Raj Parikh, MD, MPH - phaware® interview 534

Dr. Raj Parikh from Hartford Hospital discusses building on foundational pathways with treatment options for Pulmonary Arterial Hypertension (PAH) patients. He also emphasizes the value of clinical trials as well as the importance of a good doctor/patient relationship. 

This Special Edition Episode Sponsored by: Johnson & Johnson

My name's Raj Parikh. I'm the Director of the Pulmonary Hypertension Center at Hartford Hospital in Hartford, Connecticut. I did a lot of my training kind of all over. I went to medical school in New Orleans, Chicago, ended up in Boston, and then made my way back home to Connecticut where I grew up. I've been at Hartford Hospital for the last four years. I started the Hartford Hospital's Pulmonary Hypertension Program from scratch, and I've been building it up since then.

I got involved in pulmonary hypertension really during my fellowship at Boston. I really wanted to get involved in the rare disease space of PH, where patients are far and few between, but the ones that are there, they have pretty significant morbidity, mortality, and a poor prognosis. There's limited treatment options and there's limited specialty care for these patients. I really wanted to come back home to my state of Connecticut and build up a program in sort of the area that I grew up in.

Today I'd like to discuss building on foundational pathways, treatment options for pulmonary arterial hypertension patients. This is pretty exciting stuff. In the last year, we've had one of the latest agents to enter the pulmonary arterial hypertension therapy space, and that's the first and only combination pill.

When we think about PAH and the pathophysiology of pulmonary arterial hypertension, we think about three foundational pathways. These three pathways basically result in too much restriction of our pulmonary blood vessels. What that does is it creates these three pathways as potential targets for therapy down the line. What we know about PAH historically is that these three pathways have created three different classes of therapeutic agents. We think about the nitric oxide pathway and the nitric oxide agents that then therefore intervene on that pathway and can treat PAH. We think about the endothelin pathway and then therefore the endothelin receptor agents that again, can intervene on that pathway. Then we think about the prostacyclin pathway. 

As the first and only combination pill, what it does is it takes two of these foundational pathways and develops it into one, combination, once-a-day, easy to use, easy to prescribe, cost-effective pill for patients. We just think about what that can not only do for patients in terms of compliance and adherence, but also decreasing their pill burden, making sure they're getting this dual therapy upfront, which is part of really our standard guidelines now for PAH treatment, which is using multiple pathways, multiple agents, not just one agent from one pathway for sort of standard of care. That's really what the foundational pathways and building on that and creating this treatment option for PAH, which is the first and only combination pill is really all about. 

A lot of what we do in pulmonary arterial hypertension, what we've learned is the more aggressive we are upfront, the better the patient's overall morbidity and mortality and prognosis will be on the back end. We've shifted away from a gradual, let's do one medication, let's assess your response. Let's do a second medication, let's assess your response. We've become a little bit more, what I would say aggressive upfront. Because what we've seen with that is that while we are aggressive, we're able to take a patient's, what we call risk score, risk stratification from something like high risk or intermediate risk and really bring them down to a lower risk score. When we do that, it's not just about creating a number of a risk stratification score of 12 to two. That two is really where the patient's quality of life improves. The patient's able to breathe better. The patient's able to do the things they want to be doing. The patient's able to live longer. The patient's able to stay out of the hospital, stay out of having to do routine invasive tests and things like that. Overall, the prognosis, the morbidity, the mortality changes as we have a lower risk stratification score. 

We really use our risk stratification tools. There's two or three out there. There's the European tool, there's the REVEAL score to really guide our therapy. What we've learned and what we've actually made standard of our clinical practice based on standard guidelines mentioned by the World Symposium on Pulmonary Hypertension, standard guidelines mentioned by the European risk stratification scores and European guidelines is to think about dual upfront therapy. That is basically taking a medication from one pathway, taking a medication from that second pathway and getting patients on two medications upfront right away for patients who have certain degree of risk. 

What that does is it improves their morbidity and mortality and prognosis by bringing their risk score down. So if we think about a medication like this, which is essentially saying, okay, well, we know standard practice is to be on two types of pathways, why not take those two types of pathways, spit it out into this one combination pill, the first and only ever combination pill in pulmonary arterial hypertension and make it easier for the patient.

