|
 This discussion was moderated by James P. Maloney,
MD, Associate Professor, Division of Pulmonary
Science and Critical Care Medicine, University of
Colorado, Denver, Colorado. The participants included
Robert P. Frantz, MD, Assistant Professor of
Medicine, Division of Cardiovascular Diseases, Mayo
Clinic College of Medicine, Rochester, Minnesota;
Michael A. Mathier, MD, Assistant Professor of
Medicine, Director, Pulmonary Hypertension Program,
and Associate Director, Cardiovascular Fellowship
Program, University of Pittsburgh, Pittsburgh,
Pennsylvania; and James B. Young, MD, Professor
and Chairman, Division of Medicine, and George and
Linda Kaufman Chair, Cleveland Clinic Foundation,
Cleveland, Ohio.
Dr Maloney: How big a problem is pulmonary
hypertension associated with left heart disease,
particularly pulmonary hypertension out of proportion
to left heart failure?
Dr Young: I can speak as a heart failure clinician
and also as someone interested in sorting out
those patients with heart failure and pulmonary
hypertension who might benefit from heart transplantation.
It’s a huge problem for us and not one
that’s been very carefully studied. We see several
scenarios in our advanced heart failure patients.
One, patients with terribly disturbed left ventricular
systolic function and very high pulmonary artery
pressures noted in conjunction with a high wedge
pressure that responds to dropping the wedge
pressure with different tools that cause the pulmonary
hypertension to improve, but leaves the
patient still walking around with pulmonary artery
systolic pressures in the 50 to 60 mmHg range.
This is still disturbing. Then you see the patient
with ejection fractions in the 35% to 40% or
maybe 50% (low normal) range, with severely
hypertrophied ventricles and so-called “diastolic
dysfunction” and pulmonary hypertension that is
surprisingly out of proportion to where one would
think those pressures should be. Finally, you can
see a third type of patient who clearly has two distinct
physiologic problems and will have pulmonary
hypertension with clear-cut gradient across
the lungs that is significant and a pulmonary artery
diastolic pressure to wedge pressure gradient that
points toward two different processes. Now, how
does one sort out those three scenarios without
catheterization and simply with noninvasive studies?
What we do with brain natriuretic peptide
measurements, and even more important, how do
we treat them with the medicines we have available,
is a contentious subject.
Dr Maloney: That sounds like that’s particularly a
problem with patients who are being evaluated for
heart transplants in that now they have these
chronically elevated wedge pressures and you
know that once you get them a new heart that pulmonary
vascular remodeling is not going to go
away. How do you approach those patients pretransplant,
and then also posttransplant when you
are left with a well-functioning left ventricle but
you have someone who’s had pulmonary vascular
remodeling from years of heart failure? How do you
evaluate those patients beforehand for such problems,
and how do you approach them after the
transplant?
Dr Mathier: During pretransplant evaluation we
largely screen out patients who are eventually
going to end up in that category, so if we see, as
Jim pointed out, a high transpulmonary gradient
during the transplant evaluation process, we
actively look to see if we can bring that gradient
down into a normal or perhaps just mildly elevated
range. If we’re successful at doing that, we generally
feel comfortable going on with an orthotopic
heart transplant, and in my experience, in general,
those patients don’t tend to go on to have very high
pulmonary pressures following transplant.
Occasionally, one will sneak through so that you
are left with significant pulmonary hypertension
even with normal or near normal left-sided filling
pressures and normal cardiac function. If that’s
the case, then that person in my mind falls into
that nebulous category of pulmonary hypertension out of proportion to left heart disease and I would consider
specific pulmonary hypertension therapy in that setting.
Fortunately, this is not a terribly common patient in our
experience.
