Welcome. Today's webinar will be the second in a two-part series on the outpatient treatment of patients with COPD. My name is Dr. David Menino. I'm a U.S. medical expert with GlaxoSmithKline and also a professor of medicine at the University of Kentucky in Lexington, Kentucky, and I'm pleased to have with me today Dr. Gary Ferguson, who's the director of the Pulmonary Research Institute of Southeast Michigan and also a clinical professor of medicine at Michigan State University. Our disclosures are noted on this slide. We're going to start today's webinar with a patient presentation, and this is a patient similar to many people who show up in our practice. This is a woman in her 60s who's been diagnosed with COPD for about two years. She has a smoking history. Her lung function is diminished. She has a history of dyspnea on exertion and is currently using a dual bronchodilator every day and uses a short-acting inhaler in addition two to three times daily. She presents after having a recent exacerbation that required a trip to an urgent care clinic, and this exacerbation was treated with antibiotics and five days' worth of prednisone. So with this, I'm going to hand this over to Dr. Ferguson to talk about how we approach COPD exacerbations. Gary? All right. Thank you, David. I'm glad to be here, and this is a great topic to discuss. So the first thing is talking about this. So our patient has symptoms that suggest an exacerbation, and kind of the first question is, what is an exacerbation? Because people use a lot of different names in terms of attacks, flares, and things like that. But basically, you're talking about this sudden worsening of symptoms. Usually, it's a fairly acute onset. It has to be for more than a day or two to be considered an exacerbation. It really is more than what we would say is our day-to-day variation, because as people know, they do come and go, and symptoms can be better on certain days. Most commonly, they are triggered by very specific things, as you see on the slide, bacteria, viruses, pollutants, irritants. They then cause local inflammation, which in turn then leads to increased bronchomotor tone, narrowing of the airway, sometimes increased mucus that also further causes airflow obstruction. That can in turn lead to hyperinflation, gas trapping, all of which then leads to these symptoms that these patients have of increasing cough, sputum, and shortness of breath. If you look at exacerbations, they are generally classified as mild, moderate, or severe. Again, these acute worsening of symptoms beyond their day-to-day variability. A mild exacerbation would be just something that you might use, rescue inhalers on, a little more consistent therapy with maintenance therapies and things like that, not needing more aggressive intervention. Moderate exacerbation is considered bad enough that healthcare utilization is required. They're put on antibiotics and or steroids or both. And then a severe exacerbation is one that's bad enough to put somebody in the hospital or at least in the emergency room for at least 24 hours. And as you can expect, these things have increasing severity of symptoms, as well as potential outcomes, all of which are important. We've tended to focus on the moderate and the severes, but I will say that there's more and more evidence showing that even mild exacerbations, especially in patients that require at least two or four extra puffs of albuterol a day for a couple of days in a row, actually do end up with very significant outcomes that can have negative impacts on our patients. So David's just going to take a quick run through the risk effects of COPD exacerbations, and then we'll talk more details. Yeah, yes. Thank you, Gary. And as this slide shows, exacerbations are bad. I always tell my patients that my goal for exacerbations are zero, because I think each exacerbation, in fact, has the opportunity to either put you in the hospital or end your life. So we should aspire to zero exacerbations. But even those exacerbations that don't result in bad events can affect one's quality of life. And we now have data showing that risk of heart issues, either heart failure or even heart attacks, are increased in that period of time following an exacerbation. And each exacerbation that one has increases the chance that you're going to have another exacerbation in the relatively near future. So our goal is always zero. So let's take a second then and look at some of the details on that, because you're absolutely right. So this next slide is looking at cardiovascular events and cardiovascular risks. This is data taken from the SUMMIT trial, which is a very long-term, large trial, and was looking at some cardiovascular outcomes. And I just want to highlight a couple of the bullets. So this one bullet is that if you've had a moderate exacerbation, or severe, but if you've had an exacerbation that required intervention, that your cardiovascular risk is up almost four-fold in the 30 days after that event. Cardiovascular events are heart attacks and strokes and things that we don't want for our patients, separate from their COPD. And then if you look at that bottom bullet, if you've been hospitalized, a severe exacerbation, you actually have almost a tenfold risk for the next 30 days of having these events. And so we have lots of consequences that I think are really, really important. Certainly, if you look at the ultimate consequence of mortality, here's data on that. And again, this