Dr Courtney Crim Outlines Creating Personalized Treatment Regimens for COPD

Choosing the right regimen for patients with chronic obstructive pulmonary disease (COPD) requires considering the individual’s symptoms, said Courtney Crim, MD, COPD360 medical director for the COPD Foundation.

Physicians may take 1 of 2 approaches during treatment: (1) either starting the patient on a long-acting or dual bronchodilator and stepping them up to a triple therapy, if needed, or (2) “hit them hard” with a triple therapy and stepping them down when their symptoms are under control.

In this interview with The American Journal of Managed Care® (AJMC®), Crim also discusses the study designs and outcomes of the ETHOS, IMPACT, and KRONOS trials, and the need for the next generation of therapies that can truly affect the underlying pathobiology of COPD.

AJMC®: With many available treatment options for COPD, where do you start? What are the 2022 Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommendations for COPD management?

Crim: Every year, the GOLD Scientific Committee reviews recently published research on COPD management and prevention in order to update the GOLD strategy document, and it has emphasized splitting between assessing the severity of lung function versus things such as symptoms and exacerbations that impact the patient. GOLD’s treatment strategy takes patient impact into consideration. Whereas, in the past, the treatment paradigm considered both the severity of airflow limitation, as well as the symptom burden from the standpoint of just exacerbations. They have split that off such that—although you still can assess the severity of airflow limitation based on what they call the stages—the treatment paradigm is based on their symptom burden. That takes into consideration patients’ level of shortness of breath or impact on their quality of life, assessed either by the modified Medical Research Council (mMRC) scale on assessing dyspnea or the CAT [COPD Assessment Test] score, and then, their level of exacerbations in the previous year.

For patients who have few symptoms, few impacts on their quality of life, and no or very minimal exacerbations, the treatment paradigm is that you would start with a bronchodilator. For example, if a person has minimal impact in terms of shortness of breath and has not had any exacerbations, you can just use a simple short-acting bronchodilator. This choice can be independent of the severity of airflow limitation. On the other hand, if they have significant symptoms or a significant impact on their quality of life, as assessed either by the mMRC or the CAT score, then they are suggesting that you use a long-acting bronchodilator. This could either be a LABA, a long-acting beta-agonist, or a long-acting muscarinic antagonist [LAMA].

For those who have more exacerbations, then you use a higher level of therapy. Again, we're talking about initial therapy. If you're starting a patient on therapy, and the person has 2 or more moderate exacerbations, that is exacerbations that can be treated as an outpatient with systemic corticosteroids or an antibiotic, versus a severe exacerbation, which means the person's being hospitalized, that will determine the next level of treatment.

If a person has fewer symptoms [based on mMRC or CAT scores], but they've had 2 or more moderate exacerbations or 1 severe exacerbation, the GOLD strategy document suggests that you use a long-acting muscarinic antagonist because the data has suggested that is a better treatment in that patient population than a long-acting beta-agonist. But on the other hand, if a person has significant symptoms or impact on their quality of life and has 2 or more moderate exacerbations or a severe exacerbation, then the recommendation is that you use either a LAMA, a dual bronchodilator of LAMA and LABA, or you could even consider using an ICS-LABA, that is an inhaled corticosteroid (ICS) and long-acting beta-agonist.

GOLD indicates one can take it into consideration the person's blood eosinophil level, and that is because the data has suggested that for patients who have relatively high eosinophils—and the document cites various cut points, for example, either over 300 or between 100 and 300—having an inhaled corticosteroid regimen appears to have better efficacy than a non–steroid-containing regimen.

Whereas for those who have low eosinophils, there is no treatment advantage with using an inhaled corticosteroid compared with a non–steroid-containing regimen. Conversely, for patients who have severe airflow limitation, the risk of pneumonia is greater with an ICS-containing regimen. We're talking about 2% for a non-steroid regimen versus 4% for steroid-containing regimen.This means that the physicians should take into consideration how concerned they are about that difference of 2%, and then have a conversation with the patient.

So, that's what the GOLD strategy document says as it relates to initial therapy.

What I do is consider the patient. I use that to an extent to [determine] whether the person has more of a problem with dyspnea or whether the person has more of a problem with exacerbations. Also, to what extent the dyspnea is impacting their quality of life. That's how I choose therapy.

I recognize that as a pulmonologist, by the time the patient presents to me or gets referred to me, they're symptomatic. So rarely do I ever start a person on a short-acting bronchodilator. That is something that I can see a primary care physician doing, but as a specialist, by the time they get to me, they have a significant impact on their quality of life or they're having exacerbations.

