Roundtable: New Treatments, New Challenges for Pulmonary Hypertension

Dr Brown: I would like to welcome everyone and thank each of you for your time and willingness to talk about the changes in the pulmonary hypertension community in the last year, especially the addition of 3 new pharmacologic agents: macitentan, riociguat, and oral treprostinil. There are many benefits to having new medications available for the treatment of pulmonary hypertension but having these medications also adds a level of complexity in caring for patients. I want to utilize this time to discuss some of these complexities. My first question is how we go about choosing a drug. How do you go about selecting a particular agent for a particular patient?

Dr Krasuski: I'll try to start the discussion going. Obviously as the choices that we've got in our armamentarium have grown, this has become a much more complicated question than it was a few years ago. Initially our only available therapeutic options were epoprostenol and calcium channel blockers. And then the endothelin antagonist, bosentan, came along and made things a little bit easier, in that we finally had an effective oral medication. And now when we look at our choices, we have several different manners of drug administration. We've also got several different agents in each therapeutic class. One key point to remember, however, is that the only drug with which we have clearly proven a mortality benefit in the sickest population of patients is epoprostenol. We are now recognizing in our large registries that our sickest patients are not getting the drug. It's a little daunting to look at statistics and find that over 40 percent of patients with pulmonary hypertension in their end stages die without getting an agent that has a proven mortality benefit. So we shouldn't forget that we have agents like this, which can change the natural history of the disease. I am happy to say that at this point in time, we have ample clinical data and we have evidence-driven guidelines; but we also have a lot of studies published over the last 5 years that have made some of those guideline recommendations a bit obsolete. Fortunately they're getting revised and we'll soon be able to look at the guidelines again, when the new document comes out, and feel comfortable that we're appropriately utilizing the various types of therapies we have available. At this point, the first thing I look at is how sick my patient is. Certainly, in patients that are sicker, I'm going to be much more aggressive and go to the IV prostanoids immediately. But you also have to take into account what does the patient wants us to do. Are they willing to let us go straight to intravenous therapy? Or do they prefer a trial of oral therapy or an inhalational agent first? And after that, you have to take into account what the patient is able to afford and what their insurance is (unfortunately), which agents we can get quickly and what agents are on the patient's formulary. So there are a lot of things that need to be considered when answering your question.

Dr Souza: I think that Rich mentioned a very important point. Because adherence to the best evidence that we have is something that we still don't see. So I think that the REVEAL registry really pointed this out when it showed that functional Class IV patients, almost half of them, just were not on epoprostenol. And most importantly, you had about 15 percent use of monotherapy, oral therapy, on functional Class IV patients. So I think, of course, we do like to have new treatment options, but I think that we first have to emphasize sticking to the best evidence that we have. So we have to improve adherence to the evidence that we already have to the drugs that we have. And now recently, although we moved a lot in terms of the complexity of the clinical trials, we now have trials with different endpoints. This certainly also increased the complexity of having a head-to-head comparison. Because although, for example, if we mention macitentan, the trial has theoretically a more robust endpoint. However, if we're only considering first line therapy, it's really difficult to compare to any other trial with oral therapies. So we have to separate the confusion on having a trial with a more robust endpoint and consider this as necessarily the best evidence. This was one of the reasons why even having these trials, macitentan was not considered a first line therapy. So I don't think that we still have it.

And just to share with you the situation that we have in Brazil, we do have to account a lot regarding costs. We do not have access to prostanoids. We have a generic bosentan, generic sildenafil, so certainly these would be our first line therapies, just for the lack of a head-to-head comparison and second, because of price. We also, in terms of public policies, have to take cost into consideration. For a functional Class IV patient, for example, since we don't have prostanoids, we have to start with combination therapy. So we use the maximum therapy that we have, which is the combination of two oral therapies. So I agree with Rich, it's really a complex question because of the lack of evidence in terms of head-to-head comparison. But I think that we can do better with what we have, independently of our first-line therapy.

Dr Brown: I think you bring up excellent points as far as adherence to guidelines. Are there any other factors that weigh heavily into selecting a medication such as side effects?