is a composite of a lot of data, as you see down at the bottom left corner from lots of studies. But if you're in the hospital, 90 days later, there's a 11% chance that you are dead. A year later, 26%. And in fact, if you look at people that have been hospitalized, their average or 50% mortality is 3.6 years. And the numbers will vary a little bit, but these are just incredibly high numbers, especially if you look at that middle 26%, which if you look on the average one-year mortality for a myocardial infarction, it's less than that. So these bad exacerbations or lung attacks, as some people like to call them, really do have significant impacts on mortality. So not something we want to go to. Do we catch them all the time? I don't know. What do you think about this, David? Well, I think we clearly don't. People that have actually, for example, compared exacerbations using administrative type data to report it, say using a diary, find that exacerbations are underreported. And as noted in this slide here, that daily diary, which is something that it's difficult to get patients to do this for long periods of time, but certainly over short periods of time, one has the potential to do that. And it demonstrates that things aren't always captured. Yet those exacerbations that are captured on a daily diary like that still lead to bad outcomes. So even these exacerbations that might go under the radar seem to predict bad outcomes. Yeah, and that's just so important for our patients is finding them. Some of this data about exacerbation and frequency exacerbation comes from a trial called the Eclipse trial. Again, a very large trial over several years focusing on exacerbations. And from this, we've learned a lot. But if you just look at patients who have had a history of exacerbation, one exacerbation in the prior year, you're twice as likely to have one this year. If you've had two exacerbations last year, you're six times more likely to have one this year. So it's a huge risk. So you have to not only identify that exacerbation to treat it at the time, but it also has to be identified because it's a huge risk profile factor for this. Now, having said that, as you look at this and track this, and this is a somewhat complex graph we're showing on this slide, the people with two or more exacerbations are the darker colors. And year by year by year that, you know, not everybody does have them the same amount every year. In fact, if you look at the whole population over three years, there's about 30% of them never had an exacerbation. 12% or more had two exacerbations or more every single year, all the way across. And so that means that the majority were somewheres in between having one or two, one or two, things like that. So you have to look back a little bit on there. But it is an incredibly important predictor of who's at risk for that exacerbation with all those bad outcomes. One of the other big predictors is lung function. And this is just more detail on what lung function was relative to risk of exacerbations, one, two or more, things like that. And as you move from the gold stages of 2, 3, 4, which is moderate, severe, very severe lung function, 50 to 80%, 30 to 50%, less than 30%. If you just look at the yellow bar, looking at the two or more, it definitely goes up from about 20% to over 45%. So as your lung function worsens, certainly your risk of more frequent and more intense exacerbations occurs. But I would also remind you that even though this is an important risk factor, there's a lot more patients out there with gold two than gold four. So this doesn't mean that the only patient you're going to have to see or worry about is the very severe patient because there are patients and lots of them in the gold two and three category that will end up in your hospital with exacerbations. And so being aware of that is really important as well. And then this third point, I think, in terms of risk factors is something we're just trying to get a better handle on now. For those of you that are involved with a lot of this data, know that we've been looking at eosinophils, these are just peripheral blood eosinophils, to try to see if they can be a predictor, in particular, for future exacerbation risk, and maybe even help us identify patients who would potentially most benefit from therapies such as inhaled corticosteroids in our additional interventions to prevent exacerbations. And as you can see from this slide, as you just kind of make various cut points from less than 50, 150, 300, 400, 500, that your risk for exacerbation goes up consistently. This is just a large observational data set from Kaiser Permanente over about three years. And you look at the rate ratios, you're going from, you know, basically about one up to 1.76. So very significant added risk from that alone, enough so to where what we're starting to see is in not only studies, but in even some of our guideline recommendations with GOLD and ERS, that this is to be considered in helping us decide who should be on certain therapies for exacerbations. And so, you know, I've started actually doing this in my practice on just sort of a personal basis. And actually, David, what about you? What do you think about these eosinophils? Well, as you stated, right now, and the guidance is inconsistent, and some guidance is saying that this is something that should be looked at. Others are saying we need more data. In my clinical practice, it's something that I will take a look at