Understanding and Preventing Exacerbations in COPD

Peter L. Salgo, MD: How do you identify patients who are at risk for exacerbations? Are we simply saying that with the LAMAs and LABAs, we don’t have to pay attention that much because they’re going to prevent them? How do you deal with that?

James F. Donohue, MD: The best predictor is history. We know, from a previous study, that when you enrich your study, you want to study a drug that’s reducing exacerbation. What was done, last year, was a big thing. One or 2 is a pretty good predictor. Maybe you could elaborate on that, Fernando?

Fernando J. Martinez, MD: Here’s the way that I look at it. Here’s the way that I would conceptualize your 10,000-foot view, Peter, and then bring it down. The first thing is, you’ve got to, in your own mind, try to get a sense as to whether you’re dealing with asthma or COPD. If you’re going to follow the asthma side of the equation, it’s symptoms: inhaled steroids, first, and then, modifications based on symptoms and acute events. In COPD, it’s the opposite. It’s bronchodilators, first. That’s the first thing you’re going to consider, whether you consider a dual, 1 of these combinations, first, or a single agent. This is dependent upon the level of symptoms.

If a person is having very few symptoms and you appropriately ask what that implication is, you can get away with a single agent. I think most of the patients probably will benefit from having a dual bronchodilator. Then, the next series of questions you ask are, as you said, “How are you doing,” and, “What are you doing?” And then, the extra question that we throw in on top of that is, “Have you had any episodes,” flares or whatever those components may be, “that have required antibiotics or steroids in the last year?” If the answer to that is yes, then, as Jim says, that’s where you see the best predictor in an individual patient for future events. And, as we already said, preventing those future events is a key component. In that situation, you start considering a dual bronchodilator if they’re not on one, or, potentially, an inhaled corticosteroid, because those effects are primarily exacerbation.

Peter L. Salgo, MD: How important, clinically, are exacerbations anyway? If somebody has an exacerbation, you bring them in, you treat them, and you send them home.

Fernando J. Martinez, MD: That question is not infrequently asked. When you talk to patients, they don’t like these because they feel there’s a loss of control of their life. They can sense that their disease has worsened. From a patient perspective, it has a lot of impact. Patients do not like exacerbations, and it’s particularly those that lead to hospitalizations. So, the patients’ perspectives, they don’t like those things. And so, they get a sense of the value in preventing them.

The second component is a lot of what Frank has talked about, in terms of the biology of disease. Many of the components that relate to lung abnormalities, peripheral abnormalities, and comorbid conditions are actually worsened by exacerbation events. So, for us, the patient doesn’t like them. Preventing them is important. And, by the way, preventing them has additional components that will have benefits on the progression of their disease, over time. They are important events. This is why almost all therapeutic guidelines, now, not only ask, “What are you doing,” but, “Have you had any events in the last year?” Those 2 components are going to drive how you’re going to manage the available therapies that we have.

Byron Thomashow, MD: Let me ask Fernando a question. The holy grail is survival, right?

Fernando J. Martinez, MD: Yes.

Byron Thomashow, MD: And one of the reasons why everyone in the world is on a cholesterol-lowering drug or a hypertensive drug, appropriately, is that there are survival benefits. We have struggled with that, from a medicine standpoint, at least. Yes, oxygen certainly, when indicated, does have effects. Lung volume reduction surgery does, as well. We struggle with it. Exacerbations do all of these terrible things. If we can cut down on exacerbations, doesn’t it make sense that we’ll improve survival?

Fernando J. Martinez, MD: Yes, and I think that you’re absolutely correct. I think we’ve struggled with that in the COPD world. I think you’re right, all of us would love to have a simple therapeutic intervention that clearly improves survival, as statins have done in the cardiovascular world. We’re still moving in that direction, and I think that’s an important component. But when you query patients now, they love the idea of improving survival, but they’re going to want that quality of life and prevention of those acute events as well.

James F. Donohue, MD: One of the things that’s fascinating with exacerbations, again, is that the event-driven kind of decline in lung function and quality of life is very important. But many people don’t report exacerbations. So, if you look at some of the diaries from London, and then some of what’s called the EXACT-PRO data on exacerbations, it turns out that, fully, half of the exacerbations are not reported to the physician. Now, some of that is because they’re so tired with the fatigue that they can’t get up and get to the doctor. But a lot of patients have an incredible fear of losing control. They are not going to the hospital because so many don’t come home. They go to skilled nursing, or other places. Particularly, in the more severe population, there’s incredible resistance. They might take a phone call if you gave them something over the phone. I think that’s a phenomenon you see in the more severe patients. If everything is the focus of the patient in personalized medicine, you have to incorporate that into your thinking. The primary care physicians do that better than we do.

Peter L. Salgo, MD: But they’re getting cause and effect backward, right?

James F. Donohue, MD: Yes.