<p><strong><font color="#003399">Dr Frantz: </font></strong>For patients with left heart failure who are undergoing
heart transplant evaluation and are found to have pulmonary
hypertension that raises concern about risk of donor
right ventricular failure, we administer nitroprusside in the
catheterization laboratory in an effort to document reversibility
of the pulmonary hypertension. The goal here is to mimic
the posttransplant state, ie, what would the pulmonary artery
pressures be if left-sided hemodynamics were normal? If
the pulmonary capillary wedge pressure normalizes but pulmonary
artery pressures stay high, eg, with a transpulmonary
gradient of 14 or greater, then transplant will
be risky or impossible. Sometimes ability to
administer nitroprusside is limited by systemic
hypotension, and it may not be possible to
bring down the pulmonary capillary wedge pressure
because of advanced cardiac failure. If the
pulmonary capillary wedge pressure cannot be
corrected because of advanced congestive heart
failure, and the pulmonary artery pressures stay
high, then other maneuvers such as short-term
administration of inotropes to increase cardiac
output may be helpful in demonstrating
reversibility. Occasionally we add inhaled nitric
oxide to intravenous nipride in an effort to maximize
pulmonary vasodilation while still trying to
lower pulmonary capillary wedge pressure. In
addition, sometimes administration of inotropes
such as milrinone continuously for several
weeks as an outpatient (if the patient has a
defibrillator to protect against risk of sudden
death) has been successful in our experience in
lowering pulmonary artery pressures into a
transplantable range. This may reflect a more
sustained unloading of the pulmonary vasculature.
Occasionally this phenomenon occurs following
left ventricular assist device placement
as well, thereby making the patient a more suitable
heart transplant candidate.
Dr Maloney: What are the lessons you feel we can draw from
trials such as the epoprostenol in chronic heart failure trial,
which was called FIRST, the Flolan International Randomized
Survival Trial? As new drugs come on board for pulmonary
arterial hypertension, the pharmaceutical companies
look to expand indications to more common disease, such as
congestive heart failure. It seems that just about every time
that’s been done, the drugs that work for pulmonary hypertension
don’t work for congestive heart failure, such as
endothelin receptor antagonists. Still, some people were
tempted to use these drugs in patients who had a component
of pulmonary hypertension related to left heart disease.
What’s your experience in interpreting these studies and
your advice to clinicians?
Dr Young: I’m old enough that I participated in some of
those “ancient” trials. The FIRST was pretty disappointing,
with observations indicating that Flolan, though effective in
some individual patients with high pulmonary artery pressures,
produced problems more often than not. You could
turn some patients awfully blue pretty quickly as you precipitated
intrapulmonic shunting if you weren’t terribly careful.
Indeed, it remains a bit of a mystery why some vasodilators
have been associated with less than robust and beneficial
outcomes, including the endothelin antagonists. If you
think about it, in congestive heart failure, endothelin antagonists
should have worked great, and in some of the initial
dose findings studies, data raised great hope based on pulmonary
pressure lowering as well as improvement in flow
through the lungs. In the end, it just didn’t quite pan out.
That suggests maybe it’s the wrong dose we’re
using. Maybe there are other subtle issues
related to right heart and left heart function
that we haven’t quite cleared up, but interestingly
enough, I’m not ready to completely
throw out those drugs in the patient with terrible
pulmonary hypertension. I just think we
need to do some smarter studies to, perhaps,
figure out the nuances of dosing these drugs.
Dr Mathier: If I might add, the studies we
have available were performed in patients with
heart failure, but not specifically with pulmonary
hypertension complicating it.
Dr Maloney: Very good point.
Dr Mathier: And secondly, with the endothelin
antagonist trials, the REACH-1 (Research on
Endothelin Antagonism in Chronic Heart failure)
is the only one for which we have detailed
data. The doses were clearly inappropriate
compared to those we use for pulmonary arterial
hypertension today. So I think Jim may be
exactly right that there are dosing issues that
were just not well worked out at the time those
studies were performed.
<p><strong><font color="#003399">Dr Frantz: </font></strong>I agree that we may have missed an opportunity
with endothelin antagonists in left heart failure by virtue of
having the dosing wrong, but we have to acknowledge that is
conjecture. In addition, we are wiser now about the issues of
fluid retention sometimes accompanying use of endothelin
antagonists, and might have dealt with that better with
diuretic adjustment. I draw an analogy to the lessons of
beta-blocker use in congestive heart failure, where we need
to be very cautious initially in order to reap the longer term
benefits as the heart remodels.
Dr Maloney: The FIRST results were interesting in that the
dose of epoprostenol was quite low compared to what is
used for pulmonary arterial hypertension, yet those congestive
heart failure patients hemodynamically improved. But
they had increased mortality. I guess it gets to the bigger issue in that very commonly patients are referred to a pulmonary
hypertension center because an echocardiogram
shows a pulmonary systolic pressure of 50 mmHg and a left
ventricle with diastolic dysfunction. We do a heart catheterization
and find out they have a wedge pressure of 30
mmHg. Yet their main pulmonary arterial and pulmonary
diastolic pressures may seem elevated out of proportion to
that. At what point, even if you pushed treatment to such
patients for their diastolic dysfunction, do you become nervous
on the level of wedge pressure? Where do you like to see
that wedge before using drugs that we typically would
reserve for pulmonary arterial hypertension? Is there a wedge
pressure cutoff that either of you have that you just simply
won’t treat someone with a pulmonary hypertension drug?
