Ivan Robbins, MD |
Pulmonary Hypertension
Roundtable
Bench to Bedside:
Principles and Practice of Epoprostenol Therapy,
from Maximizing Benefit to Minimizing Side Effects
Ivan Robbins, MD, Director, Pulmonary Hyper-tension
Center, Vanderbilt University, Nashville, Tennessee,
conducted this discussion. The panel included
David Langleben, MD, Director, Center for Pulmonary
Vascular Disease, Jewish General Hospital, McGill
University, Montreal, Quebec, Canada; Michael
McGoon, MD, Consultant in Cardiology, Mayo Clinic,
Rochester, Minnesota; and Abby Krichman, RRT,
Pulmonary Hyperten-sion Coordinator, Duke University
Medical Center, Durham, North Carolina.
|
David Langleben, MD |
Michael McGoon, MD |
Abby Krichman, RRT |
Dr Robbins: I have always
been interested in why investigators decided to try intravenous
prostacyclin, or epoprostenol (Flolan), as long-term treatment.
Dr McGoon: It was recognized
as a very potent vasodilator, with the additional theoretical
benefits of being one of the most potent endogenous platelet
inhibitors. So it made some sense to use it in a dis-ease
in which vasoconstriction was felt to be a pre-dominant
causal mechanism.
Dr Langleben: It was a serendipitous
concurrence of a novel molecule and a pharmaceutical company
that held very basic research in high regard. Prosta-cyclin,
as an endogenous vasodilator was initially described in
1976. The major clinical phase in pul-monary hypertension
began later in that decade, extending to the mid-80s.
So it took a while to work its way down to clinical use.
I think it was its potent vasodilator effect with a probable
short duration of action that made it very attractive
as an acute vasodilator for testing.
Dr McGoon: The other serendipitous
aspect of this drug is that it came when we were getting
disillu-sioned with other vasodilators, most specifically
hydralazine. So the concept of a short-acting pul-monary
vasodilating agent, which was actually replacing deficient
endogenous production of prostacyclin, made a lot of sense.
Dr Robbins: How did you
come up with the dosing scheme?
Dr McGoon: Initially it
had been identified during the acute-stage dose-ranging
studies that preceded our involvement. It became clear
very soon when using epoprostenol that if you gave too
big a dose you were going to get a lot of side effects
and you had to creep up on the dose if you were gong to
get benefit over the long haul. About 2 to 3 ng/kg/min
was the initial starting dosage in the early studies and
is clearly the way to go. Typically, most pa-tients, by
the time they were dismissed from our initial care, were
receiving around 6 ng/kg/min when they went home, and
after that point we increment-ed gradually by 1 or 2 ng/kg/min
every week or so, particularly if a patient was still
symptomatic, which was frequently the case. Later, based
on conversa-tions with other clinicians nationwide, we
evolved into more or less routinely increasing the dosage
regardless of symptoms. The idea was that we wanted to
stay ahead of symptoms preventively and continue to have
a vasodilator effect that would hopefully impart some
vascular remodeling and permanency to the decreased resistance.
Eventually it was recognized that there was a state in
which symptoms of high cardiac output could overtake the
benefits of decreased resistance. It has always been observed
that the predominant effect of administer-ing epoprostenol
was to increase cardiac output with modest decreases in
pulmonary pressure at best, resulting in a decrease in
calculated pul-monary resistance.
Dr Robbins: Abby, what has
the experience been at Duke?
Ms Krichman: Initially,
in the early days of epoprostenol dosing, the prevailing
practice was to continue increasing dosages on a regular
basis and just tolerate the adverse side effects. We certainly
have come full circle. Now we try to maintain the lowest
dose (of epoprostenol) possible to ameliorate symptoms
but also to minimize the side effects.
Dr Langleben: Our practice
was exactly as Mike described initially.
Dr Robbins: We were just
looking at our 5-year experience, and our average dose
is probably somewhere around 25 ng/kg/min. We have very
few people receiving more than 50 ng/kg/min.
Dr Langleben: Our early
patients, the ones who have had 10 or 11 years of treatment,
have reached high-er dosages. Most of the recent patients
are not at that dose level, though. Our average is probably
45 to 60 ng/kg/min after many years. After a year of therapy
most people are receiving about 20 ng/kg/min.
Dr McGoon: We are all over
the board, to be perfectly honest. It is such a moving
target at this time, when we have the option of combining
or transi-tioning to other medications. We can talk about
averages, but at least in our case, the standard deviation
of doses at any given time is extremely broad.
Dr Robbins: Should we talk
a bit about combined therapy?
Dr McGoon: It is at an early
stage. We are still learning about it. One pattern we
have seen is that when we add another agent to epoprostenol,
even one that is not a prostenoid, like bosentan, for
example, there can be an exacerbation of what we would
normally call epoprostenol side effects, such as flushing,
headache, and gastrointestinal disquietude.
Dr Langleben: The concept
of attacking an illness through a variety of mediators
and mechanisms is standard for other types of illnesses.
Perhaps, because of the relative rarity of pulmonary hypertension
or the lack of availability of easy therapy, we have not
been able to consider combined therapy until now.
Ms Krichman: There are a
lot of physicians out there who think they can just give
patients bosentan and completely wean them from epoprostenol.
We may be able to accomplish that in some patients, but
with very careful monitoring.
Dr Robbins: You are absolutely
right.
Ms Krichman: We ought to
make it clear that we are using combination therapy to
hopefully improve outcomes, not solely to wean epoprostenol.