That's the process of initial therapy. Afterwards, you assess the patient to see to what extent they're receiving benefits. If they're adequately controlled and they're happy with their treatment regimen, you can leave them there. But if they're not, then the GOLD document has ways or things to consider for stepping up the therapy.

If exacerbations are a big issue, that's when you would consider a regimen such as triple therapy. Or, if they're on a single bronchodilator, and they're having more problems with dyspnea, then that's when you consider stepping them up from a single bronchodilator to a dual bronchodilator. That's how GOLD has updated the strategy document.

AJMC®: What are some considerations for a personalized COPD treatment regimen? Are patients' preferences evaluated? If so, when is a dual or triple therapy inhaler considered over another form of treatment for a patient?

Crim: There are 2 approaches that clinicians can take. One: You would consider a dual bronchodilator over an ICS-LABA regimen if the patient has more symptoms of shortness of breath, dyspnea, or things of that particular nature. This is because 2 bronchodilators are better than 1.

If, on the other hand, dyspnea is not a big issue, and they have exacerbations—maybe some moderate exacerbations—and particularly if they have an eosinophil count, let's say, greater than 100, then you may prefer using an ICS-LABA over a dual bronchodilator because dyspnea is not that big of an issue.

However, if exacerbations and shortness of breath is a big issue with the patient, then you would consider using a triple regimen because now you have the dual bronchodilators.

Now, some physicians will take the approach of stepping up; that is to say, starting on either a long-acting or dual [bronchodilator], and then stepping them up to triple, and that's what the guidelines would suggest you do. But in practice, one may consider for the person who presents to the physician with significant dyspnea and frequent exacerbations going straight to triple therapy and then potentially, if you get them controlled, stepping down in that regard.

The rationale behind that is, patients come to you because they are symptomatic, and if you give them treatment, and they don't get any benefit, then they may not be inclined to come back. So, it's sort of like using the asthma paradigm, where you hit them hard and get them under control and then step back down.

The GOLD strategy document suggests starting off an initial regimen and then stepping up, and then if you get control, then you can consider stepping them down. In practice, recognizing the patient you may have in front of you, a physician may consider hitting them hard and then stepping them back down.

AJMC®: What is the study design and patient population involved, as well as the outcomes, of the phase 3 ETHOS trial in COPD as it assesses the triple therapy of budesonide, glycopyrrolate, and formoterol fumarate?

Crim: I'll cover the ETHOS trial and the IMPACT trial together, because basically, the designs were somewhat similar although there was one important difference between the 2. The ETHOS trialassessed triple therapy—in this case, the ICS was budesonide, the LAMA was glycopyrrolate, and the long-acting beta agonist was formoterol.

The investigators compared triple therapy to the 2 duals of either the LABA-LAMA or the ICS-LABA. IMPACT also investigated triple therapy of the ICS—in this case, fluticasone furoate—with the LAMA being umeclidinium, and the LABA being vilanterol, and then the 2 duals, either being the LABA-LAMA or the ICS-LABA. They were both yearlong studies, looking at exacerbations as the primary endpoint.

The difference was that during the run-in phase of the ETHOS study patients had stopped their inhaled medications, unless they were taking an inhaled corticosteroid, prior to the randomization phase. That is, they were allowed to continue the inhaled corticosteroid.

They were given a short-acting [muscarinic agonist], like ipratropium, and allowed to take a short-acting beta-agonist for the run-in period. After the end of the run-in period, they were randomized to each of those therapies: the triple or the 2 duals. In the IMPACT trial on the other hand, patients were allowed to stay on whatever regimen they were taking beforehand during the run-in period, which could have included an open triple, so to speak, or dual bronchodilators.

Then at the time of randomization, they were immediately switched to either of those 3 regimens: the triple or the 2 duals. So, the difference was that the IMPACT trial had a run-in period on prior baseline therapy, whereas ETHOS didn't. The rationale behind this difference in the IMPACT trial is that when physicians see patients in the clinic, they are on some therapy. Clinicians don't put patients through a run-in period; they immediately switch them to something else. So, therefore, the IMPACT trial was more akin to what one would see in a real-life clinical setting.

Both studies demonstrated that the triple therapy, in terms of reducing exacerbations, was significantly greater, compared with the non–ICS-containing regimen. Both studies also demonstrated that for the moderate exacerbations, the triple therapy was also better than the ICS-LABA combination. Interestingly, the treatment difference was greater between the triple and the dual bronchodilators. For example, in the ETHOS trial, the exacerbation rate was 24% lower with the high dose of the triple, compared with the dual. But somewhere in the ballpark of 13%, with the triple versus the ICS-LABA.

