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 This
discussion was moderated by Michael McGoon, MD,
Professor of Medicine and Consultant in the Division of
Cardiovascular Diseases and Internal Medicine, Mayo Clinic
College of Medicine, Rochester, Minnesota. Participants
included members of the Editorial Advisory Board of Advances
in Pulmonary Hypertension: Victor F. Tapson, MD,
Professor of Medicine, Division of Pulmonary and Critical
Care Medicine, Duke University Medical Center, Durham,
North Carolina, and Editor-in-Chief of the journal; Richard
N. Channick, MD, Associate Professor of Medicine,
Pulmonary and Critical Care Division, University of California,
San Diego Medical Center, San Diego, California; Vallerie
V. McLaughlin, MD, Associate Professor of Medicine,
Director, Pulmonary Hypertension Program, University of
Michigan Health System, Ann Arbor, Michigan; Ronald
J. Oudiz, MD, Associate Professor of Medicine,
UCLA School of Medicine, and Director, Liu Center for
Pulmonary Hypertension, Division of Cardiology, Harbor-
UCLA Medical Center, Torrance, California; and Ivan
M. Robbins, MD, Director, Pulmonary Hypertension
Center, Vanderbilt University, Nashville, Tennessee.
Dr McGoon: Judging
from what’s been discussed at the recent Pulmonary
Hypertension Association Conference, what would each of
you consider to be the main themes emerging in the field
of pulmonary vascular pathobiology?
Dr Tapson: Genetics
will be crucial. There is a genetic basis for the disease
and we will likely learn much more about the genetic basis
for response or lack of response to different therapies.
The development of, for example, specific molecular probes
is allowing the characterization of growth factor genes,
and markers of cell growth. Gene expression profiles will
enable the distinction of different forms of pulmonary
arterial hypertension.
Dr Oudiz: Mike,
what I got from the scientific presentations this year
was a renewed excitement about the progress made in understanding
pulmonary vascular pathology. The multiple mechanisms
involved in propagating the disease process are coming
into better focus, and this is exciting because it puts
us that much closer to finding ways to stop it or at least
slow it down.
Dr Robbins:
I think that a major theme is a shift away from vasoconstriction
as the primary abnormality in pulmonary vascular disease
to abnormal proliferation as a much more important process.
As such, therapy is starting to target inhibition and
regression of proliferation as opposed to mere vasodilation.
In addition to the emphasis on the proliferative aspect
of pulmonary vascular disease, emerging therapy is targeting
specific pathobiological pathways and mediators that have
been shown to be dysregulated in pulmonary vascular disease,
such as the nitric oxide synthesis or endothelin. The
serotonin pathway, particularly abnormalities in the serotonin
transporter, seems to have come full circle. That is,
serotonin was evaluated as a potential mediator 20 years
ago and is now being reevaluated both as a primary cause
of disease and as a modifier, affecting expression of
BMPR2. In addition to abnormal pathways, additional genetic
factors besides BMPR2, affecting disease expression, are
starting to be evaluated. It seems that mutations in BMPR2
are unlikely to explain the development of disease in
patients other than those with IPAH. Analysis of common
polymorphisms in a variety of vascular mediators and pathways
may provide significant information of disease expression.
Dr Channick:
I agree. The area of growth and proliferation and what
drives these processes may be fundamental for devising
novel therapies in the future.
Dr McGoon: Are
any or all of these concepts ready to be translated into
clinical research, or are they already? For example, when
the current crop of medications was under investigation,
we talked about them as vasodilators, and their efficacy
was thought likely to be a function of their vasodilator
potency. We still do vasodilator studies in trying to
guide therapy. Now there’s a sense that some of
these drugs’ effects derive from other mechanisms.
Should we be more aggressive in identifying, testing,
and using drugs that are less vasodilatory and more something
else?
Dr Channick:
Definitely. Examining true“ antiproliferative”
or even antithrombotic
agents may yield exciting results. In fact, we may be
able to take lessons from novel treatments used in coronary
artery disease.
