Murali Chakinala, MD Transcript (Part 1 of 2)

Jul 21, 2017

Murali Chakinala, MD discusses the role of combination therapy in treating PAH. Dr. Chakinala is a Professor in the Division of Pulmonary and Critical Care Medicine. His areas of specialty include pulmonary vascular diseases, including pulmonary hypertension and pulmonary arterio-venous malformations.  

Hi, I'm Dr. Murali Chakinala. I'm a pulmonologist at Washington University in St. Louis, Missouri.

I'd like to discuss the role of combination therapy in pulmonary arterial hypertension, especially up front combination therapy.

Since medications became approved for pulmonary arterial hypertension, our treatment approach has always been to start with one drug, and then perhaps add a second drug, if we're dissatisfied with the result, or someone starts deteriorating.

Recently a study was completed, the Ambition trial, and in that trial we tested the hypothesis that starting right away with two different drugs in a new patient with pulmonary arterial hypertension might be better than just starting with one drug. The treatment arms were set up so that patients received a drug known as a PD5 inhibitor, or a drug known as an endothelial receptor antagonist, or both drugs together. When we completed the study, we realized that the group of patients who received both drugs right away fared better in the long term, with less likely the chance of meeting a clinical failure endpoint, that was the focus of the study.

Based on that study, where patients were less likely to be hospitalized in particular, but other things like disease progression, or inadequate response, or death, which was all part of the definition of clinical failure, we now generally start newly diagnosed patients with two drugs, both a PD5 inhibitor and an endothelial receptor antagonist. Now, it doesn't mean that every single PAH patient has to have both drugs, but in general, that's the way the field is going, and most of the PAH physicians in the community or in the country are relying more and more on up front dual combination therapy.

Most of the medications that we use in pulmonary hypertension are what we call "fixed dose", meaning there's really just one approved dose, or maybe two approved doses. Certainly, there's a class of drugs called the prostacyclin analogs, where that's not the case, where the dosing is quite variable, but for other drugs, like the endothelial receptor antagonists and the PD5 inhibitors in particular, we generally don't have a lot of options on the dose, so it's not too much an issue of, are we maxed out on the dose of those drugs.

We, in general, try to assess people on those maximum doses, and if they're meeting our treatment goals, then we're satisfied. If they're not meeting treatment goals, then we often look to see what changes need to be made.

When we, as physicians, discuss treatment goals, it's really both a combination of what we think directly the patient experiences and lives from day to day, as well as more objective treatment goals that we're measuring in the clinic, or in the cath lab, that the patient really isn't going to feel directly, but it's still important objective information, so it's kind of a combination of both.

To give you some examples, measuring the pressures, the cardiac output, or other hemodynamic measures in the cath lab are really important, and something we put a lot of stock in, but those don't really correlate very well with what patients feel. When we talk about things that patients feel, we really look at their symptoms, we look at what's called the functional class, from I to IV, and really, we make that determination of I, II, III, or IV based on what patients tell us they're able to do and how difficult it is to do those things. We also look at the six-minute walk test, for instance, and now that's a patient-driven patient effort that really heavily sways the output. We really look at a combination of those direct patient influence things, as well as things that are strictly measured in the lab or in the hospital, and put it all together, and we want our patients to meet a comprehensive set of those goals, before we're satisfied with a therapy.

In the trial, the Ambition trial, or in clinical practice, it's important that patients are followed longitudinally because how they're doing today may have nothing to do with how they're doing six months from now. We're constantly re-assessing patients, looking at how they're meeting their treatment goals, and looking at their regimen and how they're tolerating it. We have to be prepared to make a change at any point or any visit, depending on how the data looks, and how the patient feels.

There are a couple of things that I think were a little surprising to some of us in that when we talked about the primary analysis, or the primary measure of interest was this composite definition of clinical failure, and there were different parts to that definition. I think many of us thought that perhaps the thing that was going to differentiate the arm of patients with two therapies versus one therapy was maybe the rates of disease progression, or maybe the percentage of patients who had an inadequate response after six months.

Instead, it was hospitalization, meaning that that measure, by itself, really drove the overall definition of clinical failure. The difference in the hospitalization rate for the patients on single drug therapy versus dual therapy was pretty robust, and that's what drove the whole study. That was a little bit surprising to many of us. I think also the other thing that was a pleasant surprise is that one would think that perhaps it's the sicker patients that maybe the benefit is really appreciated, or being on two drugs versus just one drug. Well, we found out in the study, it didn't matter if you were on the sicker half of the spectrum, or the less-sick half of the spectrum, everybody, or in both groups or both camps, there was benefits from being on two drugs right away, as opposed to just starting with one drug.

This was a very important, scientifically-driven study, because we know none of our therapies are curative, and patients often progress on one drug over time. They progress on two drugs, and because the mechanism of actions of these medicines are so different, and because the pathogenesis, or the origins of pulmonary arterial hypertension is more than one thing, meaning that there's many things that are going wrong in an individual to get to the point of having PAH, it made a lot of sense to attack the condition with two drugs that work completely differently.

We have plenty of examples of this in medicine. Heart failure, diabetes, cancer, asthma. It makes a lot of sense that when you're dealing with a chronic, difficult to treat disease, that you would attack it with more than one drug at once.

My name is Dr. Murali Chakinala, and I'm aware that I am rare.

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