Similar results were seen in IMPACT. The treatment difference between the triple and the ICS-LABA was less than the difference between the triple therapy and the LABA-LAMA, suggesting that the ICS was having a significant impact in those patients.

Likewise, these studies demonstrated that the treatment difference between the triple therapy and the LABA-LAMA was less in those patients who had lower eosinophils, compared with those that had higher eosinophils. In other words, there was no treatment advantage in patients who had lower eosinophil with the triple therapy compared with those who received the dual bronchodilator.

What it basically says is, for patients who have a history of exacerbations—and both IMPACT and ETHOS required patients to have a history of exacerbations—that triple therapy reduces exacerbations to a greater extent than either a dual bronchodilator or an ICS-LABA. This is good because it gives you a way to go for patients who are not being adequately controlled on either an ICS-LABA or a LABA-LAMA. Now, that was ETHOS. I just wanted to make that comparison with the IMPACT trial, because they basically showed the same type of results. They just used different ICSs, different LABAs, and different LAMAs. But they basically showed the same thing, in terms of the greater efficacy with the triple compared with the dual.

AJMC®: Could you please discuss the study design and the patient population included in the outcomes of the KRONOS study, and what are the practical implications of the data derived from this study?

Crim: The KRONOS study was different in that that was a 24-week study, as opposed to a yearlong study, and the primary efficacy with the KRONOS study was lung function. What the KRONOS study demonstrated is that patients who were receiving a dual bronchodilator had a greater improvement in lung function, as measured by FEV₁ [forced expiratory volume in the first second], compared with the patient who did not receive a dual bronchodilator. What they did in terms of a secondary analysis, was to look at exacerbations over that 6-month period. Even though in the KRONOS study patients were not required to have an exacerbation history in the prior 12 months, the investigators still looked at exacerbations. What they demonstrated in that study was that patients still received an exacerbation benefit over the 6 months in the KRONOS study.

So, it supports the ETHOS study, because in the KRONOS study, it was the same ICS, the same LABA, and the same LAMA, as in the ETHOS study, although KRONOS was a 6 month trial. So, the ETHOS trial expanded upon the KRONOS study. But then looking back in the KRONOS study in a post-hoc fashion, that is, looking at exacerbations in those who did not have an exacerbation history prior to coming into the study, as well as those who did, it demonstrated an exacerbation benefit. So, it just supplemented the ETHOS study in that context.

AJMC®: Out of all 3 of these studies, were there any major safety concerns that came about or any limitations?

Crim: The major safety issue with all of these studies, which we have recognized for some time now, is that patients with COPD are at greater risk of developing pneumonia than people who don't have a history of COPD. And we also know that in patients with COPD who receive an inhaled corticosteroid, they are at even greater risk of developing pneumonia. This difference is approximately 2% if they're not receiving a steroid versus 4% if they are receiving a steroid. These studies basically demonstrated the same thing: the patients who were randomized to an ICS-containing regimen had a greater incidence of pneumonia than those who did not. This difference was in the ballpark of 2% or 3%.

Other than that, although we recognize that inhaled corticosteroids have the potential for having other adverse effects, such as on the bone or, in terms of a person who has diabetes, potentially making their blood sugar worse, really, that was not a major issue. The biggest safety issue that was observed in all these studies was pneumonia risk in patients who received an ICS-containing regimen. But again, it was something that's been recognized. The difference is in the ballpark of 2% or 3%. Therefore, what it basically means from a clinical standpoint is the physician and the patient have to make a decision when they're initiating therapy, or even stepping up therapy, to what extent that difference of pneumonia riskis important.

In terms of making a decision as it relates to use an ICS-containing regimen or not: If the physician and the patient don't think that that 2% difference is important to them, then they'll take that information in terms of making that decision whether to go with an ICS or not.

One thing we have noticed is that the risk of pneumonia is a function of the severity of airflow limitation. The more severe your airflow limitation is—an FEV₁ less than 50%—that risk is clearly evident. On the other hand, if you look at patients who have moderate airflow limitation—an FEV₁ greater than 50%—then you don't see an increased risk of pneumonia with a steroid-containing regimen versus a non–steroid-containing regimen. These are the types of things that physicians and patients need to take into consideration. But the big safety issue with all these studies is the pneumonia risk in the ICS-containing regimens, because all these studies, for the most part, took patients who had severe airflow limitations.

AJMC®: Real-world evidence suggests that inhaled corticosteroids have been prescribed to patients with COPD with varying degrees of severity and exacerbation risk. In your opinion, is it better to initiate aggressive treatment early, or escalate therapy based on the exacerbations and worsening symptoms?