Dr Oudiz:
I agree that we should focus more on the mechanisms that
our guest lecturers spoke about. What I worry about is,
as you say, that many of the cardiovascular drugs we use
today seem to work by mechanisms not apparent when they
were first developed, not only Flolan but statins and
beta blockers, etc. So how can we be sure that, going
forward, we're focusing on the correct targets and mechanisms?
Hopefully, researchers like the ones who spoke are better
equipped today to stand up to this challenge.
Dr Tapson: It
is clear that vasodilation is not the answer. Very abnormal
vessels need to be remodeled. We need to impact on angioproliferation
and combat cancerlike lumen-obliterating cells. We need
a more multifaceted approach.
Dr McLaughlin:
I agree that vasodilatation alone is not the answer, and
that chronic remodeling plays a role also. One other area
that I would like to see us start investigating is right
ventricular function—how the disease affects the
right ventricle and how we might treat the right ventricular
dysfunction.
Dr Robbins:
Yes, as mentioned already, the importance of the proliferative
aspect of pulmonary vascular disease is being increasingly
recognized. Medications such as bosentan, although possessing
some vasodilatory properties, are likely to work much
more through inhibition of fibrosis and inflammation.
Even epoprostenol, long used as a vasodilator, is becoming
recognized as being much more. It is likely that its long-term
beneficial effects result from inhibition of platelet
aggregation and smooth muscle growth as well as direct
inotropic effects. It is still important to find the rare
acute vasodilators (using the new classification of acute
vasodilator effect, that is, decreasing the mean pulmonary
arterial pressure to less than 40 mm Hg and maintaining
a normal cardiac output) because these patients can safely
and effectively be treated with inexpensive medications.
These responders likely represent a subgroup of patients
with a different disease, one that is predominantly vasoconstrictive
as opposed to proliferative. One wonders if other antihypertensives,
for example ACE inhibitors, which have never been evaluated
in more than a handful of PAH patients, would work as
well if not better in this group. I think what may be
of great benefit in guiding therapy will be genotypes
or haplotypes of common polymorphisms. For example, some
patients may have endothelin polymorphisms that predispose
to increased synthesis and would be expected to respond
to endothelin receptor antagonists or patients with increased
serotonin transporter activity may benefit from serotonin
reuptake inhibitors. Identifying genotypes and haplotypes
to predict clinical disease is at least one major way
to guide therapy. Finally, investigators have just begun
to think about known antiproliferative and antiangiogenic
agents such as thalidomide which deserve more consideration
Dr McGoon: If
it’s true that we need to look at new avenues of
treatment, then from a practical perspective, how will
we design future clinical research? Controlled prospective
studies of specific drugs, registries of experience using
empiric drugs or combinations, unique pilot studies of
novel drugs like immunosuppressives or angiogenesis inhibitors?
Who should do these studies? Where should funding come
from?
Dr Oudiz: This
is a big barrier to seeing novel research move forward.
The government is not likely to provide sufficient funds
for such research, and the pharmaceutical companies may
not be interested if it does not affect their bottom line.
Not only that, but the choice of what end points to measure
for these newer treatments, even if we can find funding,
is becoming even more difficult.
Dr Robbins: As
we are all aware, it is becoming increasingly difficult
to conduct studies of investigational agents in PAH. Although
industry can supply funding for studies, such interests
are focused, and there is little, if any, funding for
purely scientific questions. The NIH can supply some funding
for scientific questions but this is limited. Establishment
of a network of centers, such as has been done in ARDS
with the ARDSNet, to conduct studies that are industry
sponsored with substudies funded by the NIH may be one
solution. In addition, placebo-controlled studies, at
least in the United States, are no longer possible. I
think there will be a growing emphasis on combination
over solo therapy. Less mainstream therapies will have
to be evaluated in small pilot studies, which may mean
some therapies that are potentially helpful will be overlooked.
