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PAH Today: The Pathways To Treatment - phaware® interview 355

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: 

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 Consider joining the PAH Initiative, where you can stay informed, stay motivated, and stay focused. Thank you.

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