Dec 9, 2020
SPECIAL EDITION: The Pathways To Treatment
The PAH Initiative and United Therapeutics are excited to
bring you the PAH Today National Broadcast Series. This series of
virtual events is intended for adult patients with pulmonary
arterial hypertension (PAH) and their caregivers.
Advancements in the care and treatment of PAH are improving the
lives of those impacted by this life-threatening disease. The
National Broadcast Series will include insights and perspectives on
today’s approaches to managing PAH from nationally recognized PAH
healthcare providers. Join patients and caregivers across the
nation to hear current considerations in the care of PAH.
This is the 3rd of 4 PAH Today
broadcasts to learn about how medications work to treat PAH and how
finding the right combination of medications could help improve
your symptoms.
Presented by Dr. Lana Melendres-Groves the Director of the Pulmonary Hypertension Program at the University of New Mexico and Dr. Sean M. Studer Chief of Medicine at NYU-Woodhull Medical Center in Brooklyn, New York. Learn more at: www.pahinitiative.com
Lana Melendres-Groves, MD:
Good afternoon
and welcome to the PAH Today National Broadcast Series: The
Pathways to Treatment. My name is Dr. Lana Melendres-Groves, and
I'm the medical director for the pulmonary hypertension program,
and an associate professor at the University of New Mexico. On
behalf of United Therapeutics, myself, and everybody who's able to
join us today, I want to welcome you. Whether you were on your own
PAH journey or you're here to support a loved one, I hope that this
program enlightens us about the pathways to treatment, and we have
the opportunity to really delve into some of those questions that
you may have toward the end.
This presentation is sponsored by and made on behalf of United
Therapeutics. Healthcare professional speakers are compensated by
UT. UT does not provide medical advice. Not all drugs are
appropriate for all patients. Speak with your healthcare
professional to determine which treatment plan is right for you.
Patient experiences relayed during this program may not represent
the experience of all patients.
So today we're going to cover two areas. The first is going to be
understanding treatment pathways. I think before we can really
understand the pathways, we really need to go over some of the
basics of pulmonary arterial hypertension. Then, we'll move into an
update on a treatment pathway, which specifically we'll dive just a
little deeper into one of those pathways for treatment called the
prostacyclin pathway. We'll talk about what it does, where it has
come from over 20 years ago when it was developed, and how much
we've learned and how we can treat our patients better as we move
into the future. So let's start with those treatment pathways.
Now, as I mentioned, I think before you can dive into talking about
treatments, we have to have a little bit better understanding about
really what is PAH? Now, if you had the opportunity to join us on
one of our previous broadcasts, you would have heard about and
learned about how the heart and lungs work as a team. Don't worry.
If you didn't get to that broadcast, we're going to do it again.
Hopefully this time, everybody will have a little bit better
understanding of how the heart and the lungs work. So the first
thing I always like to start with with my patients is just a
discussion of what the heart is. It's a muscle, but it has four
chambers to it. We often talk about it as having a right side of
the heart and a left side of the heart. We may also describe it as
having two small muscle chambers that sits toward the top of the
heart, which are called the atriums, or the two larger chambers
that sit below, which are called the ventricles.
Now the left side of the heart receives blood that has been
oxygenated by the lungs. It's depicted in red in this picture, and
it pumps that oxygenated blood out to the rest of the body. The
oxygen is then delivered to the tissues and the organs. Once that
oxygen has been depleted, it returns to the right side of the
heart, depicted in blue. Now the right side of the heart has the
job of getting that low oxygenated blood into the blood vessels of
the lungs, where more oxygen is picked up.
Unfortunately in PAH, things start to change. Those blood vessels
begin to narrow and thicken. As those blood vessels in the lungs
become thick and narrow, the resistance for that blood to get
through the lungs is more difficult. It increases, and it causes a
back pressure on the right side of the heart. As that pressure
increases and the heart has to work harder, the right ventricle
begins to enlarge. It becomes dysfunctional, and it just can't keep
up with the job it's being asked to do. This is often the time when
patients really start to feel those symptoms of shortness of breath
or fatigue.