Dr Langleben: Would everyone
agree that epoprostenol remains our gold standard for
the medical treatment of advanced functional class III
and IV patients?
Dr Robbins: Yes.
Dr Langleben: So, has everyone
around the table seen failures of other therapies already
and resorted to epoprostenol?
All: Yes.
Dr McGoon: Our prediction
was, and I think it is coming true, that the oral therapy,
bosentan, would be used widely, but that not all hopeful
expectations would be met. There has been more recently
the feeling that “Well, we haven’t seen all the benefit
we want, so maybe we should think about adding or transitioning
to epoprostenol.”
Ms Krichman: At our center,
and probably for most of you as well, when somebody’s
more of an early Class III patient, our preference is
always oral therapy first, but for those with later Class
III symptoms, we are initiating epoprostenol in most cases.
Dr McGoon: That would be
my preference, and that is what I express to most patients.
Ms Krichman: There are always patients who refuse epoprostenol
and want to try oral therapy first. In most cases we’re
amenable to a short trial of oral therapy with careful
follow-up and monitoring.
Dr McGoon: The key, particularly
if you are going to start with conservative therapy, is
the follow-up. The whole process of the pulmonary hypertension
specialty clinic has to be geared to establishing communication
with the patient about the treatment options, the pros
and cons, and then to very inten-sive follow-up and reevaluation.
Dr Langleben: What are your
standards for follow–up?
Dr McGoon: Of course, it
varies from patient to patient. We follow patients in
terms of clinical symptoms with 6-minute walk testing
at intervals of 3 to 6 months and with echocar-diography,
usually at 6 months. If there is disparity among clinical
impression, examination, and echocardiographic data, we
will do right-heart catheterization.
Dr Langleben: We prospectively
follow patients with echocar-diography at least every
6 months. Our population numbers aren’t huge, but we can
tell who is doing well on the basis of the Doppler echocardiography-derived
index of myocardial per-formance (the TEI index)) and
how their ventricles are coping.
Dr McGoon: At some centers,
some clinicians clearly feel that regular, periodic right-heart
catheterization for hemodynami-cally precise characterization
provides additional information about cardiac output.
Ms Krichman: I think a lot
of centers do that.
Dr McGoon: We don’t do it
on everybody because the specific number doesn’t really
help me too much, compared with the global assessment
of a patient’s status, which includes many factors. I
think all of us employ multiple criteria in deciding how
patients are doing and what changes, if any, in therapy
should be attempted.
Dr Langleben: The other
thing we pay particular attention to on our echocardiograms
is an estimate of cardiac output.
Ms Krichman: What is the
prevailing thought about patients who continue to have
severely enlarged right ventricles, but who symptomatically
are doing okay?
Dr Langleben: With those
patients, we follow the TEI index. In many of these patients
the index is greatly and abnormally elevated. If the index
is slightly improved, despite the fact that they have
right ventricular dilatation, we gently increase the dosage.
If the index hasn’t really improved with epo-prostenol,
we give them a couple of months, then that is an indicator
to list them for early transplantation, regardless of
their symptoms. Then we more aggressively increase the
epoprostenol dosage to try to buy them time to get their
transplant.
Dr Robbins: David, I am
just not impressed with aggressive dosing. And by going
up on the dose aggressively, we find you get a lot more
side effects.
Dr Langleben: We do increase
the dose more rapidly than we would in more stable patients.
We don’t get a lot of epopros-tenol side effects beyond
jaw pain and a little bit of diarrhea.
Ms Krichman: We see a lot
of musculoskeletal pain.
Dr McGoon: The problem is
knowing in the individual patient whether you have reached
the optimal dosage. I agree with David that if a patient
is not doing well, then you don’t know that a higher dose
won’t work until you have tried. So it does stimulate
a strategy of going up on the dosage. If you find the
side effects overwhelm the benefits, or if you really
don’t get any additional benefits from the inconvenience
or expense of a higher dosage, then it may make sense
to try tapering off again.
Ms Krichman: I think we
should talk about general dosing strategies for patients
who have just started receiving epoprostenol. We usually
have a 3- to 4-day hospitalization with a goal of sending
patients home taking 4 to 6 ng/kg/min of drug, somewhere
in that range. For sicker patients we’ll be more aggressive,
titrating up during the initiation period. Once they are
home, we call patients weekly for at least a month following
initiation of therapy and go up 1 or 2 ng/ kg/min a week.
Dosing is very individualized, depending on symptoms and
side effects. Once symptoms are somewhat under control,
we back off on dose titration, typically to every 2 weeks
and then every month. When we reach a dosage where there
is a balance of symptomatic improvement and minimal side
effects, we stop going up.
Dr Robbins: That is pretty
close to what we do, and what is probably done in a lot
of centers.
Ms Krichman: Except for
the very sickest patients, there is no need to rapidly
titrate epoprostenol
Dr McGoon: Oh, I agree.
Dr Robbins: You raised a
very good point, Abby, the fact that these patients need
very close follow-up. You can’t just send patients home
taking 3 or 4 ng/kg/min and then say, “Okay, we’ll see
you back in a month or so.”
Ms Krichman: It doesn’t
work well for physicians taking care of epoprostenol patients
without some kind of physician extender. There is clearly
a role for health care professionals who work very closely
with physicians and who talk with patients on a regular
basis and see them in clinic periodically. This is not
an easy disease to manage.
|