Crim: Personally, I prefer the aggressive approach to alleviate the patient’s symptoms. If it works, then the patient will be happy. If I put them on a dual regimen, have them come back in 2 or 3 months, and they return and tell me they're not feeling any better, I would need to step them up and give them another 2- or 3-month trial. That approach would likely take up to 6 months to see what benefitthe patient will get, with an inhaled regimen. Some patients may be happy with that; whereas, other patients may not because they've gone 3-plus months of not being adequately controlled.

So, personally, what I do is, if the person has a significant exacerbation history and they’re symptomatic in terms of dyspnea, I will give them a triple regimen. Because if that doesn't work, then I have to start thinking about non-pharmacological things, with that particular patient. Whereas, if it does work, then I can consider stepping back to see what the minimal number of medications I can use to keep them as controlled as possible. Based on the patient, that's the approach that I take. But I recognize that some physicians, because they're concerned about the potential adverse event profile, and because all medications have side effects, some physicians may want to start with either a single or dual bronchodilator, again, depending upon where the patient is, and then step them up. Clearly, if a person doesn't have exacerbations and that's not a big issue, and shortness of breath is their issue, then I'll start with a dual bronchodilator and then consider stepping back to a single long-acting bronchodilator.

So that's how I do it. I'll hit them hard, based on where the symptoms are, and step back. But I recognize that some physicians will start small and step up, and it’s just a preference.

AJMC®: In your opinion, do you believe that initiating aggressive treatment early would reduce the amount of health care resources utilized in COPD, like hospitalizations, emergency department (ED) visits, exacerbations?

Crim: I think it has potential. The biggest cost for payers is when a patient ends up in a hospital or an ED, because that significantly consumes resources compared with the cost of the medication.

And then the differential cost between a dual versus a triple is far less than an ED visit or a hospitalization. I'm certain that patients would prefer not ending up in a hospital or an ED. So, therefore, if I can achieve that by being aggressive—and aggressive doesn't necessarily mean triple therapy at the beginning for everybody—but if I can achieve that by being aggressive early and therefore minimize these extraneous health care visits and then step down, then I think patients would appreciate that. I also think payers would appreciate that if I can keep the person out of the ED or the hospital.

That's why I think that could potentially be an advantage of being aggressive early and stepping back, as opposed to starting small and stepping up. That's why I take that approach.

AJMC®: With your background in trials, what trials would you like to see conducted for improving treatments for patients with COPD and with the hopes of reducing that health care resource utilization?

Crim: I think we have gone as far as we can with inhaled bronchodilators. So, I think what’s next is to develop medications that can truly affect the underlying pathobiology of COPD, whether it's from mucus plugging, or whether it's from airway inflammation. I think coming up with therapies that will address those things would be phenomenal. Ideally, if there were treatments, and whether down the road we are talking about stem cell treatments that can help rejuvenate or regrow the damaged lung tissue, that would truly be a game changer. But I believe we're maxed out in terms of bronchodilators, in that regard. I think anti-inflammatory therapies that will affect mucus will be treatments that I think would be a big step forward, as it relates to where we need to go in the future.

We also have treatments, for example, lung volume reduction surgery, and valves that can be placed into patients' airways, particularly those who have significant bullous emphysema that give some patients significant relief. But clearly, those are more costly types of procedures, compared with some types of pharmacotherapies.

In the context of treatments that will decrease health care resource utilization, one would have to weigh more invasive procedures, like valves and lung volume reduction surgery, with the associated cost; the long-term cost associated with repeated exacerbations, hospitalization, and things of that nature. I don't think we have good data yet to say to what extent these invasive procedures will mitigate the long-term costs associated with hospitalizations, etc.

AJMC®: Moving forward, what other focuses do you see for COPD management?

Crim: I think rehabilitation is important for patients. Unfortunately, the reimbursement is not universal in that regard or even the availability of rehabilitation programs. To the extent that we can expand upon that and have payers more willing to support that in terms of reimbursement, more rehab programs can be created. Clearly, that's not an issue with cardiac rehabilitation for patients who have bypass surgery. That's sort of like a given, and it's accepted. But I don't think it's to the same extent as it is with COPD, that is, in terms of the rehab programs. Basically, what rehab programs do, is allow patients to become more functional with the degree of limitation that they currently have. Patients appreciate that and patients benefit from that. So, I think to the extent that we can expand upon these types of rehab programs would be very important. I think that's the theme that I could see in the short term, because anything else is definitely going to be a long-term solution down the road.