Now, I know we've talked a lot about the heart and the lungs, but
really I think it's the blood vessels that need more explanation.
We haven't talked about why those blood vessels start to narrow and
start to thicken. That is where these three substances come into
play. The nitric oxide, the prostacyclin, and the endothelin
pathway are what become dysfunctional in pulmonary arterial
hypertension. Now, your body naturally produces these three
substances and it helps keep the blood vessels open and the lungs
healthy and everything working properly.
In pulmonary arterial hypertension, or PAH, those substances start
to change. They're not produced in the same amounts. Because of
that, we're not able to have the same reaction within those blood
vessels. In the nitric oxide pathway, this substance helps to keep
those blood vessels open, letting blood move through them freely.
The prostacyclin pathway also helps to keep blood vessels open, but
it has a couple other jobs. It prevents clotting and it slows the
thickening of blood vessels. In the endothelin pathway, this sort
of acts in the opposite way. It starts to cause the narrowing and
thickening of blood vessels. In PAH, one or more of those
substances may become out of balance. When the nitric oxide
substance is not available, you start to have this closure of those
blood vessels, that narrowing. When the process cycling substance
is not there in an abundance, again, those blood vessels start to
narrow. You start to see clotting.
When we talk about endothelin, too much of it is produced. So now
we have a speeding up of the thickening and narrowing of those
blood vessels. You may have one, two, or all three of these
substances out of balance. Unfortunately, at this point in time we
don't have a test to figure out which substance or substances may
be out of balance in you. What you might feel if those substances
are not appropriately produced, you may feel new symptoms, or you
may notice that your symptoms are not improving, despite getting
therapies.
So let's talk a little bit about not just the pathways, but how we
have been able to develop medications to affect those pathways and
improve the outcomes of our patients. When we talk about nitric
oxide, we have two different classes of medications in that
pathway. We have the phosphodiesterase five inhibitors, or we call
them PD5s, or the soluble guanylate cyclase stimulators. In the
next pathway, the prostacyclin pathway, we have an abundance of
therapies available that can be taken in oral forms, inhaled forms,
or in a pump form. And the third is the endothelium pathway. We
have what are called endothelin receptor antagonists.
So I guess that brings us to the question of how does your
healthcare provider determine which combination of PAH medications
may be right for you? The answer is partially determined by your
risk status. Now, in one of our previous broadcasts, we talked a
lot about risk status. Essentially your risk status helps predict
your chances of survival over the next five years. Now, your risk
status is determined by multiple variables and tests that we often
ask you to get. That will help us to decide if you are a low-risk,
intermediate-risk, or high-risk for your disease progression, or
for survival over the next five years. Knowing your risk status
helps your health care provider, adjust your treatment plan to find
the right combination of medications for you. Today's PAH treatment
guidelines recognize the importance of risk assessment to help
determine your treatment plan. That brings me to a very good friend
of mine, a fellow pulmonologist, Dr. Sean Studer. He's here to
discuss PAH treatment guidelines.
Sean Studer, MD, MSc:
Thank you, Dr. Melendres, and very nice presentation of the first
part of this as you always do. I found it always informative. So
I'm going to talk a little now about the pulmonary arterial
hypertension treatment guidelines, or the PAH as it's abbreviated,
treatment guidelines.
So the first question is what are these things? Well, they're
documents that guide healthcare providers on diagnosing and
treating a disease. They're not so much like a recipe. A recipe
might be something you do when you're baking, you add the same
ingredients over and over. Same temperature in the oven, you cook
for the same time, and you get something that's very predictable.
Guidelines accept the fact that people are a little bit different.
They're not exactly like baking a cake. You can't have the same
recipe for every person, but it does give us some guardrails and
some ways to say, "This is the practice patterns that are suggested
and likely to achieve the best outcome based on what we know."
