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Nancy Halnon, MD - phaware® interview 446

Dec 12, 2023

Pediatric cardiologist, Nancy Halnon, MD, discusses treatment goals for pulmonary hypertension, the various routes of administration and the importance of using combination therapy to improve survival. 

Hello, I'm Dr. Nancy Halnon. I'm a pediatric cardiologist at Mattel Children's Hospital at UCLA and I take care of a lot of kids who have pulmonary hypertension. I want to talk a little bit about the treatments that we use. I'll start with what the goals are for the treatment. It's not like an infection that you can use an antibiotic and kill the infection. Pulmonary hypertension is a disorder that's going to be with you. Depending on what causes it, there's probably not a way to cure it, so it's going to be a chronic disorder that you're going to live with for a long time. 

Our treatment goals, therefore are going to have more to do with minimizing symptoms to make your symptoms more manageable, to improve your functional capacity, your ability to be able to do things, to exercise, to be active, to do regular living exercises and activities to work, to go to school, that kind of thing. Also, we aim to improve some of the hemodynamics, some of the physiology of the pulmonary hypertension. The goal of that is to protect the rest of your body that might be impacted by the pulmonary hypertension. To protect your heart a little bit, to protect your liver, to protect other organs. 

We want to try to prevent clinical worsening if we can. Sometimes some of the treatments we use, maybe they won't reverse the disorder, but they can help to prevent it from progressing so quickly. Overall, we want to improve your quality of life and we want to improve survival. Sometimes the treatment of the pulmonary hypertension isn't so much to treat the pulmonary hypertension is maybe to help treat the heart disease that led to the pulmonary hypertension. Then, sometimes the treatment isn't for noticeable symptoms that you have, but to prevent complications in the setting of heart disease, especially patients who might have surgery or a heart transplant. In general, the targets are really the physiology and not often the pathology because we're really limited in what we can do about the pathology itself. 

The choices that we make for the treatments are going to depend on a lot of factors. For example, you know how severe your disease is, the more severe your disease is, the more aggressively we're going to use medications and other therapies. Sometimes it's going to be based on what we have available to you, what's approved for use in your particular situation. Often most of the medications that we use for children at least they're partially tested but not really labeled for use in children. So we might be a little bit limited in how we can use it. The root of administration matters. There are inhaled medications for example, that the devices that are used for the inhalation are a little bit difficult to use for people who maybe can't follow instructions to breathe them in or inhale them in the right way. Imagine trying to use an inhaler with a toddler, especially one that has to be used in a certain way at a certain frequency and things like that. So we might be limited in what we can use based on the root of the administration. 

Some people don't tolerate side effects from one medication or another medication and then we make choices based on that. Sometimes there's a preference for one medication or another from the patient themself. We can always discuss what might work out better for you. Sometimes the experience with medications, especially for the kids, certain medications that we just have a lot more experience with than others. So our comfort level as physicians in using them, we might have a preference for one medication or another because we're just more familiar with it. We're more familiar with the side effects. We're more familiar with adjusting the doses. We're more familiar in what kind of efficacy we can expect. 

We often use multiple medications because they target different pathways of the physiology of pulmonary hypertension. So you can often have an additive effect. So one medication may do a little, a second medication added on may do a little more. Sometimes together they can be better than either of the effects alone. There's also the setting of clinical trials. Most of the medications are approved for adults first. They're tested in adults first. The absorption of the medication is known best for adults. The metabolism of the medication is going to be known best for adults. But there's a role for clinical trials for children, even if the drug doesn't eventually reach approval, at least it gives some supervised and experience in using it in how to administer it to kids, maybe using it, the timing of the administration maybe could be a little different. The route of administration, whether it's pills or it's crushed or not crushed or mixed with water or not or taken with food or not. Things like that might be different for children than they are for adults, and a clinical trial can help to address some of those differences in the way that it might be used. 

The clinical trials that we do for kids also are targeted to demonstrate the efficacy, because the reasons and the severity and features of the pulmonary hypertension in children might be different, so a drug that works great for adults maybe won't work as well for kids and we'll want to know that rather than just use everything that there is because there. We'll want to know that it's actually helpful.

The current approved and available treatments for pulmonary hypertension work along three pathways. One is the nitric oxide pathway. Nitric oxide is a chemical that your body makes and it's a very powerful chemical that causes blood vessels to dilate. The next is the endothelium pathway. Endothelium is a chemical that's made by cells in your blood vessels and it causes a lot of constriction of blood vessels. Sometimes constriction of blood vessels is a good thing to happen in your body, but in your lung blood vessels, it's not as helpful. So the drugs that target this pathway are going to oppose the effect of the endothelium. Finally, there’s the prostacyclin pathway. Prostacyclin again is a chemical that's produced in your body and it affects blood vessels as well, causing them to dilate, but using a different part of the cell physiology than the nitric oxide uses. So you can use all three of these different categories of medications together because they're all targeting different parts of the constriction and dilation properties of blood vessels.