if it is available, but I think going forward, I think there is something to be learned from this, particularly when you sort of evaluate patients during a stable state, because I think one does get information from eosinophils. And I would absolutely highlight that as well. We still need to know a lot more. We haven't done a lot of prospective interventional trials to nail this down yet, and timing of when your eosinophil counts are measured, obviously, if you've just been put on steroids, they may be unexpectedly low. Certainly during certain exacerbations, they may even be up a little bit. So we have a lot to learn, but I do think we're looking for more of these things to try to identify these phenotypes of patients at greater risk, who we need to really work on more. And there are some other risk factors as well, and this highlights a lot of them, certainly recent exacerbations. The closer you are to a previous exacerbation, separate from the number, the more likely you are to have another exacerbation. Other markers of more severe disease, whether it's looking at pulmonary artery cross-sectional area, in other words, signs of maybe pulmonary artery dilation, pulmonary hypertension, severity of emphysema, airway thickness consistent with chronic bronchitis or just a history of chronic bronchitis, all these things do come into play as well. And so those are all little things that help us have an idea of who's at that greatest risk, who's the one you really need to target, recognizing that you don't have to have all of these risks in order to do that. So how are we going to fix this and how do we approach this? So for this one, basically there's kind of two ways of dealing with it. One is acute treatment. And then the more important one, I think, in addition to that is chronic treatment. So if we take a second and talk about the goals of acute treatment, it's to minimize that acute negative impact as well as to then try to prevent future exacerbations. Now where do we treat them? It can be anywhere. And sometimes that's actually a challenge for us, right? Because it could be, if you're a specialist, it could be a primary care or vice versa. It could be an urgent care. It can be telephone calls. But the net effect is it, depending on the severity of symptoms, intensity of problems, this can be an outpatient, inpatient, in today's world, a telemedicine approach to how we handle these people. The actual treatment points for acute management, you know, it's again, good initial bronchodilators, good actings are critical and highlighting not only that, but that, you know, extra maintenance therapies, although ultimately may be a very important, adjusting maintenance therapies and throwing that on as a means of treatment probably is not the most effective. Certainly the issue of systemic steroids for a short period, about a week is appropriate. Antibiotics in the right situation with appropriate changes in sputum, sputum color, volume, shortness of breath, methylxanthines are certainly in most guidelines because they're relatively inexpensive, generally not recommended unless you have no other options. And then one of the key ones of acute intervention today is non-invasive positive pressure ventilation, the BiPAP kind of therapies, which has dramatically changed what we can do for these patients, especially if they're bad enough to go to the emergency room, hospitalization, to keep them from being intubated, keep them from being placed in the ICU. So those things are essentials for what we do acutely. The chronic one has again, evolved and it's evolved a lot in every year it's evolving significantly. And this is just kind of a general algorithm suggested by the gold guidelines as therapies in terms of monos, duals and triples and steps. You know, bronchodilators are a cornerstone therapy. It's a starting point. In the United States, mostly that's long-acting muscarinic antagonists. It does vary around the world a little bit. And occasionally it's ICS-LABA, but quite honestly, that's being more pushed to the side as a early therapy, unless people have concomitant asthma related problems, or maybe in some very selective other situations. Certainly dual bronchodilators has become a cornerstone therapy and many people now believe it should be an initiating therapy, but certainly if not, it's a step up from monotherapy. And then as we move across, and now what you're starting to see is that we're actually starting to look at some of these modifying factors. So what are their eosinophil counts? Well, we think that if your eosinophil counts are really low, you may be less likely to get an ICS response. And so that's a person who you're going to be on a dual bronchodilator and consider an alternative therapy for exacerbations. If your eosinophils are a little higher and what that number is, it says 100 here. Some people put it at 150, some people put it at 300. They would certainly say history of, or it's association with that goes from that dual bronchodilator to triples. And then we have other things. So patients who have chronic bronchitis, they're former smokers versus active, and they're on triple therapies, which is what a lot of us see. When do you place the PDE-4 inhibitors and the macrolide therapies and things like that as alternatives? And so these are all parts of our algorithm for how do we actually not only make our patients feel better, but how do we do reduce those future exacerbations, which I think is a credibly