the phaware® interview
Mitesh Thakrar, MD is a Clinical Associate Professor at the University of Calgary and the current Deputy Medical Director of the Southern Alberta Transplant Program. In this episode, Dr. Thakrar discusses titration of pulmonary arterial hypertension therapeutics.
My name is Mitesh Thakrar. I’m a pulmonary physician based in Calgary, Alberta, Canada. I’ve been a pulmonary hypertension specialist and a lung transplant specialist now for about 12 years there. I work primarily at the Peter Lougheed Centre and Foothills Medical Centers in Calgary looking after patients that have both PAH as well as lung transplant.
Today, a really important topic for us to think about and talk about is titration of our medications. Why we pick which drug we pick. Why we have different doses of our medications. What does that mean for a patient. And to just give an overview of what’s available to us in the sphere.
One caveat is that, in Canada, we have a certain list of medications that may not be reflective of what’s available in other countries. There are some medications available in the United States, for instance, that we don’t have access to. So, what I’m going to offer you today is fairly Canadian-centric protocols and procedures that we follow. When I was training in the UK, we had a totally different way of doing things. I think the wonderful thing about pulmonary hypertension and the small community we have. We all get together and we talk about why does my recipe work better than your recipe or vice versa. Then, we start to converge on recipes that seem to work for a lot of our patients. We can talk a little bit today about why we do what we do and why we pick what we pick.
The first step of pulmonary hypertension management that we think about is obtaining the right heart catheterization. You’ll hear us talk a lot about right heart catheterizations, or RHCs. Right heart catheterizations give us the data of what you look like in this moment in time from the inside, the part that we can’t measure. We can measure a blood test called an NT-proBNP that tells you how stretched out your heart is. We can measure your six-minute walk test. But we can’t measure the pressure in the heart in a reliable way. An echo is not bad, but really the right heart catheter tells us that.
The right heart catheter also tells us potentially if you are in the very, very small group of patients that are what we call a vasoresponders. Those are patients who normalize their pulmonary pressures when we apply nitric oxide for a period of time. Those patients we have often and treat very, very differently. We put them on high-dose calcium channel blockers. We can essentially put them into remission from their disease for many, many years. But I think the right heart catheter also offers us some insights as to how one may actually respond to our conventional pulmonary vasodilator medications.
We have three groups of medications. We have those that work on the prostacyclin pathway. We have those that are working on the endothelium and then those that work on the nitric oxide pathway. What I do personally is, if I see a patient who’s improved a modest amount with nitric oxide, that tells me that that nitric oxide pathway is ripe for the picking. It’s the pathway we want to focus on first and foremost in terms of improving pressure.
The other thing that the right heart catheter can tell us about response to treatment is, again, the severity that we might see. If a patient comes into the right heart cath lab and they have very, very severe hemodynamics, now that might inform me to tell me that, hey, this is a patient that I probably want to get on three drugs right away as opposed to trying two oral medications. Those are the kinds of decisions that we make right then and there while we’re in the cath lab.
Once we get out of the cath lab, now we have a discussion with the patient. We’ve got two different options for PDE5 inhibitors. We’ve got riociguat in the background as well, which works in the same pathway. Which one are we going to pick? Similarly, with our endothelial receptor antagonist, we’ve got three different options available there. If we’re thinking about a prostanoid, we’ve got a subcutaneous version, an IV version. How are we going to pick these things?
The next step is to talk to the patients. We usually come up with a mutually agreeable solution. There are some medications that require really no titration. You’re either on them or you’re not. I personally like using those medications up front because there is no titration of some of our medications. Now that’s great if you have really no other comorbidities, you have no other issues, you’ve just shown up with pulmonary arterial hypertension. But sometimes, we can use the titratable drugs to our advantage. We can say, “Well, I don’t know, you might get side effects. I’m worried about those side effects and how you’d tolerate those side effects.” So maybe we use a drug where we’re starting at the half dose because that’s what we’re supposed to do anyways. We’re going to titrate you up. That gives us time to see if at a low dose are you going to have a side effect. If you don’t, then we’re slowly building up these drugs.