Dr Mathier: I don’t think there is any hard and fast number
in my mind. If a patient presents, and we see this quite a
bit, especially with so-called diastolic heart failure, where
they may have a wedge pressure of 30 mmHg, then obviously
we try to optimize their heart failure care and drive
their wedge pressure down to what we think is the optimal
level for that patient. I like to see a wedge pressure under
20 mmHg with a persistently elevated transpulmonary gradient
before I would consider a specific pulmonary arterial
hypertension therapy in a patient who appears to have heart
failure with complicating pulmonary hypertension.
Dr Young: Yes, I would agree with that number too. That’s
exactly the target I would endorse. I usually tell the fellows
who are watching the patients in the unit, 16 to 20 mmHg.
The magic number of 20 or 16 mmHg isn’t necessary, but
somewhere in that range, I agree completely. The problem is
if that wedge drops too low, and you start giving these
agents, and that left ventricle underfills, you can get into a
lot of systemic problems with hypotension and renal dysfunction.
<p><strong><font color="#003399">Dr Frantz: </font></strong>I agree that the probability of causing more harm
than good is very real when using selective pulmonary
vasodilators in patients with a wedge of 18 mmHg or above.
For patients with preserved systolic function but documented
diastolic heart failure, it is critically important first to
achieve excellent blood pressure and heart rate control. This
includes documentation of good blood pressure control during
exercise, since high systemic and left ventricular pressures
during exercise often drive the symptomatology. Many
patients with longstanding systemic hypertension, especially
the elderly, develop substantial diastolic heart failure that
may be improved just with really good conventional antihypertensive
therapy.
Dr Maloney: What percentage of your patients in that range
of wedge pressures you gave us would you estimate you
actually have on additional therapies, such as sildenafil,
endothelial receptor antagonists, and prostenoids?
Dr Young: Well, it’s not very many, and the reason it’s not is
because there still is some concern about a) which patient
might benefit from this off-label use of these drugs, and b)
how to dose the drugs and maybe even how to choose the
drugs that are available. There is some reluctance to turn to
these agents, which I think actually could be very helpful
based on data from small clinical trials. Usually what happens
is they’ll get admitted to the hospital and pounded with
phosphodiesterase inhibitors like milrinone or maybe a trial
of nitric oxide inhalation will be attempted. It’s rather paradoxical,
because if you think about it, there aren’t any more
data with phosphodiesterase inhibitors than with these other
newer concepts. If you look at the number of patients who
would be eligible for these tactics, I would say as many as 1
in 10 of the real serious patients who get evaluated for heart
transplant are. I’d be curious to hear other estimates.
Dr Mathier: I agree that 10% is a reasonable number.
Another reason for the reluctance to use these agents offlabel
is that patients must meet every one of a set of criteria:
They must have a degree of pulmonary hypertension that
is judged to be “out of proportion” to their left heart dysfunction;
they must be able to attain a low enough wedge
pressure to give an adequate safety margin with which to
work before we begin a specific pulmonary arterial hypertension
therapy; they must be persistently symptomatic
despite having a reasonable wedge pressure so as to warrant
a trial of a specific pulmonary arterial hypertension therapy;
and lastly, they must have some evidence of a clinical
response for me to want to continue to use that agent. It’s a
relatively small percentage, I think, that meets all of those
criteria.
<p><strong><font color="#003399">Dr Frantz: </font></strong>I agree it is a small number of patients. Most of
these patients with left ventricular systolic failure and pulmonary
hypertension benefit most from optimization of conventional
heart failure therapies.
Dr Maloney: In those patients who get a heart transplant, a
small subset develops symptomatic pulmonary arterial
hypertension afterward. It’s challenging to choose what
would be the drugs to treat those patients. Sildenafil might
be chosen, but could interfere with antifungal drugs; we like
to avoid epoprostenol because of line infection risk;
endothelial receptor blockers might seem a good choice as
long as fluid retention isn’t an issue. Is there any particular
go-to drug you might tend to use in that postoperative setting?