Ms Housten: For us, I think we do take tolerability of a drug into consideration, especially if we made a decision that oral therapy is appropriate to start with. We do take convenience and cost into consideration when thinking about what we put a patient on first. But I think we're also clear with the patient from the beginning that everything we do is going to require close monitoring. And the first drug you're on is probably not going to be the last drug that you're on. The only way to be able to evaluate that very closely is by coming back to see us in the office and getting additional testing and talking on the phone in between. We do see a lot of patients referred to us from outside who are put on one medicine and then a lot of time goes by before there's any additional testing or follow up done.

Dr Brown: I think that's an excellent point. Our medications are for a very severe disease and they come with a lot of associated risk. I think that some of the new medications, such as oral treprostinil, are going to take even more monitoring. Does anybody else have any thoughts as far as how to increase patient compliance with medications?

Dr Grossman: I think it definitely takes a team approach. Speaking from a pharmacist's point of view, you need a dedicated team to effectively manage pulmonary hypertension. You need to take a look at the patient overall and make sure they have the right support. Maybe they can tolerate the medication but are they able to administer it properly? Are they able to get to a hospital in an appropriate manner if they run out of drug or if there's a pump malfunction? You need to weigh in the side effects, as well. Oftentimes, patients can't tolerate the subcutaneous administration. One patient I had described it to me as being stung over and over again by a bee. Last, you need to consider what other medications they're taking. How well is their body able to metabolize and what types of drug interactions do we need to consider? Are they receiving other medications that are going to be metabolized through the cytochrome P450 enzymes which may interact with your new and old ERAs? So there is a lot to consider and if we can address these issues early on, chances are patients are going to be more compliant with their regimens and follow up in clinic.

Dr Brown: I think it's a good point that our patients certainly should not be out there, isolated, and trying to take care for their disease. That's very important. I know that one of the other things that we think about a lot in choosing medications, especially in the Intermountain West, is how far patients are from us and whether they're living in a rural versus an urban environment. I don't know if there are any other special considerations that anybody has run across in their practice that might be important to note as far as how to choose the right medication for a patient?

Dr Souza: I think that this is a very good point; the distance from the referring centers is something really to consider. Mainly considering now that we have some alternative drugs for which you have to have a titration process in order to determine the dose on which the patient will be maintained. So first, this is an issue. And the other point now, we're seeing patients, older patients, with many more comorbidities than we used to see about 10 years ago. So drug-on-drug interaction is really an issue, because now it's becoming much more common to have patients with coronary disease or diabetes, metabolic disease. And if we were to be honest, none of our drugs has been really tested in these environments, with this amount of different drugs being used at the same time. I think that we have to pay closer attention to this particular issue. I do not really believe in the change of the phenotypes of patients, but at least the change in the diagnosis that we've been performing. I think that now that there is more disease awareness, we diagnose more pulmonary hypertension. Also, that is in a population of patients with more comorbidities. And so now, drug-to-drug interaction has become a more important issue.

Dr Krasuski: Those are great points, Rogerio. This emphasizes the importance of not only looking at evidence-based data from clinical trials, but also looking at real world data from the registries. A lot of the clinical studies are done in very pure patient populations, which are very carefully screened and selected. But as you mentioned, many of the patients we see in our clinics come in with very complex disease, not always just pure Group I, and they also need therapy. This is what makes it so imperative that all of us collect registry data, so that we can more carefully assess how these drugs work in these varied patient populations, whether it be older patients or patients on more medications with greater potential for increased drug-drug interactions.

Dr Brown: I cannot tell you how many times I've had a patient on a phosphodiesterase inhibitor and they have chest pain and are given nitrates because they're assumed to have coronary artery disease. I think things like that are very scary and very dangerous. Now we even have to worry about the drug-drug interactions within our population, such as using riociguat and the phosphodiesterase-5 inhibitors.

Traci, I was wondering how you feel about patient involvement in making drug choices? How can we best inform our patients about options and to help them be active participants in making decisions about drug therapy?