The drugs that target the nitric oxide pathway are going to increase guanylate cyclase. They're going to cause a very direct vasodilation, which means that the blood vessels relax. They work particularly well for the lung arteries, especially if you just use the drug as an inhaled drug. In the hospital, we use nitric oxide inhaled a lot. You can put it through a ventilator or you can put it in a nasal cannula. We use it a lot in inpatients in the hospital. It's not something that can be used outside the hospital, but it's very quick acting because as soon as you breathe it in, it's going to have effect and as soon as you take it away, it stops having the effect. 

More practical for use at home would be drugs that help to prevent breakdown of phosphodiesterase, which helps to prevent the breakdown of the guanylate cyclase and allows the nitric oxide to stay around longer. So the drugs that work in this pathway are Sildenafil or Tadalafil. Sildenafil was the first drug that was found. Some of the original marketing for that drug was for erectile dysfunction, but it also allowed for that drug to be developed and created for the use for a more rare disease, pulmonary hypertension, when otherwise there just wouldn't have been as much motivation for a drug company to make something like that. 

Sildenafil is the first. It's a little bit more difficult to use than Tadalafil because Sildenafil has to be used three times a day compared to Tadalafil, which you can take once a day, but there are some patients who prefer it. The side effects are pretty similar for the two drugs, usually a little bit of flushing, sometimes a little swelling, but usually pretty tolerable. Very, very, very commonly used. These are very available drugs again because they're used for other disease, so they're very easy to get. Pharmacies always have it, and so it's a great drug to start with. 

There's some drugs that also stimulate the guanylate cyclase. The newest one is called Adempas. The chemical name is riociguat. It's a newer drug, which had more recent approval. There's not much information about using it in kids, so my own experience with it is a little more limited, but it also works through the same pathway. So you'd use either Sildenafil or Tadalafil or the Adempas, but you wouldn't use any combination of those. 

The next category are the endothelial receptor antagonists. They bind the endothelial receptors and so prevent that chemical from engaging in the blood vessels and causing that constriction. There's several of these drugs, Bosentan, Ambrisentan, and Macitentan. Of those three, the Macitentan is probably becoming much, much, much more common to use, especially for older children and adults. It's a drug that you can use once a day. The common side effects for that are kind of similar to what you see with the nitric oxide pathway drugs, which is things like flushing, headaches, but there's also a couple of other side effects that are a little more particular to this group of medications, particularly the Bosentan, which is some liver toxicity. So that's why when if you're taking particularly Bosentan, you have to have blood work done pretty frequently to monitor for toxic side effects. 

You definitely cannot take these drugs while you're pregnant, so if you're entertaining a pregnancy, you need to discuss with your doctor about that, because they're particularly toxic to a fetus. While you take the drugs if you're a female of reproductive age, you're going to have to have pregnancy tests monthly. So it's a little bit cumbersome to do it, but most folks, once they've started to get kind of in the rhythm of going for their monthly pregnancy test, it becomes a routine and it's not as bad as it sounds when you kind of talk about it on paper.

These drugs are dispensed by specialty pharmacies, because particularly they do need to monitor for pregnancy and things like that. They're a little more paperwork intensive for the prescriber, and so you're going to want to make sure that your doctor's invested in being able to manage this sort of process. If you could benefit from it, but your physician just isn't familiar with it or comfortable with it or registered to prescribe it, you may want to discuss with them if there's other centers to help to augment some of your care so that you can have access to some of these other remedies. 

The next group of drugs act in that prostacyclin pathway, and there's a big variety of medications in this category. Again, if you use one, you're going to use only one from these categories. These are drugs that we tend to use in patients with a little bit more severe disease. We might use one of the drugs from the first two categories in patients with mild or mild to moderate pulmonary hypertension, but these prostacyclin analogs are going to be drugs that are going to be more in the patients who have more severe and significant disease. One of them is Treprostinil, also called Remodulin. It's used mostly intravenously or by a little pump that's injecting under the skin. It's kind of like the little pumps that they use for insulin if you've ever seen those. Those are maybe a little more commonly seen in people, but it's a little pump kind of like that. That drug can be used subcutaneously. The pumps take a little bit of maintenance and care. They're not very hard to use. They're dispensed by specialty pharmacies who have nurses and other people who can assist with using these pumps and things like that. If it's suggested, you don't have to be that intimidated by it, you're going to be supported in using it. 

