Gerry Lee, MD (Host): [00:00:00] Asthma exacerbations continue to affect over 40% of patients each year, which not only disrupts their quality of life, but can lead to permanent loss of lung function. The goal of this podcast miniseries, Shifting the Asthma Rescue Paradigm, is to review why an anti-inflammatory reliever has become the standard of care in asthma management, and also to provide tips on how to implement this therapy in your practice.

Well, hello everyone. My name is Gerry Lee. I'm an Associate Professor at Emory University, and the host of this third part of a three-part series entitled, Shifting the Rescue Paradigm: A Call to Action, from the American College of Allergy, Asthma, and Immunology.

In this episode, we will discuss maintenance and reliever therapy in moderate to severe asthma patients. And I'm excited today to be joined [00:01:00] by two experts in the field. Our first expert is Dr. Alan Baptist. He is a professor and Division Head of Allergy and clinical Immunology at Henry Ford Health in Detroit, Michigan, and holds a joint appointment at the University of Michigan School of Public Health in Ann Arbor, Michigan. He previously served on the NHLBI 2020 Asthma Guidelines Update Committee, and his research interests include asthma in older adults, asthma healthcare disparities, and the implementation of asthma guidelines. Dr. Baptist has authored or co-authored over 80 peer-reviewed articles that have been published in journals such as the Journal of Allergy and Clinical Immunology and Annals of Allergy, Asthma, and Immunology. Alan, thank you so much for coming back to the podcast.

Alan P. Baptist, MD: Thanks, Gerry. Happy to be back.

Host: And our next expert is Dr. Leonard Bacharier. He is the Janie Robertson and John Moore Lead Chair in Pediatrics at Vanderbilt University Medical Center. He is a Professor of [00:02:00] Pediatrics and Allergy Immunology Pulmonary Medicine. And he is also the Scientific Director of the Center for Clinical and Translational Research at Vanderbilt.

Dr. Bacharier's career has been focused on clinical research to help understand and improve the care of children with asthma, and his clinical translational research efforts are directed at the pathogenesis of asthma in early life, and approaches to asthma management throughout childhood, including multi-center, federally-funded clinical trials in asthma. Len, thank you. Welcome back to the podcast.

Leonard B. Bacharier, MD: Thanks, Gerry. Looking forward to our discussion.

Host: We got one more episode to go. And we're focusing on the maintenance or reliever therapy. And the last time we were talking about the anti-inflammatory reliever therapy. So, Alan, could you make that distinction again, just to remind the audience between AIR and MART?

Alan P. Baptist, MD: Yeah, Gerry, happy to. And Mart, while there are some differences, really, fundamentally, they're both very [00:03:00] similar. And here's the theory underlying both of them. The theory is that when you treat an asthma exacerbation, yes, you need a bronchodilator effect, but you also need to take care of the inflammation that occurs in asthma. The anti-inflammatory medication is in the form of an inhaled corticosteroid. So, if we look at MART or maintenance and reliever therapy, you typically use one inhaler. One inhaler is used for the daily use, that's the maintenance, and it's the same inhaler that you use for reliever therapy. So, this is done when you combine an inhaled corticosteroid with formoterol. And formoterol, it's a LABA with a unique property that it's onset of action is as quick as albuterol. That's unlike most other LABAs, which is why, really, formoterol right now is the only one that we can use for MART therapy.

If you contrast that with AIR therapy or anti-inflammatory reliever therapy, here typically the maintenance [00:04:00] inhaler and the rescue inhaler are different. So for example, you might have a patient who uses an inhaled corticosteroid daily. They use it every day as their maintenance therapy. But then, when they have symptoms, they use a reliever. And in AIR therapy, you combine that reliever, the rescue medication, which is typically albuterol with an inhaled corticosteroid. So, AIR therapy uses a bronchodilator and an inhaled corticosteroid at the same time. We used to have to use two inhalers to do that and now this type of therapy is available in a single inhaler for adults ages 18 and above.

And finally, in mild asthma patients, they may not need a daily medication. And in such a case, what are the options? Well, the options include using albuterol alone for a rescue therapy or this new paradigm-shifting approach of an anti-inflammatory reliever therapy. And so, kind of as we discussed before, the AIR therapy options could include an [00:05:00] ICS combined with either formoterol or albuterol.

Host: So, as we focus on maintenance and reliever therapy, again, like last episode, let's just focus on a patient and see how we would implement this in this particular case. So, I'm going to present to you a 44-year-old. She's an executive. She had an exacerbation during business trip, and so she couldn't complete her work there. She's previously been on a fluticasone metered-dose inhaler, which she takes most days, she's rather busy, but despite this, she does often use just a SABA rescue inhaler like albuterol, maybe about four days a week. She might have nighttime awakenings about once a week. And when you do the breathing test today, on spirometry, she does have mild reversible obstruction. So, Len, for this patient, what is the recommended management according to our current asthma guidelines?