One possible solution to this is to perform parallel design
studies in which subgroups of patients receive an additional
medication.
Dr Tapson: Although
we would prefer to, we will not be able to rely on large,
multicenter, prospective, randomized clinical trials as
much as we have in the past. With new agents and limited
funding resources and patient supply, we may have to build
on basic science hypotheses with open-label, nonrandomized
trials and registries, and more carefully choose our large
evidence-based studies. I believe this kind of preplanning
and pilot protocols will be even more vital. A more solid
genetic understanding may aid in more meaningful clinical
trial design. Competition between protocols is already
upon us. With the advent of new oral therapies, treatment
may (unfortunately) become less centralized and we may
find ourselves expanding our PH centers to include smaller,
less experienced centers. This may impact on our clinical
trial capabilities unless it is done in a supervised,
organized manner. Funding will be difficult.
Dr McLaughlin:
I agree with Vic. Clinical trials in PAH have become increasingly
difficult to enroll as more therapies become FDA approved.
Ethically, it has ecome more difficult to conduct placebo-controlled
trials, at least in de novo patients. I suspect that combination
therapy trials will become more commonplace. Although
good for the patients, the commercial availability of
more and more drugs may make both funding and enrollment
more challenging.
Dr Channick:
Given the number of possible targets and agents that might
act on the pulmonary vasculature and the limited number
of patients, clinical trials will become increasingly
more difficult. It is likely that future studies will
be “add-on” in nature. I believe the NIH needs
to play a greater role in funding studies, especially
examining drugs currently approved for other uses (eg,
statins).
Dr McGoon: How
should clinicians respond to ideas or early favorable
research? Take statins or sildenafil—should clinicians
begin using them liberally or wait for further data?
Dr Oudiz: This
is a personal practice choice. Some clinicians like to
be aggressive and others like to wait to see the data.
For them, it is a good thing that the aggressive bunch
do their thing, because this is sometimes, at least in
part, how the data are generated. Overall, I think we
should remain fairly conservative and not jump the gun.
Dr Robbins:
Although it is tempting to use medications based on anecdotal
results or positive outcomes in small, uncontrolled studies,
we all can cite numerous medications that looked good
initially but proved to be ineffective or harmful when
studied in a randomized fashion. Since large randomized
studies will not be practical for all potential therapies,
the idea of cautious use, initially under very controlled
circumstances, in conjunction with a database registry
has a lot of appeal. Of course it is crucial to ask the
right questions and keep the database focused on specific,
answerable questions.
Dr Tapson: I
believe that registries and open-labeled pilot studies
may assume increasing importance in determining the clearest
phase 3 approaches.
Dr McLaughlin:
I agree with that. However, we should always strive
to rely on well-designed, placebo-controlled trials. Sometimes
we rely on registries and open-label pilot studies when
we don’t have well-designed, placebo-controlled
trials, and that’s OK. What I don’t think
is OK is giving a patient a new “hot” drug,
without good data to back it up, in lieu of a drug that
has been critically studied in phase 3 trials.
Dr Channick:
I feel that it’s important that clinicians avoid
off-label use of drugs unless there is either a contraindication
to the approved drugs or failure of therapy. For instance,
the only time I prescribe sildenafil outside a clinical
trial is in patients who cannot receive bosentan or as
add-on therapy in patients in whom bosentan is failing.
I agree, though, it is important to collect these off-label
data, possibly by
means of a large registry.
Dr McGoon: In
view of all the developments in less than a decade, as
high volume PH practitioners with referral-based practices,
do you feel the general medical community has made progress
in the understanding of PH, diagnosing it, and referring
it? Where should PH best be treated, at least initially,
now that therapeutic alternatives have broadened? With
the primary physician, the secondary specialist (cardiologist
or pulmonologist), or the tertiary subspecialist referral
PH clinic? And why?
Dr Tapson:
In spite of tremendous advances, there is still a clear
sense in the community that PAH is untreatable. It remains
a rare disease in smaller cardiology and pulmonary practices.