So now they're not taking up to 13 pills at three time intervals in a day, they're taking one pill at one interval once a day. This is cheaper for the patient. This is easier for these rare disease offices like PH clinics who have to order and get these medications approved through insurance. Now, they just have to get one medication approved instead of multiple, two or three or something like that. When you think about it from that angle and you think about rare disease in general, I think getting involved in clinical trials is almost like what you kind of have to do when you have, let's face it, limited options when it comes to pulmonary arterial hypertension therapy. 

I've been in this space managing and directing the PH Center at Hartford for four years. Prior to that, I've been as a fellow, really involved in learning about pulmonary hypertension for three years prior to that. In the last seven years, only one new medication, except for obviously this combination pill, has entered the PH space. There is limited options as a whole when it comes to pulmonary hypertension. Pulmonary hypertension is a rare disease. It's rare because it's overlooked sometimes. It's missed sometimes. It has a poor prognosis, and therefore there's not a lot of patients living for 15, 20 years with pulmonary arterial hypertension. That's just not the longevity of the disease. 

So when you're dealing with rare disease, when you're dealing with limited therapeutic options, getting involved with clinical trials is really important, especially when you're somebody who is a little bit more advanced, or you have a patient in your office who's a little bit more advanced than the common patient in PH who has a lot more deteriorated quality of life, a lot worse prognosis. Then, you're really looking at things outside of the box, outside of really these three foundational pathways, outside of what's really FDA approved for these patients and what else can you offer them? Can you get them involved in a brand new clinical trial for a medication that A, might have amazing outcomes, B, may have really neutral outcomes or C, god forbid, may have an increased signal for harm? But sometimes some of those risks really outweigh the benefits and sometimes the benefits really outweigh the risks for a patient who has poor prognosis in a rare disease space such as pulmonary arterial hypertension. 

When this combination pill, got FDA approved and was available in the market, what we did in our office, in our center was literally went through our list of patients and cold called them. We said, "You are already on the therapy that really this new medication contains." It contains one product from a phosphodiesterase or nitric oxide pathway, one product from the endothelin pathway, and it really takes it in and just spits it out into this one pill. "You are taking three pills once a day or you're taking 13 pills three times a day. That's really the combination that really would translate over to this new option." 

We called them up and we said, "You are welcome to make the transition.” It is, of course, rocking the boat. Now maybe you are fairly stable, maybe you are just freshly on these pills. Maybe you are on these pills for a long period of time, but you're not really stable and you could feel like you could get better. It's a balance between all those three types of subpopulations. Naturally speaking, the patients who are on only three pills and they're going from three to one and have been very stable and have been on that regimen for years, probably are a little bit more hesitant than, let's say the patient who's on 13 pills, three times a day and switching it over to just one pill once a day. Or if you take the patient who's on three pills, but it's for some reason for their insurance, that's a very expensive three pill regimen, and they're going to be able to really cut down their monthly costs in terms of pills and costs for the medications by switching over to this combination pill. So that's another type of patient, even though they're very stable, even though they've been on this regimen for several years, they really want to transition over. 

I would say that for the patients who were not treatment naive who have been on the different products that are contained into this combination pill, really anecdotally speaking, we have seen no sort of adverse or new developments or really curveballs in terms of making the transition. It's been pretty seamless for patients transitioning from being on the separate therapies into this really what we call loose dose therapies into this combination pill.

My relationship with my patients is very important, and I think that focus is really because it's a rare disease space. When I'm going into my clinic day and that clinic day may have 20 patient visits for that day, 12 of them are follow-ups, patients I know. But eight of those 20 patients, almost half are brand new referrals, new patients I've never met before. They've never probably seen a pulmonary hypertension specialist before. They could be traveling from an hour, hour and a half, two hours away. Pulmonary hypertension, as we know, it's a rare disease. There's not a lot of providers who specialize in just pulmonary hypertension. There might be cardiologists who can dabble in pulmonary hypertension. There may be pulmonologists who dabble in pulmonary hypertension, but the space of pulmonary hypertension is limited in terms of how many providers are available nationwide, even worldwide.