Leonard B. Bacharier, MD: So, based on her [00:06:00] symptom frequency, her need for rescue multiple times a week, her nocturnal symptoms, she is not meeting the goals of asthma care and has uncontrolled asthma based on this. This is in the context of her receiving daily low-dose inhaled corticosteroid therapy, and thus the stepwise paradigm of all major guidelines indicate that she needs a higher step of care.

In this situation, both our GINA guidelines and the NAEPP guidelines are consistent with one another in that both recommend the initiation of the maintenance and reliever therapy approach with ICS/formoterol at this juncture. And that's really because this strategy has clearly and definitively been demonstrated to reduce her risk of severe exacerbations going forward and is more likely to do this than an increase in her dose of inhaled [00:07:00] corticosteroids.

Host: So, Alan, could you go over the evidence that Len was referring to? How did these studies lead to the change in the asthma guidelines and the adoption of MART?

Alan P. Baptist, MD: Yeah, Gerry. Happy to kind of briefly go over some of the evidence there. So, for patients, especially with those with moderate and getting into severe asthma, the evidence is actually very strong that MART improves outcomes. And if we go back and look at the NHLBI guidelines, the NAEPP recommendations and guidelines, they use something called GRADE methodology. And I'm not going to get into all the specifics of GRADE methodology, but know that they involve epidemiologists, biostatisticians, they have evidence-based medicine experts, and they were trying to look at all the evidence that was there, and they were trying to answer the question. And the question was, is MART therapy better, or is it better if a patient's on an ICS/LABAto use that, keep it where it is, and use albuterol as a rescue? So, that was the question they were trying to [00:08:00] answer.

So, they did thismeta-analysis. And in it, they had five very well-designed trials, approximately 8,500 patients in this meta-analysis. And what they found is that using MART therapy, it decreased exacerbations by 25-30% compared to using an ICS/LABA with albuterol as the rescue therapy. And so, in the entire NHLBI guidelines, this is one of the very few strong recommendations with moderate to high certainty of evidence that this works, meaning this really is what we should be doing for our moderate to severe asthma patients. MART works.

Now, sometimes the argument comes up that, look, this is in a randomized double-blinded, placebo-controlled trial, studies are very highly regulated, they're highly controlled. Does this work in the real world? And actually, in 2022, a meta-analysis of real world, more pragmatic trials came out, again trying [00:09:00] to answer this exact question. Which is better, MART therapy or ICS/LABA with albuterol as the rescue? And in this, they had 11,000 patients and they found a whopping 50% reduction in exacerbation. And so, both in trials and in real-world evidence, this seems to work.

Host: So, there's just overwhelming evidence for MART. We have two asthma guidelines that recommend MART, that agree with each other. But Len, I think we're noticing that even MART therapy, despite this body of evidence, is not being implemented in the community. What do you perceive are the barriers to the implementation and why we have not seen this broad uptake given the body of evidence?

Leonard B. Bacharier, MD: So, this is a real challenge and a real concern for how we deliver care. It requires a paradigm shift in how clinicians think and how we teach and train our [00:10:00] patients. It is a very different strategy than every asthmatic has learned since their day of diagnosis. When their very first asthma medication is uniformly albuterol, they've become confident and reliant on that albuterol inhaler to provide relief when their asthma is bothering them. And to help patients understand and use a different strategy can be sometimes quite challenging. So, part of it is educational for both our healthcare providers as well as our patients.

We are further challenged by the fact that the FDA label does not include the MART approach in the indication formoterol-containing inhaled corticosteroid combination products. And both of them clearly state that these products should not be used for the treatment of bronchospasm. So, folks who read those large white documents that come [00:11:00] with their inhalers, see a statement that seems counter to our recommendations.

Now, the FDA has never actually evaluated the MART approach as an indication. So, it has not been denied by the FDA. It has never actually been prospectively evaluated. However, as we've discussed, the literature in this area is extremely robust, including in children, and the safety records for MART therapy are extremely strong. This is further evidenced by the fact that there are 120 countries around the world where the MART approach is an agency-sanctioned strategy. It was really this overwhelming evidence base, combined with the worldwide experience, that clearly drove both GINA and NAEPP to recommend MART as a preferred strategy in steps 3 and 4, despite being a [00:12:00] bit counter to what the FDA label indicates.

Host: I do think that recognizing the burden of evidence and also the global shift toward MART really should be with the standard of care for the rest of the world. And I think another thing that I'd love for you to talk about, Alan, is just the other options that patients are already receiving for asthma care, because some of them are receiving inhaled steroids paired with salmeterol. Some are receiving inhaled steroids paired with ultra long beta agonists like vilanterol. So, what would be the recommendations for those patients or those medicines? Do those medications have a use in step 3 or 4 asthma? Should we be shifting everyone to ICS/formoterol? What's your thoughts on this?

Alan P. Baptist, MD: Yeah. This is a really important point, Gerry. And I think it kind of gets into the whole difficulties with implementation, a little bit of what Len is touching on as well. So, as you mentioned, look, you can [00:13:00] only do MART therapy if you use ICS with formoterol. Now, could you use it with vilanterol? No, you can't because vilanterol won't work as a rescue. So, when might I use something like an ICS with vilanterol or an ICS with some other LABA?