Dr Mathier: In the immediate postoperative setting, we tend
to look for a quicker acting agent with direct delivery, so it’s
not unusual for us to use inhaled nitric oxide immediately
post-op. I don’t think that’s terribly controversial. I believe
most centers that do a reasonable volume of transplants are
using that sort of approach. The question gets a little trickier
when you start to think about medium and longer term
therapies, and as you point out, each of these drugs—just as
they do in the nontransplant setting—has pros and cons
associated with them. I think that if somebody has really significant
pulmonary hypertension and I feel that a prostanoid
would be of value, then I’m increasingly comfortable using
inhaled iloprost in that setting, specifically to avoid catheter-related complications, as you mentioned. If I think an oral
drug will be valuable, I tend to use an endothelin antagonist,
but with a careful eye on hepatic function, especially since
we like to employ statin therapy simultaneously in the posttransplant
patient.
<p><strong><font color="#003399">Dr Frantz: </font></strong>It is important to point out that there is a serious
pharmacokinetic interaction between bosentan and
cyclosporine, and concomitant use is not recommended.
Dr Young: I think that’s a great summary and it points to the
fact that there are really separate periods where pulmonary
hypertension after heart transplantation can get you into
trouble. One is the immediate postoperative period, including
challenges and troubles weaning off of cardio pulmonary
bypass. Generally, if there are any issues in the operating
room or early on in the intensive care unit,
inhaled nitric oxide is what we turn to. Actually
in the operating room, we have a low threshold
for putting in a right heart mechanical bypass
system. The second group represents a problem
where you come out of the operating room
with pulmonary hypertension, but it doesn’t
cause cardiogenic shock or an early disastrous
problem, but then at day 10, 12, 14, three
weeks, the patient is swollen with terrible tricuspid
insufficiency and right heart failure due
pulmonary hypertension. In these patients I’ll
move toward a phosphodiesterase inhibitor earlier,
and lots of diuretics to try to dry them out,
as much as their kidneys will let us, in hopes
that we will see a turnaround. If they don’t, you
have to turn to some of the other agents that
were mentioned. The third type of patient is
the one who’s out long term, and to me that’s
the biggest problem because these patients
usually have renal insufficiency. Their livers
aren’t in the greatest shape either. They’ve had
pulmonary hypertension ever since transplant
and the right heart is now really failing. This is
a miserable patient and a terrible outcome is
usually guaranteed.
Dr Maloney: Are there other issues you would
like to bring up?
Dr Young: I have two issues I’d like to see addressed and,
really, it’s a plea for better studies. Perhaps we could do
multicenter studies focused on how best to handle these
patients in the early postoperative phase when we see a lot
of tricuspid insufficiency and pulmonary hypertension that
can’t really be sorted out; how much is fixed and how much
is going to turn around over time. The second issue relates
to tricuspid insufficiency itself and to determining how
much might be due to the mechanical implantation of the
allograft versus right heart failure due to pulmonary hypertension.
It’s always been challenging to sort through these
difficulties related to the way the heart was sutured into
place versus a variety of combinations of right heart failure
and pulmonary hypertension. I’d be curious to hear what
others think about that.
Dr Mathier: I would add one other thing to the mix, and that
is what we do to a patient’s tricuspid apparatus with repeated
endomyocardial biopsies. I’m not sure that any of us have
a good way to really reliably assess right ventricular structure
and function and their interrelationship with tricuspid valve
function. One thing I would like to add to this discussion is
a plea, an ongoing plea, from a cardiologist to other cardiologists
in the pulmonary hypertension community to recognize
the absolute importance of right heart catheterization.
Too often, as you pointed out, Jim, we see patients with a
suggestion of elevated pulmonary pressure on echo, with
perhaps normal left ventricular systolic function, with or
without ancillary evidence for a diastolic abnormality, who
are just started down a pathway of pulmonary
hypertension therapy without a formal hemodynamic
study to determine whether there are,
in fact, elevated left heart pressures. These
patients, in my opinion, absolutely must
undergo a hemodynamic study so that we can
know exactly which disease it is we’re dealing
with.