Ms Housten: Well, I would say 2 things. I wanted for a second just to get back to the issue of adherence in patients. And I think that many of us would probably be shocked at how often the patients don't take their medicines as directed. And I know I spend a lot of time, if I even get a whiff of somebody not taking something as directed and really being upfront and confronting the patient about that. And trying to explain to them, to us, it is so important to know whether they're failing their medical therapy or whether they're failing to take their medical therapy. Because we can continue to put them on medicines and then find out they're not really taking them more than half of the time anyway. And sometimes, it's even hard for me to get my physicians to recognize that. I might say to the physician, “The patient has not filled that drug in a month,” and the physician will say, “Well, the patient tells me he's taking it.” And I said, “Well, why don't you ask some more questions? Why don't you ask to see it?” Because, for us, in our population, that's been a huge issue with people just not taking their medications and not being honest about it. I try to make it safe for them to admit that they might not be taking it. For instance, with t.i.d. dosing, I up front say to them, “It's really hard to take a t.i.d. drug. Let's talk about how you can remember it,” to make it kind of safe to admit they're not, so that we can work on strategies to get them to be more adherent with their medications.

In terms of patients' choosing, the thing that I always have in the back of my mind–and these are a patient's words and those are usually the most profound–was when a patient who had come to us on epoprostenol from somewhere else, and from his perspective, he really had gone to the hospital and woken up on a pump that he really didn't want and didn't think he needed and felt like it was making him worse and he had come to us for a second opinion. I was very worried about him and so had the talk that we all have, trying to convince him about how important this medicine was to his, medical treatment and his life. He very calmly, at the end of my speech–which I'm pretty good at the speech by now, after all these years–he said, “Traci, I appreciate all the time that you spent with me. And I hear that you're telling me that this drug is the best for my disease. But what I'm trying to tell you is, it's not the best drug for me.” So whenever I'm talking to patients about therapies, I try to keep that in mind, that I need to know not just what the best drug for their disease is, but what's the best drug for them as a person and their lifestyle–as you talked about, where they live and all of those other issues that come into play when you practically try to take care of patients.

Dr Brown: It would be nice to put people in a situation where it's easy to control everything, so that they are able to be safe in taking their medications. Do you think that family support is important here?

Ms Housten: I think family, friends, any type of support. Support can come from a variety of sources. Sometimes, friends are more reliable than family, actually. But it's essential for people to help. To have help with not just their medical care, but just in terms of getting to appointments, having food in the house, getting to the pharmacy to pick up those medications.

Dr Brown: Do you find sometimes that it's easier with the medications that have monthly testing to try to make sure that you can stay on top of whether someone's getting their labs done to get their medications?

Ms Housten: I don't know. I don't know if either one are easier, you know. We struggle with patients on all types of therapies. Potentially, people who need to enroll in the REMS programs are a little bit easier to keep track of or you can at least get the information about refills and things easier.

Dr Brown: I understand. Has the requirement of a REMS program been a big problem or is it just something that needs to be done so you have good practitioners with good practices?

Dr Grossman: Getting involved with the REMS programs is not only required by the FDA, but a great idea. They are there to ensure the benefits of these medications are not overshadowed by the risks. The process of enrolling in REMS programs is fairly simple and something our drug information pharmacists are able to help with.

Dr Brown: It's one way that we can make sure that providers are prescribing these medications appropriately and know that the appropriate testing is being done.

Since you are an inpatient pharmacist, how involved are you in making sure that the medications are prepared correctly? Is this something that you're involved with or is it something that's dealt with by the pulmonary hypertension nurses? What's your practice?

Dr Grossman: Pharmacists are getting more and more involved these days. We've revamped our program here at Intermountain Medical Center the last few years. We've worked with a multitude of professionals in the pulmonary hypertension group as well as nurses, pharmacists and respiratory therapists around the hospital, so we can make sure we prepare and administer the drugs safely. I think it's essential to get pharmacists involved. We're an additional set of eyes. These medications have a very narrow window for catastrophic events, so having somebody around to double-check the dose, concentrations, infusion rates, and drug interactions is vital. It's also important to have a sterile environment to prepare these medications in-house. It may seem counterintuitive because patients will go home and prepare these medications in their homes. But in the hospital, we are responsible to prevent central line-associated blood stream infections, something that CMS is definitely cracking down on. So having pharmacy involved and partnering with the pulmonary hypertension team is a way to ensure that we're compliant with the Joint Commission and other regulatory agency standards. It's a double-check to promote safety. Now at our hospital, we have every order checked by two pharmacists. We're able to incorporate bedside barcode scanning upon administration at the bedside, which is essential in this day and age. We're able to utilize a dose rate calculator. And we're able to incorporate the parenteral prostanoid therapies into our drug interaction alert system, as well. So I think having pharmacists involved at our institution has been very positive overall and a step forward for promoting patient safety.