A lot of times patients who may have pulmonary hypertension, may have a concern that they may have pulmonary hypertension, may have already formally been diagnosed with pulmonary hypertension, may have to travel hours out of state, out of their area to come and visit a pulmonary hypertension specialist. With that visit comes a lot of pressure, comes a lot of pressure on the patient's end, comes a lot of pressure on the pulmonary hypertension specialist's end, comes a lot of pressure on the doctor who made the referral. That patient may have been for 30 years following with this cardiologist who is well renowned in their local town, who has managed all the cardiology issues for all of that patient's family members, their parents, their grandparents, and what have you. Now, that cardiologist is saying, "As seasoned as I am, as well as I know you, as well as I know your family, as well as I know this community, I'm sending you out of this state to a specialist in the city who is 30 years younger than I am and is not as experienced in the field in general as I am, but he or she is a pulmonary hypertension specialist." There's a lot that really comes with that. I think we sometimes don't put as much weight into all of that, but I think that's what is the pure beauty of really rare disease. That's what accompanies rare disease cases and rare disease patients and rare disease specialists. 

Now, you walk into their clinic room and they've traveled an hour and a half, they've been Googling about their disease state, rightfully so, doing their research. They've talked to the referring doctor who maybe is a long-term doctor of theirs, and they really have certain expectations from the provider. Now, I'm walking in and I want to make sure I can meet those expectations. I can really tell this patient, this is truly what I think is going on. These are the X, Y, or Z ways I think we can potentially make you better. And if those things don't work, this is my backup option. 

Or I'm walking in and saying, "Hey, you are very advanced, and if we don't do these two things, I don't think you can live this much longer." It's hard to say that to someone you've just met for two minutes who really is expecting to really make significant improvement by seeing you. It's a fine balance. I think sometimes being confident in your subspecialty disease, knowing what's available, knowing how to assess the patients, their prognosis, just having confidence in that process helps you maybe gain confidence from your patient. It's really hard. It's something that we all deal with in the rare disease space, is that how do we manage those expectations from the patient, from the referring doctor, and how do we invoke confidence in our patients? We want patients to trust us in this small field, in this rare disease field. We know what we're thinking about doing. We know what we want to do. We hope that it's going to be successful. If it's not, we know what our backup option will also look like too. 

When you stop and think about pulmonary hypertension patients, it's not just about the pulmonary hypertension pills that they're on. There's a couple pathways out there, like I've talked about. Those pathways yield certain types of medications. There's three or four maximal medications a PH patient can be on from a PH specific standpoint. But what about what other medications are they on? A lot of patients with pulmonary hypertension, they deal with heart failure. For that reason and that reason alone, these heart failure patients are on water pills. Sometimes they're on one water pill. Sometimes that water pill is dosed two to three times a day. Sometimes it's two pills three times a day. Now, a lot of times you're on two or three total water pills. So think about the pill burden from just the heart failure perspective. And the heart failure is simply a consequence of the pulmonary hypertension, but not treating the pulmonary hypertension itself. 

When we think about pill burden in PH patients, it's not just the PH pills, the three to five to 13 pills that they're taking three times a day. But now you add on the water pills, which are two to three times a day, two to three pills at every interval. Then with the water pills, you have electrolyte imbalances. So, now these patients are taking potassium supplements once or twice a day, magnesium supplements once or twice a day. Let alone if they have any other comorbidities such as diabetes or hypertension or hyperlipidemia. But let's just say just this pill burden alone is so overwhelming for these patients. So, to be able to take that pill burden and bring it down from 13 to one, from five to one, from three to one, in the large scheme of things, is a huge win in regards to patient adherence and patient compliance and cost-effectiveness, as well, for the patient.

Thanks for listening everybody. A couple takeaways from my standpoint is obviously talk to your care team, talk to your provider before making any significant medication regimen changes. It's always important to be aware and ask about what active clinical trials may be going on, if that's something that you would be a good candidate for. I think that's important from just a disease perspective to know that these are the other options that are available to you out there.

With pulmonary hypertension, this is a rare disease. I think the more we as a community can discuss amongst each other options that we have available to improve our quality of life, improve our prognosis, improve our medication adherence, these are all opportunities that we have to take advantage of. 

My name is Dr. Raj Parikh, and I'm aware that my patients are rare.

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