Dr Maloney: That’s an absolutely key point. I
think we all in the pulmonary hypertension
community have tried to convince people that
pulmonary arterial hypertension cannot just be
diagnosed on an echocardiogram, but dictates
hemodynamic evaluation with right heart
catheterization and very often, left heart
catheterization. Let’s say a patient undergoes
right heart catheterization and is found have a
mean pulmonary artery pressure of 30 mmHg
but suspiciously has a wedge pressure that is
18 to 19 mmHg, long-standing systemic
hypertension, and a prior suggestion of diastolic
dysfunction on the echocardiogram. Many
people, myself included, would work with a
cardiologist, do an exercise study with this
patient in the catheterization lab, and follow
the wedge pressure and LVEDP to see if this is
a patient who has exertion-related pulmonary
hypertension due to diastolic dysfunction. There is a fair
spread on how people evaluate that in these cases of mild
pulmonary hypertension. What are your experiences and
biases?
Dr Mathier: I’m still uncertain about what role measurement
of pulmonary pressures during exercise is going to have in
the long run. In the situation you described, where there is
a relatively modest transpulmonary gradient and elevation of
the wedge pressure with evidence of what we would call
diastolic dysfunction, I generally would stop there in terms
of evaluation and focus my efforts on optimizing the care of
the underlying diastolic abnormality, and then follow the
patient to see if there is clinical improvement. If, however,
there is evidence of a wider transpulmonary gradient, but the mean pulmonary pressure is still not through the roof,
then I might move toward an exercise study to see if there is
more of an exaggerated rise than I would expect with exercise.
Dr Young: After having been involved with doing a lot of
these studies, I virtually gave up because of the inability to
really predict outcomes in patients, but even more, the hassles
of trying to do one of these studies. They’re extraordinarily
bad in reproducibility of information and are just trouble.
So I agree completely with that response.
<p><strong><font color="#003399">Dr Frantz: </font></strong>In my experience, occasionally exercise hemodynamics
in the catheterization laboratory can be helpful in
the differential diagnosis of dyspnea. Just today I performed
a right heart catheterization for a patient with a history of
systemic hypertension that had been variably controlled, but
who was still having complaints of exertional dyspnea. Her
resting hemodynamics were normal, but her wedge and right
atrial pressures rose to around 20 mmHg after 6 minutes of
exercise. I think that helped explain her dyspnea.
Dr Maloney: Patients with mitral regurgitation can often be
difficult because that can be worse with exercise. There’s a
subset of patients who have mitral regurgitation who with
exercise get pulmonary hypertension from the regurgitation.
It’s difficult to figure out the best way to evaluate those
patients. Some centers have a protocol for exercise such as
echocardiography with a recumbent bicycle; some people
prefer to do it in the catheterization lab. What do you do?
Dr Young: Again, in the past, I’ve run into the same problems
with getting good reproducible measurements. Getting
good pressure tracings you can evaluate is a problem.
Personally, I’m not sure what intracardiac pressures mean
when obtained lying on your back pedaling a bicycle. If your
wedge goes up really high, or your pulmonary artery pressures
shoot up, I think it’s a bit of problem from a physiologic
standpoint, but how do you relate that to someone who
is upright walking about? So, rather than doing a lot of exercise,
in my experience, if you’re trying to flush out the severity
of mitral regurgitation, simple things like hand grip,
where you’re increasing SVR arguably tell you as much as
anything. Even more important is careful measurement of
the regurgative wave in this situation, and that’s a lot different
from trying to look at pulmonary artery pressures. I’d be
curious to hear what others think.
Dr Mathier: We are primarily doing stress echocardiographic
assessment in these patients, with the specific stress
employed determined more often by sonographer preference
and patient ability than by any programmatic decision.
We’ve done recumbent bicycle, treadmill, and dobutamine
protocols. We have, however, shared Jim’s observation that
trying to do exercise hemodynamic studies is just logistically
so difficult that we only rarely do it unless the referring
doctor feels that it is the only way to get at the question at
hand.
<p><strong><font color="#003399">Dr Frantz: </font></strong>We do exercise echo assessments, but also sometimes
do supine bike exercise in the catheterization laboratory.
I have also had occasional patients with functional
mitral regurgitation in the setting of an element of systemic
hypertension, where pulmonary artery pressures and wedge
pressures come down like a rocket with nipride in the cath
lab. In those patients it is a further incentive to aggressively
manage their systemic hypertension. Aggressive blood
pressure control can be recommended without such hemodynamic
assessment, but when patients are referred
because of their pulmonary hypertension, the ability to drastically
improve it acutely makes the case for the proper medical
approach, if mitral surgery is not advisable or appropriate. |