On the right side there, you see an example of the 2015 European
Society of Cardiology, ESC/European Respiratory Society, ERS
guidelines for the diagnosis and treatment of pulmonary
hypertension. Now, who develops these guidelines? Well, top experts
in the world who stand for and about research often involving
thousands of patients. So it's not just their own experience of who
they're treating in their own group or their other own center, but
it's what they're reading. It's often the research that they
themselves are involved in. Examples of meetings that have reduced
these guidelines are the World Symposium on Pulmonary Hypertension,
the European Society of Cardiology, European Respiratory Society,
as shown over there on that right panel, and the American College
of Chest Physicians.
Now for someone like myself practicing on the East Coast, if I ever
wonder, “I wonder what Dr. Melendres would say? I wonder what one
of my colleagues in California who practices an expert center would
say about this,” I can't reach them on the phone immediately. I
can't catch them by email in front of a patient, but looking at the
guidelines and gives me their impressions as a consensus with
others of how people are thinking about a specific area. It's also
a good touch point. If the patient says, “well, is there a reason
you're taking this approach,” I can tell a little bit about my
personal opinion and what I think of the medical literature, but
citing a set of guidelines gives it the weight of a group of my
colleagues who are very knowledgeable about pulmonary arterial
hypertension, and I can explain that to them as the reason why I'm
making a recommendation for diagnosis and/or treatment.
So why do we have them? I've explained a little bit of it already,
but guidelines help us ensure that you receive consistent effective
care, to help us stay on top of advances in care and best
practices. You see over there on that right panel another example
from the American College of Chest Physicians, and these guidelines
are produced at slightly different periods of time. So there might
be one meeting that occurs last year, one that occurs this year,
and one that occurs next year. So just that slight variation in the
research occurs between each year might give us a little different
insight into how this group of experts answers a question. It's not
like the Supreme Court, it's not the same group of people each time
that do this. It's a group of experts that often changes a bit,
with a lot of overlap. So when you add in a few other voices, you
often get a little nuance of opinion. I wouldn't say the guidelines
are really ever in conflict, but slightly different nuances or
variations in approach are sometimes seen between the two
guidelines. So especially read by someone outside of the field, it
might seem like there isn't any consensus on some of these items,
when I think actually what you're seeing is slightly variations on
a theme.
So what do these guidelines say? Well, the 2018 World Symposium on
Pulmonary Hypertension Guidelines said something very important,
which is that most newly diagnosed patients with PAH at low or
intermediate risk status should be treated with oral combination
therapy. So something that can be taken by mouth, the oral piece,
in combination two medications upfront as part of their treatment
regimen. You see a little asterisk right there. It has the footnote
at the bottom that according to the treatment guidelines, initial
monotherapy may have a role in treatment for certain patients. So
if someone was started on one medicine that's not in violation or
inconsistent with the guidelines, but it doesn't describe our
approach to treating the majority. So if you talk about a practice
like mine, or many experts with whom I speak with, our goal for
many of these patients is to start most newly diagnosed patients on
an oral combination upfront, or meaning in the early period. That's
if they're low-risk or intermediate-risk.
If they're high-risk patients, an infused prostacyclin class
medication, one of those that's given my pump often with a catheter
or a tube in the vein, or a needle or some device into the skin,
that medication class should be included in those patients because
they've been shown to be effective for patients in a state to
improve their functional class and their state to a lower-risk
state. That is from high-risk to intermediate or low.
Now it's important that whatever point at which you start, so let's
say you're on a dual oral combination. You're taking two
medications by mouth, that every three to six months to the right
side of that panel, a risk assessment is performed. Now if you were
an intermediate-risk status, which is not our goal, our goal is
always low-risk status, and you took dual oral combination therapy
and you improve to low-risk status, that suggests that we're on the
right track and the effectiveness of the medications for you is
moving in the direction we want it to be. If on the other hand,
you're an intermediate risk status and at a three to six month
follow-up, and when you first started medications, I tend to weigh
a little bit earlier on that range. I don't want to go more than
six months, but I’d certainly go closer to three months, when I
can, to stay in that range, that visit, if it shows you're still an
intermediate-risk, I might be making decision whether or not, like
the bottom says, you're not yet at low-risk. We may need to change
to dual or triple combination therapy. So my example, if you start
in the dual combination, which is where most patients are going to
be treated, and you've not yet achieved low-risk in the follow-up,
I might want to add a third agent and you would then be on triple
combination therapy.