Examples of those would include older oral medications like bosentan or ambrisentan. Some of our newer medications like riociguat or selexipag would do that, and all of our prostanoids work that way when we titrate them up. Depending on the patient in front of me and how severe their disease might look in the cath lab informs whether I want to use a titratable drug or an on-off kind of medication.
One of the other things that I think about when I’m starting a medication is what is the chance that the patient is actually going to be able to undertake the therapy we’re going to propose. One of the biggest examples of that is, unfortunately, we still get patients who show to our clinic with very, very, very severe disease. The sickest of the sick. Very severe pulmonary hypertension. Now, the guidelines will tell you, “Well, you should start this patient on triple therapy including a parenteral prostanoid. They should go on to either Caripul or Remodulin, so a continuous infusion of something.
Now, you have a patient in front of us that we’ve never met who has a very severe disease, and we’re going to commit them to a 24-hour a day therapy. Many of these patients are young who, up until they showed up, didn’t have a diagnosis, didn’t have a disease. They’ve never been sick a day in their life, and now you’re giving them this life-altering diagnosis and life-altering treatment. So it does become a real challenge in some cases to identify patients in whom this is going to be a safe, long-term option.
Some of these patients are going to either willfully or un-willfully choose not to engage with that therapy. It becomes potentially even more dangerous to have used it. That’s a tricky space because you want to offer the best treatment, you want to offer the treatment that’s going to improve their function and keep them alive, but we don’t know. Are they going to be able to adhere to that and stick to that in the long run? That patient population is a coin-flip, to be honest. It’s almost impossible to predict what’s going to happen.
A more traditional way that we get onto parenteral prostanoids, these are patients who you’ve known for a long time and, unfortunately, their disease continues to progress on our conventional oral therapies, and now we’re having discussions about parenteral prostanoids. These patients you’ve known for a while, so we have a sense of understanding of what we think they’re going to be able to do and not be able to do. The patients also have now developed their own resiliency and their own education about their disease. We have some patients that will just tell you, “No way, no, how am I ever going on a parental prostanoid,” and the conversation ends.
I think a more typical conversation we have with those patients is they say to you, “No way, no, how,” and then you say, “Yeah, but can we talk about that? Here’s why I think there’s a ‘yeah, but’ to that and why maybe I can get you through this. We can support you.” That’s the key is for the patients to understand that they’re not doing this alone. They’re incredibly supported with our clinics. Once they start to understand what that support is, and you do it piecemeal, you start with, “Here’s what the pump looks like. That’s all you got to learn today. It’s just what the pump looks like,” and the next day is, “Here’s what the drug looks like. Here’s the vial. Here’s how you draw it up.” You just do it piecemeal. We find that we can get most of our patients that we’ve built that rapport and relationship onto a parenteral prostanoid quite successfully.
Which one you pick? That is often driven by the patient. There are some patients that are incredibly worried about the line that is required with epoprostenol and say, “No. An IV infusion is not for me. I’d rather the subcutaneous one.” Others are worried about the pain that comes with subcutaneous infusions and they say, “I’d rather have the line.” Those discussions are a bit more nuanced, but most of the patients that we’ve known for a while we can get them onto these titratable drugs.
Again, we remind them that, “We go very, very slow and will increase the doses as your body allows it and as you feel comfortable with. We’re not in a huge rush. We don’t have to have them on this drug tomorrow. We’ve got time.” It’s an easier conversation to have. It’s a somewhat easier group to manage than the ones that, like I said, come in de novo. You’ve never met them. They’re deer in the headlights themselves and are really just trying to wrap their head around the fact that they’re going to be sick for the rest of their lives, let alone all the complexity of these drugs.
The next consideration is once we have a patient stabilized on a regimen, one of the questions is when do we increase the dose, because there are some medications that we want to push the dose. There’s some really good data, for instance, with pretty much all the titratable drugs that you want to try to get to either the highest dose that it’s licensed for, which is the case for things like bosentan or riociguat. The goal is to get to those doses.