Peter L. Salgo, MD: It’s understandable. But it’s “If I go to the hospital, then I won’t come home.”

James F. Donohue, MD: That’s correct.

Peter L. Salgo, MD: It’s the hospital that they see as the driver?

James F. Donohue, MD: That’s correct. And, again, they don’t recognize it’s the severity of their disease worsening.

Peter L. Salgo, MD: The other thing that I’m hearing from you guys is, you get an exacerbation, we’ll treat it, and you’ll probably go home. But every exacerbation notches you down.

James F. Donohue, MD: Correct. It’s event-driven.

Peter L. Salgo, MD: Is that fair?

Fernando J. Martinez, MD: I like it. That’s the way to put it.

Frank C. Sciurba, MD, FCCP: One of the reasons for that is patients notch their inactivity. In my experience, a concept that actually is proposed to be tested at the NIH is, if you begin rehabilitation and exercise training immediately after an exacerbation, you may, in part, prevent that notching down. Really, only 20% to 25% of patients, after an exacerbation, have any persistent decline in lung function. For the majority of patients, lung function comes all the way back up. But symptoms often don’t follow because they have that deconditioning issue.

Byron Thomashow, MD: I can’t agree any stronger than with what Frank just said. He’s absolutely correct. I’ll come back to this whole issue of hospitalizations and re-hospitalizations because we do some bizarre things to people in the hospital. So, you have these COPD patients who come in. Often, they’re debilitated. We’re so concerned with their risk for falling that we keep them on bed rest for the 3 to 5 days in the hospital. So, they often leave more debilitated than they were before. How much this sort of post-hospital syndrome actually contributes to readmissions is not clear, but it’s something that is completely under the hospital’s control.

Peter L. Salgo, MD: When I was an attending in the intensive care unit (ICU), I learned something from this man, the doctor. In the ICU, for a sick patient, a doctor said, “Get him out of bed.” And I said, “Oh, come on, Byron.” No, we got him out of bed. And you know what? The patient got better, faster.

So, the point about identifying exacerbations is to treat them and get these patients going again. And to identify patients at risk, I would expect that if you identify somebody at high risk for an exacerbation, is there something in which you can do a priori to keep that exacerbation from happening?

Fernando J. Martinez, MD: Well, I think that’s been one of our holy grails in COPD management. Some things do work. As Byron says, long-acting bronchodilators have an effect, in that respect. Inhaled corticosteroids have an effect, in that respect. There are additional agents. The phosphodiesterase 4 inhibitor, roflumilast, has an effect. We’ve spent a lot of time looking at macrolides and azithromycin’s effects on exacerbation reduction. The combinations of those have incremental effects. So, there have been a lot of therapeutic approaches that we currently have available that have been developed specifically for that reason, and they work.

Peter L. Salgo, MD: Before we move on, can you give me a checklist? For a patient who is sitting in front of you, how do you say, “You’re at high-risk for an exacerbation.” Is there anything you ask?

Frank C. Sciurba, MD, FCCP: What’s kind of funny is when you do these complex multivariate analyses, the thing that comes up every time is, “How many times have you had an exacerbation in the last year?” That is the biggest predictor.

Peter L. Salgo, MD: So, past performance is a predictor of future performance?

Frank C. Sciurba, MD, FCCP: Very strongly. That’s New England Journal of Medicine worthy. “Have you had exacerbations?” “You’re going to have exacerbations.” The other thing that comes up, frequently, is allergic asthma. Eosinophilic features, in a COPD patient, is a predictor of somebody who is more likely to have a flare-up. And so, that’s probably the second most frequent component that comes into these analyses.

Fernando J. Martinez, MD: I’m your COPD patient. I come to see Frank, and Frank asks me, “What are you doing?” And, I say, “I’m not doing anything.” Then, he says, “What have you cut down on?” “I have everybody doing everything for me.” He already knows I’m symptomatic. And then, he’s going to ask me, “Have you had any flares that have required antibiotics or steroids in the last year?” “Dr. Sciurba, the last time I had one of those was 6, 7 years ago. Don’t you remember that?” That’s a low-risk person.

If I say to him, “Dr. Sciurba, you gave me an antibiotic 3 weeks ago, and I got steroids 6 months ago, don’t you look at that?” “Don’t you look in your medical record? You’ve got your electronic health record right there.” That’s a person who’s at risk for having future events.

Byron Thomashow, MD: There are a couple of others, though, that I think we all agree are important. The severity of the COPD is one. We’ve talked about spirometry as a gauge of making a diagnosis, and we all understand it has its flaws. The more severe the COPD, the more likely you’re going to have exacerbations; and, perhaps, more importantly, the more likely you’ll end up in the hospital for those exacerbations. Then, there are some other things, like GERD (gastroesophageal reflux disease), that potentially might be a risk factor. People sometimes may not pay attention to it. So, there are a number of other factors, but I completely agree.

Transcript edited for clarity.