So why these multiple medications? Well think of it like if you had
to bring your car in for repairs, and you might say, "There are
several things that aren't working well. It's not running at its
best." You could certainly decide you're just going to start with
one thing and see how the car is running. But if it's recommended
you need spark plugs, an oil change, and a brake adjustment, you
might decide all those things are important to keep the car running
well. So you'd ask the mechanic to adjust all of those things at
once to keep things rolling smoothly.
Multiple medications in PAH take advantage of the fact that we know
that there's multiple pathways. Research has shown that taking
multiple PH medications can keep patients healthier longer. As you
see there in an analysis of 17 studies involving more than 4,000
adult patients found that those taking multiple PH medications had
a 35% lower overall chance of getting worse than patients who were
taking only one medication for PH. So if your risk status was up
here, taking multiple medications lowered it by more than one
third. That is 35% reduction in the chance that you're going to get
worse. Certainly if we have a disease such as PAH, that's
incurable, we want to keep you in low-risk status and not
progressing. So that's an important thing to make sure that you're
not getting worse, and try to give you the best treatment regimen
when we can.
That analysis quoted also showed that multiple PH medications
helped improve the six-minute walk distance, that hallway walk test
back and forth sometimes in the hospital in the physician's office.
That helps reflect for us whether or not your functional capacity,
your ability to walk and have your breathing work well and not have
you be too winded are all moving in the right direction. So a
longer walk distance suggests that you're functioning better and
may improve Functional Class. Sometimes abbreviated as New York
Heart Association, NYHA, or World Health Organization, WHO, the
Functional Classes are I, II, III, IV, again. FC IV is the worst.
If you were say a Functional Class III, we would like to see you
improve Functional Class to a Functional Class II, or if possible
to a Functional Class I. Multiple medications improved the chance
that that could occur.
We also want to reduce the risk for PAH related hospital admission.
No one likes to be hospitalized, and in PAH, that suggests that we
can't manage you effectively as an outpatient, or just through the
office, that you need to be hospitalized. So minimizing that
chance, or at least reducing the risk of it is an important thing
we are trying to achieve.
Certainly today we have multiple treatment options that offer us
quite a bit of flexibility. It's much more than we had five years
ago or even 10, 15 years ago. So you see the types of medication
listed there. You have phosphodiesterase type five inhibitors, or
PDE5Is, soluble guanylate cyclase stimulators, SGCS. I don't
suspect you say most of those two phrases very often, but sometimes
the abbreviations are used. Prostacyclin class therapy, often
abbreviated PCY. And endothelin receptor antagonist therapy, or
ERA.
How do we give these medications? Well, there's multiple ways they
can be taken in some classes, and not so many for others. So in the
PDE5 or SGCS, there's only medications that can be taken orally, or
that is by mouth. In the prostacyclin class, the medications can be
delivered by all three routes for which we currently deliver
pulmonary arterial hypertension medications. That is, they can be
given orally, they can be infused, or they can be inhaled where the
medication is delivered directly to the lungs. Then there's
endothelin receptor antagonists, or ERA, that are again, only oral
therapies. That is those taken by mouth.
So why is the right combination of those treatments so important?
Well, the right combination may help you improve symptoms. That may
help you feel more confident about running errands. It may help you
feel more functional doing things in your home, whether it's
chores, things you enjoy. It may help slow disease progression.
Very important. PAH is unfortunately currently an incurable
disease, so if we can slow the progression of that disease, we are
moving in the right direction in trying to keep you as healthy as
we can, for as long as we can. That's why the right combination is
important. It might also enable you to do more in your day. So you
can be out there with family and friends. Certainly in the present
environment, the amount you can get out and about and the risks
involved are somewhat of a challenge.
But the idea is if you want to get out and take a walk and you can
do that safely, that's the type of activity we want you to be able
to do, and promote that type of helpful behavior, because generally
the better you're functioning and feeling the better you'll feel
about your life. Now, many patients might say, "I don't like the
idea about more medicine, but I want to improve my symptoms."