There’s other medications like selexipag where what was clear from the data was that you didn’t have to get to the maximum dose, which was 1600 mcg twice a day, but you had to get to your maximum tolerated dose. What the selexipag data showed was it didn’t matter. If you got to your maximum tolerated dose, you did just as well as somebody who got to 1600 mcg twice a day, because it seems to be that there are some patients that just need lower doses and can only tolerate lower doses of that medication.
That’s one of the keys that I always think about when I think about prostanoid therapy is maximizing the dose that you can tolerate. The same applies when I start thinking about parenteral prostanoids. If I have a patient who is not doing particularly well and we’re on parenteral prostanoids, my first question always is, “Can I go higher with the dose?” The parenterals are great because they don’t really have a dose limit. I’ll increase the dose and I’ll increase the dose.
One of my mentors when I was training used to say, “What you want to do is you want to titrate the dose to the point where the patient actually feels quite miserable and then drop the dose 10%. In fact, then you might even want to try going up on the dose again. If they feel miserable again, come back down that 10%, and now you’ve got them on the right dose for now,” and then he said, “But this is a disease that’s going to continue to progress. At some point, you’re going to want to go back up on the dose.”
I think that’s one of the things that we tell patients early is that we’re not going to sit back and rest on our laurels when we get you to where we need you to be. We’re always thinking about, okay, should the dose go up again? Many times it doesn’t need to. Patients get to a really good spot. They’re very well treated. They’re not having a ton of symptoms, but the moment they start to slide again, the next thing is to just keep going up on that dose. There is no limit with the parenterals, which is nice.
The other thing that we think about as we titrate these drugs is at what speed are we going to do this? The speed is really dictated upon a couple of things. First and foremost, is how sick is the patient? If we have someone in front of us, like I said, who’s walked in the door and are dying in front of us, we’re going to crank that drug up really fast. We’re going to get them as high as we can, as quick as we can. In the average patient, what we find is that, for most of our drugs, they have an indication and a label of how quickly you should titrate them based on what was done in the clinical trial. We generally stick to that recommendation. For most patients, that works out just fine.
I do have a subset of patients who even that titration schedule is too fast. They get too many side effects if you go up too quickly. So usually, not prescriptively before I start the titration, but maybe as I’m going through the titration. If a patient calls and said, “Look, I’m scheduled to go up on my dose tomorrow, but I feel awful,” just because it’s been a week, it doesn’t mean I’m going to say, “Well, you’re going to go up on the dose regardless.” We always would take that into account and say, “Okay, let’s hold here for another week, but let’s come back to this discussion.”
What is key in my opinion is, again, to remind the patients that that maximum tolerated dose is really important to get to. It’s okay to have side effects. That’s expected. We’re going to manage those with you. Then we’re going to try again. Some of our titrations, instead of the prescribed once per week, and if you’re thinking about a drug like selexipag, for instance, that might take eight weeks to get to the maximum dose, well, I’ve had some patients that take 16 weeks or 32 weeks, and that’s okay. We just remind them that we’re here with you and we’re just going to keep going as we can go.
There really isn’t a fixed schedule. Like I said, there’s very few exceptions where I think you should go faster than what’s put on the label. Those are really critically ill patients. For the average patient who’s an ambulatory outpatient, it’s either what’s labeled or maybe even a bit slower.
I’d like to wrap up by saying thank you for giving me the opportunity to chat about what I do and what we think about in the clinic every day. Titrating medications is a huge part of what we do. It’s gratifying medicine. It’s amazing to watch patients just get better and better and better with these drugs. Hopefully, this gives all of you as listeners an understanding of what we’re thinking and why we’re doing what we’re doing, because sometimes it can seem like a bit of witchcraft and wizardry, but I promise you there’s some thought behind it.
These are the things that we think about as we make these decisions. Again, the most important thing is, of course, listening to our patients. Listen to what they tell you in terms of what their experience is and then running with that to make the next decision in the treatment plan together with them.
My name is Dr. Mitesh Thakrar, and I’m aware that my patients are rare.
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