Ms Housten: I agree. At least on our inpatient side, I think as we've added more and more drugs to the hospital pharmacy, the pharmacists here in the hospital have become more and more important in trying to make sure they're dispensed safely. Even simple things like making sure we have an adequate stock of all the medications to dispense. We just have a lot of help. You know, 12 vials of Ventavis seem like a lot, until you actually realize that's only getting you through 2 days.

Dr Brown: Especially with the half-lives of our medications, I think that's one of the things that we've always had to make sure of is that medications are on the hospital formularies. If someone comes in with an interruption or they're out of medication we need to have medications available.

I was wondering about the types of delivery methods that we have available now. How do we discuss with patients the different types of ways that they can get medications delivered? How do we help them be more comfortable with the idea of using, say, subcutaneous or intravenous infusions or inhaled delivery devices?

Ms Housten: For our program, when we're talking about infused medications, definitely while they spend time with me, the nurse, we talk about everything that's involved. It's pretty much a requirement that they actually meet another patient who's already on the therapy and talk to them, as well. Frankly, that does more for a patient to demystify it than when they spend time with the staff. Talking to another patient is really powerful. We don't do it as much for inhaled;, but sometimes we do, particularly if people seem resistant to it.

Dr Brown: I think being able to have an open communication with your patients is so important. The patient is given a lot of information when they are initially diagnosed with PAH and having so many options can be overwhelming. Knowing that there are other people that successfully deal with these medications on a daily basis, be they sub-q, IV, inhaled, or oral, is probably an incredible way for newly diagnosed patients to know that they can handle it. I know it's helpful to have the devices and the pumps available and to be able to show people and to walk them through their use. Teaching patients how to use these drugs effectively is a huge job that is taken on by a multitude of people, to try to make sure that drugs are delivered safely. Patients have a huge role in this because of their responsibility in taking care of the medications in the outpatient setting. So I think it's kudos to patients to be able to manage the medications.

Ms Housten: Yeah, I think they do it heroically. And often, we don't give them enough credit for what they do every day to take care of themselves.

Dr Souza: I think that's a very good point. Sometimes, we don't give credit to them. I think that we take more time in a role of advisor. But I think that we should take more time just to hear them and to listen to the patients and see how they adapt to the proposed treatment. Because sometimes, something as easy as taking a pill 3 times a day or more, when you put all the complexity of getting the medication, going to the pharmacy, taking other cares, and the other medications that we use altogether, for some patients–specifically those that have a more difficult case–it's a huge amount of effort in trying to take care of themselves. I think that we should also take more time in listening to those patients and try to understand, not only as an advisor to what would be possibly the best treatment, but also what will be the best treatment that would fit in the daily practice or the daily activities or even in the ability that the patient has to take care of himself. If he doesn't have family support or a friend's support or something like that, we should consider that carefully, I think. We don't necessarily do that, as a general group, but I think that we should pay better attention. Sometimes we underestimate the importance of paying attention to the patient's situation.

Dr Brown: I think our patients are amazing individuals. They can bring as much information to us as we need; it's just a matter of being able to listen to them and to be able to hear what they're experiencing.

Dr Souza: I think there was one thing that we should take a closer look. For the first time, we have in a clinical trial a situation in which a functional Class II patient is stable in monotherapy, had an add-on therapy on top of it. Or let's substitute only functional Class II, but we have a stable PAH patient, functional Class II and III, in which you have the medication on top of monotherapy with PDE-5. And you have improvement. So usually when we test combination therapy or even when we consider combination therapy, we consider add-on therapy necessarily. I think that we are looking forward to hear the results of the AMBITION trial in which we will discuss upfront combination therapy. This would create even more complexity in the disease. Now we have at least the results of the SERAPHIN trial. The results brought up one question. Should we consider monotherapy as sufficient for a great pile of our patients? I'm not talking about those patients in functional Class II, walking 500 meters in 6 minute walk test, but I think now we do have some evidence that for a significant proportion of patients, monotherapy might not be enough, even considering they are stable–just reinforcing the concept that we should establish higher goals for this patient population. Because now, if we consider the results of macitentan alone or with background therapy with PDE-5, the results are quite convincing that adding something on top of PDE-5 was important to have less morbidity and mortality. As we also get the results of riociguat and some of other trials that have been published that consider the combination therapy, I think that more and more it raises the question of whether or not monotherapy with an oral drug is sufficient. On the other side of the coin, we have negative trials with combination therapy, the combination of bosentan and sildenafil. So I think that now we would be facing an even more complex question of who is the patient that would benefit from combination therapy, independently of some markers. Or should we establish even higher goals, to be more aggressive in starting 2 combined drugs earlier in the disease? I'm just pointing some of the controversies that we have to deal in the next couple of years at least.