Again, the side effects are going to be kind of similar to some of the other medications, headaches, flushing, sometimes some diarrhea, rash, jaw pain. For particular drugs, maybe other couple of other side effects. The side effect profile is a little more common for these drugs, but then again, their efficacy for somebody with really severe disease is also going to be a lot higher. So that trade-off is usually going to be worthwhile. Epoprostenol is Flolan. That's only used by IV. That drug has been around the longest of all of these, so there's a lot of experience with use of it. Selexipag is probably the newer of all of these, also called UPTRAVI. It's an oral drug, which is kind of a game changer compared to using a pump or using IV. It's really great because it's much easier to administer if you can just use pills. 

When you use it, you titrate the dose up. There's common maximum dose, but you can go up quite a bit if you need to. The same with the Treprostinil. This drug does not have a pediatric labeling at this point and not a really great pediatric formulation. It's tablets, but the tablets come in a fairly small dose and you use multiple of the tablets depending on what dose you're going to take of the drug. 

There's a clinical trial that's about to close, the SALTO trial, so we'll probably have a much better idea of how to use it best in children. But right now we do use it in children because it is approved for adults and we can extend its use down quite a bit. It's not something that we're going to use in infants or really small children quite yet until we have a little more information about it, about how best to use it, and especially if there's a formulation like a liquid formulation or something like that.

Iloprost is a little bit different medication. It's used quite a bit for adults, a little bit less for children because it's a little bit hard to use. It's an inhaled medication. You have to use it pretty frequently over the course of the day, usually six to nine times per day. It takes five to 10 minutes per inhalation, so it's a little bit cumbersome to do. For that reason, it's maybe a little less popular than the Selexipag or the Treprostinil. Just imagine trying to get you through your workday if you know six times during the day you have to take a 15 minute break to take out your little machine and administer the drug, but it is effective and sometimes it's a better tolerated way to use it.

So in general, these drugs, because of how complicated they can be to use, they're going to be reserved for more severe cases. Sometimes we have to switch from one version to the other depending on if, for example, you have intravenous administration and you have a problem with a line infection or something like that, you may be best switching off to one of the other administration routes with one of the other drugs.

Pulmonary hypertension that maybe is short term, maybe associated with acute illness or something like that, you might only use something like the Tadalafil or the Sildenafil because it will have effect pretty quickly. You can use it for a short time and maybe something will resolve or something will get better, and then you might not need it again. So it's easy on, easy off. Medications from the endothelium pathway tend to take longer to have any effect. So if you're in a sort of acute situation, it's probably not going to have its maximum benefit for a few months. If we encounter a patient who comes in with undiagnosed or previously undiagnosed very severe pulmonary hypertension, we might start with all three medications all at the same time. 

We'll use the nitric oxide inhaled right away. We'll use the Sildenafil or Tadalafil right away and start the Bosentan and start maybe the Selexipag or the Remodulin. The Selexipag and Remodulin take a little time to ramp up sometimes between a few days and a few weeks, even a month or two, depending on the side effects and how quickly we can titrate up. The Bosentan tends not to have much effect right away, but over time it will. So a more minor situation where you can slowly ramp up medications, you might start with Sildenafil, Tadalafil, one of those two and maybe Bocentin or Macitentan, and see what you do for a few months before using the more difficult to administer drugs until you figure out that you're not getting as much effect as you need. So it could be any or all the above. 

Finally, there are drugs about to hit the market, we hope. Sotatercept is a brand new drug. It doesn't work in these usual pathways that have to do with vasoconstriction and vasodilation. It works more in remodeling the blood vessels and the blood vessel growth. It alters the balance between some of the proliferation and anti-proliferation signals in blood vessel wall formation. So it restores some of the normal growth and cell function to the pulmonary arteries. It's not been approved for clinical use for pulmonary hypertension yet, so it is not going to be available right now. The company has projected that sometime during 2024 it will probably reach approval. The trial data is completed for adults and it looked quite promising. It was people who were already on at least one or two of the other kinds of medications, and even above any effect that they had had from the other medications, it improved the six minute walk test distance. That translates directly into a daily living kind of effect, which is really, really good for patients. 

There's a clinical trial in children being developed, should be starting soon. This drug is administered by injection initially, it's every three weeks. The long-term use is not really well described yet. The drug, it's still a little bit too new. The trials that were performed to try to get the approval from the FDA to use it for pulmonary hypertension were trials that looked at effect at 24 weeks. So only about six months of use. So long-term effects aren't really well described yet. It's just a little bit too new. 

So, there's a lot of medications to use for pulmonary hypertension. Experience with kids is a little bit less, but with experience with adults is quite good. There's a long track record for some of the medications, but new medications on the way. Overall, it's often helpful to use medications from multiple categories. So rather than have a one and done kind of treatment mentality, using cocktails of medications can be really helpful. Overall, if you have any questions, you can always reach out to me. 

My name is Dr. Nancy Halnon and I'm aware that my patients are rare.

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