We are still seeing late referrals of very ill patients
and interestingly these include both late-stage untreated
patients and late-stage patients receiving some oral therapy
without a practical knowledge of when or how to proceed
when therapy fails. Many cardiologists and pulmonologists
understand that the appropriate time to refer is at diagnosis.
It is difficult for the best of clinicians to have a good
working knowledge of the disease when they don’t
follow 100 patients on intravenous prostacyclin. Family
practitioners cannot possibly deal with this disease and
should not be expected to. The range of diseases and problems
that they face is extraordinary.
Dr Robbins:
I think there has been progress in the awareness and diagnosis
of PH during this time, especially with regard to patients
at risk for the development of PH, namely patients with
scleroderma, liver disease, or HIV infection. There has
been a big emphasis on PH at numerous national meetings.
However, I think there is still a long way to go in the
general understanding of the differential diagnosis of
PH, and in particular, the fact that pulmonary venous
hypertension is a frequent cause of not only moderate
but severe PH. Obviously I am biased, but I feel that
initial treatment of PH should be at a tertiary specialty
center. These centers have access to all advanced therapies
and the support personnel to manage them. These are not
available even in big cardiology or pulmonary practices.
In addition, with a variety of medications now available
to treat PAH, the experience offered by a specialty center
is, in my opinion, very important. We are seeing patients
mismanaged in the community. They are misdiagnosed, left
on oral therapy for too long a time, or not even evaluated
with a proper diagnostic right heart catheterization.
Once therapy is initiated, I think it is very important
to work closely with local pulmonologists or cardiologists.
Dr McLaughlin: Multiple
efforts, on the part of both professional organizations
(eg, the ACCP Evidence-Based Guidelines) and the private
sector (eg, pharmaceutical-company sponsored symposia
and meetings) have assisted in educating the community
about PAH over the years. I think this has had both positive
and negative impact. In a positive sense, more physicians
are aware of the disease, and I am seeing some patients
earlier in the course of the disease than I did 5 years
ago. However, in the negative sense, I am seeing patients
treated in the community without being properly evaluated
and followed, and by the time I see them, their disease
is very advanced. I think it makes sense to have a pulmonary
hypertension specialist involved in the care of most patients.
Dr Channick:
There has been a large effort to educate physicians about
PH, much of it highly successful. There is no question
that recognition of PH has increased. However, with increased
recognition comes the risk of inappropriate diagnostic
approach and treatment. The availability of highly effective
oral therapy (bosentan) has created an opportunity for
both early treatment and misuse. It is now the role of
the expert to clearly define which patients should be
treated with which agent, how patients should be followed,
and when patients should be referred to a PH center. My
general opinion is that it is appropriate for nonexperts
to start oral therapy, provided the standard work-up is
performed, including right heart catheterization. If a
patient is getting worse while receiving oral therapy,
it is appropriate to refer to a center for consideration
of parenteral therapy, or enrollment in a clinical trial.
For example, we (and others) are examining inhaled prostacyclins
as add-on therapy in patients already receiving bosentan.
Dr Oudiz:
Until PAH becomes common enough, like heart failure, and
until medical schools start devoting bigger blocks of
time to teaching pulmonary vascular disease management,
I am a firm believer that PAH is something that should
be left, at least in the initial few months of diagnosis
and treatment, to PH specialty referral centers. Given
the rarity and complexity of the disease, patients are
much better served if they are cared for by people who
understand the nuances of diagnosing and treating PAH.
Dr McGoon:
Speaking of patient demographics, when I read the pertinent
PH literature I get the impression that there is a nice
neat population of classic PAH patients with symptoms
who should be treated with certain medications or procedures.
What about atypical (but common) patients, such as those
with quite mild resting PH with disproportionate symptoms?
Or patients with exercise PH? Or elderly patients with
significant PH but also multiple contributing factors,
such as diastolic dysfunction, some obstructive airways
disease, sleep disturbance, obesity, systemic hypertension,
a past history of PE, etc? Are these a part of your practice?