important part of what we do. And we actually have science to support it, which is great because this isn't just clinical ideas. And so I think these are two great studies that have come out in the last couple of years that are really, really important. The study on the left is the IMPACT trial. I think it's a critically important study looking at exacerbations in higher risk people. One of the really important things I like about this is it's the exact same molecules across the various treatment arms. It's the exact same delivery system, a dry powder ellipta, and it's a once a day therapy. So really the only intervention differences in this analysis is, is it a triple versus a dual Lava ICS versus a dual Lava Lama. And as you can see, as you look across from the Lava Lama to the Lava ICS to the triple therapy ICS Lava Lama, that the exacerbation rates go down very significantly. The study on the right is a little bit more complex because it is different molecules in the Lava Lama versus the triple arm. It's different delivery system, puffer versus a dry powder inhaler. It's a different dosing once a day versus twice a day, which adds confounding to the results. But even still, if we focus on the left side, the green versus kind of a purplish color blue is that the triple therapy reduced exacerbations compared to the Lama Lava. So we're learning that especially in higher risk patients who have this, that that added ICS on top of the Lava Lama Bronchodilator is really an important added value to reduce exacerbations, again, to be used on a maintenance therapy to prevent as opposed to acute interventions. And just a final reminder that there's all these other things that we kind of sometimes forget about as we get focused in the studies, but we do have other options too. Smoking cessation, vaccinations, certainly that's a hot topic again today, but you know, influenza, pneumococcal vaccination, rehabilitation, critically important. And that we do actually have some other options as well to kind of work our way through in those really severe patients in terms of lung volume reduction surgery and even transplantation. So there are things down the road to consider. We have a lot of options for these patients, even though we have a little bit way to go. So let's come back to Karen. So thank you, Gary. So, so after having gone through discussions of how we approach CPD exacerbations, what would you recommend in Karen? That, you know, she's on maintenance therapy, has had a recent exacerbation. Yeah, she's, to me, she is a person who should be on triple therapy. Yeah, I might want to look a little bit more to know more about her, but, you know, she has a clear-cut diagnosis. She has risk. She has severe airflow obstruction. She does have even her cardiovascular risk factors and ongoing dyspnea. She's on good maintenance therapy. So, I mean, that's an important part. She's on a Labalama already and using rescue inhalers a couple times a day. And that's even before she gets her acute exacerbation. So, yes, I'd like to know if she'd had more in the past or remotely or things like that. But honestly, if I was seeing Karen in my clinic today, not only would I make sure that I got her treated for her acute exacerbation, but in my case, I believe that I would clinically put her on a triple therapy unless there were other extenuating circumstances that say she couldn't tolerate an ICS. Would you look at her eosinophil count? Personally, I would. And the problems are, as you know, we don't have all that answers. And there is a little data with the eosinophils that if you're older, if you're a male, if you're thin, and your eosinophil count is less than 100, then you might choose an alternative. So, she's not quite in that category. But yeah, if I had an eosinophil count when she was stable away from exacerbations, and if it was, you know, 200, it would certainly support my notion of triple. If it was 50 on two or three times, then that's where I would have to pause. And that's where you might consider using alternatives, the azithromycins, or the riflumilaz type medications. Although I will again say honestly, I would probably, unless she had severe osteoporosis or something other, would still probably put her on a triple, irrespective of the eosinophil count as a start. Great. So, thank you, Gary. These are our take-home messages that we've talked today about exacerbations, including what things predict exacerbations. Of course, the most important factor being prior exacerbations. But there are also other factors that not only predict exacerbations, but also predict bad outcomes if a person does have an exacerbation. Certainly, I think the goal of all of our patients is to be sure they're on optimal therapy. And certainly to consider having patients who have that risk of exacerbations to be on inhaled steroid-containing therapy, triple therapy would be the appropriate. And of course, all patients should be treated with interventions such as smoking cessation if they are still smoking, vaccinations, and exercise or rehabilitation programs. And with that, if anybody has any questions, they can be submitted to webinar at chestnet.org. And with that, I'd like to thank Gary Ferguson for speaking at the webinar today. And this is David Menino. Again, thank you for your attendance and any questions, please submit them to webinar at chestnet.org. Thank you.

outpatient treatment

exacerbation

triggers

risk factors

treatment options

IMPACT trial