Dr Brown: I eagerly await the results of the AMBITION trial. And I think that your point that it's almost like saying, “is stable good enough?” Is it good enough to make certain that a disease is not progressing or should we be aiming to make improvements such as changing a functional class.

Dr Krasuski: Well, our discussion about early use of combination therapy brings up the paradigm of treating pulmonary arterial hypertension much like you would treat a malignancy. Up front you hit it hard with multiple drugs. And ideally you catch it at an earlier stage, where it is most amenable to therapy. Pulmonary arterial hypertension is a disease process that, left to itself, is going to progress rapidly and negatively impact the right ventricle. We really haven't focused much of this discussion on the right ventricle. But one of the things we really want to do for our patients, in addition to getting them to be able to walk further and feel better, is try to normalize their right ventricular size and function. And so I think this idea of hitting the disease early, with multidrug therapy, and then perhaps trying to cut it back later, as patients start to get better, may be a paradigm worth exploring. I'm certainly excited that research is moving in that direction now. And I think we'll have a much better idea in 3 to 4 years whether such a strategy is feasible and something we ought to be doing. But as Nate mentioned, once you start combining these agents, you've got to be very careful, because there are so many potential drug-drug interactions as well as different dosing schemes, etc. With certain drugs you combine them and you may lessen the combined effect–the classic example of this being sildenafil and bosentan. So there are now so many potential options; and obviously, it gets very confusing when you start thinking about how to combine agents. But I think these are good problems for us to be having. That means that we're moving the field forward quickly and we're soon going to have even more therapeutic options available to us.

Dr Brown: Changing the emphasis to the right ventricle will be exciting to see. We talked about the macitentan trial's having a more robust endpoint. It will be interesting when we start getting some good markers of right ventricular function to see how these medications are affecting the right ventricle, to see if we can make our clinical trials even more specific to the pathology of the pulmonary hypertension.

Dr Grossman: In just thinking about the macitentan trials, it will be interesting going forward to see how this affects medication selection in the clinics. And as macitentan is relatively newly approved and we'll have other drugs going generic in the future, it will be interesting to see how providers choose one ERA over another, especially with the results of the SERAPHIN trial. But when you look back at some of the outcomes, 6 minute walk test for example, macitentan really didn't perform much better than bosentan or ambrisentan. So it will be interesting to see, when faced with other issues like financial considerations, what practitioners decide to do.

Dr Brown: Is anybody having difficulty getting approval for new medications, now that we have so many therapies?

Dr Souza: Well, I think that the reality in Brazil is really similar as compared to the United States and Canada, because our government has been pushing all the pharmaceutical companies to drop the price of the drugs to the same price level of sildenafil. Which most of the companies have done. So it seems like a good thing, in short-term it is, because certainly the next year, we will be able to provide medication for a high number of patients. However, for the near future, for getting a new medication without a head-to-head comparison, it will become really tough, because I cannot see any new medication being expected to drop their prices to a price as low as a generic drug price. So it's kind of peculiar, because I think our government action was good in the short term, but it will prevent us from getting the new drugs in the near future. So it's something that we've been struggling with with the health authorities to have a kind of balance between having access to the drugs which is good, but also to open the door for the new drugs and new therapies that will become available in the near future. So we are now in the middle of this fight in which we have a small victory on providing more drugs to more patients. However, for the new drugs I think it will be that Brazil will be a tough environment to have a new drug enlisted in the treatment protocol because of that, because the government is focusing only on price and not necessarily on efficacy of the drugs and all the complexity that the disease has. This is something that I've been struggling for at least for the last year.

Ms Housten: The reality of it is even the generic drugs, while we call them cheaper, are still very expensive.