How do they tend to be handled?
Dr Oudiz:
They are a significant part of our practice, but a surprisingly
smaller part than I would expect, given the frequency
with which these entities are seen. We rely a lot on exercise
testing in these patients, since it helps us sort out
the relative contribution and significance of a confounding
disease process. Unfortunately, there is no predefined
algorithm for atypical PAH patients, all the more reason
that these patients should be referred to specialty centers.
Dr Tapson:
What’s most obvious to me is that patients with
PAH are not simply straightforward PPH patients or straightforward
patients with COPD and secondary PH. There are patients
with COPD and an FEV1 of 50% of predicted with systemic
PA pressures who should be treated like PAH patients.
There are individuals with mild and often meaningless
sleep apnea with mild nocturnal hypoxemia but who have
very “vasoconstrictive” vessels for some genetic
reason. There are scleroderma patients with severe PAH
and severe pulmonary fibrosis or with severe parenchymal
sarcoidosis who clearly respond to Flolan, even though
they don’t appear to have pulmonary arterial hypertension.
They do have it. Diastolic dysfunction means a left ventricular
abnormality, but with severe PH, should Flolan or bosentan
be administered? Perhaps so, but there are no good data.
Dr McLaughlin:
Yes, I agree. The percentage of my practice that falls
into that nice neat PPH diagnosis has been shrinking over
the years. Although I see some patients with PH related
to the pulmonary diseases that Vic has outlined, I see
many more with components of diastolic dysfunction and
valvular heart disease. We have come to refer to it as“
multifactorial” pulmonary hypertension. It is an
area that is desperately in need of further investigation.
Dr Channick:
There is no question that many of the patients we see
are of the “other” types, especially diastolic
dysfunction in older patients. I think this changing demographic
is a manifestation of increased recognition of PH in general.
In our center, we follow these patients. I think it is
useful to see these patients, address appropriate therapy,
and analyze response or lack thereof to standard PH therapies.
Dr Robbins: These
atypical patients are a huge part of our practice and
present a big management challenge. I think some of the
hardest patients in terms of deciding what to do are those
with systolic pulmonary artery pressures in the 40 to
50s range, normal or near normal RV function on echo,
but with significant symptoms. In other cases, it is often
difficult to decide what the primary problem is. Sometimes
we try an endothelin receptor antagonist or PDE5 inhibitor
in borderline cases, ie, significant PH with a mildly
elevated left ventricular end-diastolic pressure or in
a patient with sarcoidosis and significant parenchymal
lung disease but severe PH. Clearly, the longer I do this,
the less certain and neat the diagnoses become for most
patients. There are very few “pure” PAH patients,
particularly once you consider subgroups other than idiopathic
or familial PAH.
Dr McGoon:
One theme that comes up more is whether treatment should
be started earlier now that we have treatments that are
at least partially beneficial in advanced symptomatic
PH. No matter what underlying mechanisms of disease are
identified by researchers and what drugs are under development,
there’s a sense that by the time we start treatment,
the cat is out of the bag. So what goes into a recommendation
one way or the other in terms of methods of screening,
defining a point of hemodynamic abnormality, or a constellation
of risk markers that would warrant consideration of early
treatment, evidence of efficacy, etc?
Dr Channick:
This is truly the $64,000 question. Unfortunately, to
study early intervention of any kind, you typically need
large numbers of patients followed over long periods.
PAH is simply not that common, especially compared to
coronary artery disease or congestive heart failure. Hence,
we may be forced to empirically treat patients based on
biological plausibility, results in more advanced stages
of disease, and risk factors.
Dr McLaughlin:
One of the problems with drug development is that you
have the best chance of detecting a treatment difference
in the more ill group. Showing statistically different
difference in less ill groups requires more patients and
longer studies, which are expensive. With the advent of
oral therapy, I think we are all inclined to start treatment
earlier than we were with intravenous therapy. A trial
with the endothelin receptor antagonist, bosentan, in
functional class 2 patients will soon be under way. This
study will also include an exercise hemodynamic subset,
which will be very interesting.