That's why the right treatment combination is so important.
I appreciate your attention. That concludes my portion of their
presentation. I pass it now back to Dr. Melendres for her to finish
up.
Lana Melendres-Groves, MD:
Thanks Sean, for walking us through the PAH treatment guidelines.
That brings us to our second section for today, an update on a
treatment pathway. Did you know that the prostacyclin class of
medications has not only been around for over 20 years, but has
come quite a long way in that time? PAH specialists have years of
experience using these medications to help treat patients with PAH,
as well as to learn how to manage some of the side effects that
that class of medication may cause.
Prostacyclin class medications were the first approved therapy for
treating PAH. Originally, you were only able to deliver them
through a pump therapy. It was often reserved for the sickest of
the sick patients, including those in Functional Class III and IV.
If you were able to join us on our prior broadcast, we talked a
little bit about what Functional Class III and IV meant. Those were
the patients that really felt poorly even when they were doing very
little during their day, or at rest. So much progress has been made
in the recent years. Today, you have more options.
Now, Prostacyclin class medicines can be taken three different
ways. They can be taken orally in a pill form, or we still have our
infusion or pump therapy available, as well as being able to
deliver them as an inhaled form of medication. But not only that,
we've learned that these medications can be prescribed earlier in
your disease process. Where previously we thought that patients
only in Functional Class III or IV were appropriate for them, we
now know that we can use them earlier in patients even in
Functional Class II. Not only that, we know a lot more about how
these medications can be taken in conjunction with or combined with
other PAH medications.
So how do these prostacyclin class medications work? We had talked
a little bit earlier about the narrowing and thickening of those
blood vessels in the lungs. These prostacyclin class medications
work by helping to open up those narrowed blood vessels. Often, we
described that as vasodilating the blood vessels. They also slow
down the thickening of the blood vessels, and can help prevent
clotting. So you may be asking, "Can the prostacyclin class
medications help improve my risk status?" In clinical studies, the
prostacyclin class medications have been shown to improve your PAH
symptoms, like shortness of breath and fatigue. Also, they have
been shown to keep your PAH from getting worse, or slow the
progression of the disease. They also improve your distance in your
six minute walk test. I know some of you may not like that walk
test, but this is a class of medication that's been shown to
improve it.
You also are able to do more without symptoms, or improve your
Functional Class, as we talked about earlier. That relates to being
able to just do more in your daily life. It can reduce pressure in
the blood vessels in the lungs and can reduce the strain on the
heart. Often we assess what that strain is by having you get a
blood test and checking the NT-proBNP. I wish I could say that
prostacyclin class medications were just take them and you'll do
better, but we do know that these medications can cause side
effects. I actually don't talk them in terms of side effects with
my patients, because they're expected. They're actually effects of
this medication class because the things that somebody may feel,
those symptoms that they may have once taking these medications,
are really related to opening up or dilating those blood
vessels.
Now that's fantastic in the lungs, but when it does that to blood
going to your head, you can have a headache. Or if it happens when
it's going to your stomach, it may cause you to feel nauseated, or
sometimes people have diarrhea. You may also feel flu like symptoms
or jaw pain or muscle pain. These aren't all the side effects that
are possible, and there are additional ones that you should speak
to your healthcare provider about.
In summary, small blood vessels in the lungs produce three natural
substances. Nitric oxide, prostacyclin, and endothelin. These are
also the areas that we focused our treatment pathways. Each class
of PAH medication treats one of three substance pathways.
Today, patients have more options using prostacyclin class
medications. They can be used earlier in the disease, and there are
three forms of delivery that are available, the oral, infused, or
inhaled. In most patients, PAH treatment guidelines recommend
treating two or more pathways, as we learned about from Dr. Studer.
Please work with your healthcare provider to find the right
combination of therapies that could help you improve your symptoms,
do more in your day, stay healthier longer, and make progress
toward other goals.
Please join us next time. We will be discussing moving forward. You
can register today, or any day at www.pahtoday.net. Consider joining
the PAH Initiative www.pahinitiative.com, where you
can stay informed, stay motivated, and stay focused. Thank you.
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