Dr Souza: Yeah, that's it, exactly.

Ms Housten: And at least in the US, when the price of sildenafil went generic, the generic cost has continued to increase since then. So nothing in this disease is inexpensive.

Dr Souza: Just to give you guys an idea of our situation. The price of bosentan, for example, in Brazil was something like $X a month. And now it's something like $Y. So they had a drop in price because of the fight with the government in order to have the drugs enlisted in the federal protocol that would provide drugs in all the states in the country. Because until last year, we only had access to treatment in Sao Paulo–regular access to treatment was almost exclusively in Sao Paulo–which is only one of the states of the federation. So this has been a good thing for providing drugs for the whole country. However, in the near future, this will be tough for riociguat and macitentan in but also for any new drug in the next 2 or 3 years.

Dr Brown: There is so much involved in making a decision about a pharmaceutical agent in a patient. What we're seeing is a lot of insurance companies driving what medications and what agents we're able to pick as first line therapy. There's a lot of frustration on the part of our patients. We go through a very lengthy discussion about what drug to prescribe for the patient and then it's not available. It can be very difficult. But as far as the new drugs are concerned, we've actually been able to get our turnaround times for the new medication referrals in a relatively timely manner. It will be interesting to see what's paid for and what's allowed in the future, especially as we start talking about combination therapy. And even up front combination therapy may present a huge amount of additional problems. Do you have concluding remarks?

Dr Krasuski: I think you've assembled a wonderful panel and I feel honored to have been able to participate. It's been very educational for me to hear how different health care providers–physicians, nurses, and pharmacists–approach a pulmonary arterial hypertension patient, how they select their medications, and what they watch for during follow-up to ensure that patients remain compliant. I've enjoyed hearing the different perspectives of the group, as well as thinking about what this looks like from the patient's perspective. Pulmonary arterial hypertension is obviously a very serious, life-threatening disorder, with an expensive and complicated collection of medications available for it. I think it's very daunting from the patients' perspective when you first get diagnosed and are hearing all this information and trying to take in as much as you can. Today we have heard ways that we can make this easier for them and for us. We've heard the perspectives of the different parties involved and how we can work together to decide on the right therapies to use.

Dr Brown: Rogerio?

Dr Souza: Well, I also would like to thank you for being able to participate in this panel. It was really great to see different points of views and different situations that we have from different geographical regions. I think the disease and the complexity surrounding PAH is increasing a lot. Not only because of all the evidence that we are still missing in terms of having first line–deciding about combination at the first line therapy–but mainly regarding all the complexity in appropriately diagnosing the patients, all the combinations that we have with different comorbidities, and the interaction between right and left ventricle and everything else. So the complexity is increasing. The only way to surpass this is by having a multidisciplinary approach. And this is exactly what we had in this panel.The multidisciplinary view only adds and is the only way to face PAH as it has to be faced in the current day. So I think that was great and I think it was great to participate in this panel because of that also. Thank you.

Dr Brown: Traci?

Ms Housten: I like Rogerio's concept of complexity. On one hand, we have what we've been wanting for years, which is a variety of treatment options for patients that are delivered in a variety of ways. But a flip side of that is that managing all of these different medications is more complex than ever and making decisions about what medications to use when, in what patients, is really challenging and requires a lot of experience and expertise and thought.

Dr Brown: Nate?

Dr Grossman: Dr. Brown, I just wanted to say thank you. I think you've done an amazing job organizing this discussion. As Dr. Krasuski, Dr. Souza and Ms. Housten have mentioned, it is a complex issue. We're going to have many more challenges going forward. With the Affordable Care Act unfolding, we are going to be faced with new challenges and opportunities. We have new payer models so we'll need to find ways to do more, with fewer resources like never before. We need to remember who's at the center of these conversations. Doing what's best for our patient is going to make their experience much more positive. So thank you again.

Dr Brown: I really appreciate everybody's time and input. I think what we've learned by all of this is that as we are getting more medications we need more team members and a team approach so that our physicians aren't practicing in isolation. I think it's also equally important that our patients don't feel that they are dealing with pulmonary hypertension in isolation, that they have the resources that they need. In conclusion, I think that we have a lot of good voices and good comments about how to approach some of the complexities presented by having new medications for the treatment of pulmonary hypertension.