Dr Tapson: This
is an ideal setting for genetic screening. If I had PAH,
I would unequivocally want early therapy and would certainly
be minimally concerned about the prospect of developing
abnormal LFTs in a carefully monitored setting.
Dr Robbins:
Before considering early treatment, we have to be able
to diagnose PAH earlier. As we are all aware, most patients
are initially diagnosed with advanced disease. We just
reviewed our current practice and only about 5% or 6%
were not severely advanced enough to warrant specific
PAH treatment (ERA, PDE5 inhibitor, or prostaglandin therapy).
I don’t have any good ideas about how to pick out
this disease earlier. It’s a rare disorder and symptoms
mimic those of other more common diseases. Currently,
I don’t see a role for genetic screening, but in
the future, if we are able to define genotypes and haplotypes
that predict disease progression or response to therapy,
it will have a big role.
Dr Oudiz: This
is one of the hottest topics up for discussion these days
in PAH. I believe that because of our long history with
Flolan treatment, where it was easy to say that Flolan
was just too toxic for early PH patients, we are afraid
of using less toxic medications, such as ERAs and sildenafil,
when really they might be worth the risk. The problem,
as you mention, is then how do we prove that early intervention
is of benefit? In Scotland and in Venice, this was discussed
extensively, and many ideas were circulated, but there
was no definite consensus on what future end points should
actually be used. I suspect that investigators will continue
to explore their personal favorites and that some of these
end point modalities will make it into larger clinical
trials. This may be the only way that we can actually
validate a newer end point.
Dr McGoon:
The PHA is opening up membership to all interested physicians
(the PH Doctor initiative). How should the PHA, and in
particular PH Doctor, be involved in the future of managing
and investigating PH?
Dr Robbins:
I don’t know how feasible this is, but I think the
PHA, with guidance from the SLC (Scientific Leadership
Council), should attempt to work with industry to help
direct future research. The number of PAH patients is
limited and prioritization of potential treatments is
needed. In addition, through PHA-administered grants,
something akin to an RFA might be set up to focus investigators
on specific topics or areas. Providing grant opportunities,
not only for young investigators but for midlevel and
even senior investigators with a track record of research
in PH is another way to promote high quality research
involving PH. With regard to managing patients, if there
is some way to designate centers of excellence that would
be listed on the PHA Web site, I think this could improve
care. Another way to improve care might be clinical sessions
for physicians—reviewing evaluation and management
of PH—at the PHA.
Dr Tapson:
Education is key. The PHA has done a wonderful job in
getting this difficult disease some well-deserved attention.
The disease often affects young persons in the prime of
their lives. Media attention, patient and physician education,
and support for continued research will be instrumental.
And don’t forget nursing. I believe the PH nurses
have been the mortar that has held the bricks together.
We not only need funding for research, we need it for
clinical nursing support. It is becoming increasingly
financially difficult to run a PH center. It would be
impossible for small practices to handle large numbers
of patients. Education and referral to large PH centers
are key.
Dr Channick:
Increasing the involvement in nonexpert specialists may
be very important in increasing our database. As mentioned,
community physicians are already treating patients, so
developing a network or registry will become more plausible
if these physicians are invested in the PH community.
Dr Oudiz: PH
Doctor will certainly help further the campaign to educate
the medical and scientific community worldwide. Bringing
these issues to a wider audience will introduce that much
more scientific input into future diagnostic and therapeutic
modalities. It should facilitate further discussion of
what we’ve been talking about here; namely, the
issues surrounding the screening of candidate therapeutic
mechanisms, earlier intervention, and finding additional
clinical end points to measure the effects of these interventions.
Hopefully, an even more concerted effort at creating and
maintaining a sound patient database might result.
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