,
that we start proper trials because we’re taking clues
from our adult patients but we’re not certain that children
will react the same way. I am pleased to say that trials
with sildenafil, endothelin-receptor blockers, and inhaled
nitric oxide are under way in children.
Dr Barst: I would remind
everyone that for the FDA-approved therapies, even though
several, i.e., tre-prostinil and bosentan, are approved
for the broad category of PAH, epoprostenol and bosentan
were not evaluated in patients who have PAH associated
with congenital heart defects. And I think that’s very
unfortunate. It behooves us to make sure we are doing
“no harm” using these therapies in PAH patients with associated
congenital heart disease.
Dr Bridges: I think one
thing that we have to be con-scious of in making individual
treatment decisions for patients who have residual significant
structural lesions and pulmonary vascular disease is that
if they’re getting worse because of myocardial failure
rather than increasing cyanosis, they are not, in my opinion,
candidates for vasodilator therapy. In other words, if
I do a heart catheterization on one of these patients
who, say, has an unrepaired VSD or an unrepaired canal
and they have a right atrial pressure of 15, a QP/QS less
than one, and low systemic cardiac output, I don’t really
think that vasodilator therapy of any sort is going to
be helpful for any of those patients. I think that sort
of myocardial failure is really a harbinger of very end-stage
disease in such patients.
Dr Wessel: I want to underscore
the comments that were made about the true Eisenmenger
population in patients who have right-to-left shunting
and a significant degree of cyanosis. This is a patient
population that has not been well studied and we need
to be most cautious about these new therapies in that
patient population. The subgroup that Nancy has just described
with significant heart failure in association with it
is one in which we should be especially cautious about
these therapies because we do have a bit of natural history
data for Eisenmenger syndrome that I think may be a little
bit different from the adult or PPH. We know that historically
one can sur-vive several years with Eisenmenger’s physiology
and we have to be very cautious about introducing new
therapies that are sys-temic vasodilators when we have
an open unrestricted defect and the potential to go right
to left.
Dr Barst: We haven’t seen
any clinically significant right-to-left shunting but
I agree that we need to be cognizant of this poten-tial
adverse effect with vasodilator therapy in patients with
Eisenmenger syndrome. We must remember that without treat-ment(
s), Eisenmenger patients often live into their 20s, 30s
and beyond. Nancy, would you address timing of transplanta-tion
and outcome?
Dr Bridges: There are two
issues when you’re looking at thoracic organ replacement
in people with coexisting congenital heart disease and
pulmonary vascular disease. First is the technical set
of issues. It’s obviously much more straightforward when
you’re considering lung transplantation for a person with
PPH; these patients rarely need heart replacement. You
need to be sure that you have a good understanding of
the technical risks associated with transplantation for
this particular patient and make a very careful decision
about what sort of thoracic organ replacement will be
done, heart and two lungs, heart and one lung, or heart
repair plus one or two lungs. It’s a very individu-alized
decision. And then there are the physiological consider-ations:
at what point have patients with Eisenmenger syndrome
definitively failed all the available medical therapies,
making it appropriate to go on to transplantation? I still
pretty much use the hallmark in most cases of progression
of heart failure. If we have tried all of the available
vasodilator and anticongestive therapies and demonstrated
that they are not useful for the patient or that they
were useful and the patient is no longer responding and
I start to see the progression of heart failure, I think
that is the appropriate time to list the patient. If you
have a patient you know is going to need replacement of
both the heart and the lungs, then obviously you need
to list earlier because the waiting time will be longer.
Dr Ivy: In discussing a
pediatric algorithm, treatment of patients who are not
responsive to acute vasodilator testing depends on clinical
status and functional class. My algorithm would continue
that if a child presents with congestive heart failure
with a nonreactive pulmonary vascular bed, I think that
epoprostenol is the standard of care for that patient
and we would consider listing for transplantation. If
the patient is non-reactive but with normal cardiac output
and right atrial pressure and no sign of congestive heart
failure, then other therapies may be considered, such
as treprostinol, sildenafil, bosentan, or perhaps long-term
inhaled nitric oxide. I would agree with Dr Bridges entirely.
Dr Barst: Would each of
you like to comment on where you think we should be headed
in the future? I think we do these patients a disservice
when we treat all patients with PAH and associat-ed congenital
heart defects the same, regardless of age, con-genital
heart defect and its associated physiology, as well as
how symptomatic the patient is from his or her PAH. We
still don’t know if the “disease” is the same or different
in various patients with PAH and associated congenital
heart disease.
Dr Ivy: I would reiterate
that it is very important that we start multicenter randomized
trials in children with these newer agents.
Dr Wessel: As we move forward
I think it’s important that we have a more aggressive
attitude toward intervening with these patients. We are
now seeing treatments for patients referred to us as “Do
Not Rescuscitate” status because there is thought to be
no therapy. Yet they’ve had sometimes spectacular results
from existing lines of therapy for treatment of their
pulmonary hypertension. It is our obligation to really
exhaust all those forms of medical treatment and then
consider more heroic efforts like transplantations. It
is also important to inform the medical and patient communities
that trials and treatments do exist for them.
Dr Bridges: I agree with
everything that’s been said and I would add that it’s
important both for those of us who are more spe-cialized
in seeing patients with PH and the general pediatric cardiologist
to view each patient with an open mind. As I’ve had more
patients with PH referred to me, I’ve found that there
are more variations of the disease than I originally recognized
and it’s easy to be too quick to categorize the patient.
That’s a mis-take. We need to start out with the view
that we do not know the disease and make sure the evaluation
is complete and the approach to therapy is flexible. Given
how much ignorance we still have about the patients we
are treating, we need to remain humble when faced with
this disease.
Dr Barst: I think it is
also important for us to collaborate with our colleagues
in adult cardiology as more and more children with congenital
heart disease are surviving into adulthood. Each patient
with pulmonary vascular disease deserves an individu-alized
evaluation and treatment approach.
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