Well, one area is if there is implementation challenges. And what I mean by that is let's say someone's insurance doesn't cover an adequate number of inhalers to make MART possible. Remember, with MART therapy, you're using the same inhaler as your maintenance inhaler, but then also as your rescue. And if you're kind of using quite a bit of rescue, you're going to burn through your inhaler and one inhaler won't cover it for a month.

What can be done to help with that? Well, listen, there's a new program by the manufacturers of inhalers that are typically used in MART. And what it does is it actually caps the copay at $35 a month for each inhaler. And so, you know, I do want to say kudos to the manufacturers for doing this. It will absolutely help some patients, but [00:14:00] $35 a month can be too much for many patients, and especially if they need multiple inhalers or they have other medical conditions or other bills to pay. So, I do think this helps. I do think it is beneficial to get around pharmacy benefits managers or PBMs at these insurance companies, and I think all of us who practice medicine know that the PBMs really can make things difficult for us to take the best care for our patients.

Where's another reason I might consider not using MART? Well, that's for the patients who find benefit from an anticholinergic medication such as tiotropium. Tiotropium can be combined with an inhaled corticosteroid and LABA, either in one inhaler or in two inhalers. So, what does the data show really about using triple therapy, if you will, as well as MART? Well, there's no studies of that. There are no studies to date of an ICS/LABA/LAMA accommodation and then also using ICS/formoterol as rescue. So, theoretically, if you had someone in [00:15:00] an ICS/formoterol plus a LAMA and then they also use their ICS/formoterol as a rescue, so that would be, you know, they had two inhalers that they were using for maintenance and then the ICS/formoterol at rescue. Would it work? Theoretically. It should work, but it's important to note that there are no real studies that show this. So, one place that, again, I might not use MART therapy is there are certain patients who respond better to tiotropium than others. That would be one place. And if I had a patient who could obtain perhaps one inhaler that had an ICS/LABA/LAMA combination and they were having very good control and adherence, because adherence in the real world plays a role into how we take care of patients, then that may be one place that I might not use MART.

Host: You know, it's just remarkable what you're talking about barriers such as cost. You know, we're talking, as you're saying, even the challenges of, you know, an extra inhaler of a couple hundred dollars and coverage barriers for that. When you think about [00:16:00] the cost of a single exacerbation and an ED visit and so on, it just makes you want to just think about how can we be persuasive to think about real cost savings to the health care system when we know something that works very well.

And I think we're going to continue to have those conversations. So just like the previous episode, we've been focusing on 12 to above, but I think we should be talking about younger children as well. So for the school age children, or even the toddler age child, does MART have a place for those age groups, Len?

Leonard B. Bacharier, MD: The evidence for MART in younger children is clearly more limited for a variety of reasons. The data that we have to date, what we have, are consistent with those seen in older patients. Both GINA and NAEPP have recommended this strategy for steps 3 and 4 care in children as young as five to six years of age. However, we [00:17:00] clearly need more prospective trials in the school age and preschool age groups to sort this out. And fortunately, there are several of these occurring around the world. So, my hope is that within the next couple of years, we will have a more substantive evidence base for preschool and school age children to further clarify the role of this approach in those age groups.

Host: So, that's definitely something to look forward to. And again, there's just so much more we need to learn about this new approach. So, I do want to appreciate both you, Len and Alan, for talking about this review of this new standard of care for asthma management. But, you know, Len is alluding to unanswered questions, I'd like to have both of you just talk about what do you think are the unanswered questions regarding this new rescue paradigm. Alan, we'll start with you.

Alan P. Baptist, MD: Yeah, Len brought up some great points about there is certainly a lack of data [00:18:00] around different questions of how medications can be helpful in asthma, but I think there's also plenty of non-medication questions that we haven't answered in asthma. For example, we know that comorbidities and the adverse environment significantly can impact asthma control, significantly can worsen asthma outcomes. It can be difficult to address these, whether it's because of resources, whether it's because of time, so what's the best way to efficiently address things like comorbidities and the adverse environment?

Something else that talked about in this podcast and some of the earlier ones, there are very good recommendations. from both the NHLBI and from GINA. But many primary care physicians and many even asthma specialists don't know about these recommendations or what the new guidelines are. And so, how do we disseminate, how do we implement this knowledge in a timely fashion?

And finally, you know, there are plenty of medication questions around [00:19:00] asthma that still aren't answered. For example, virtually all the biologic studies that have been done to date were on patients who were not on MART therapy. That was often an exclusion. So now, you wonder how much of an additional improvement in exacerbations are seen in patients on MART therapy, because that's what we're doing for our patients now. We really don't have a good sense of how effective biologic therapy is in such patients.

Host: Yeah, there seems to be this strong desire then to convince yourself the patient does not respond to MART therapy before committing them to biologic therapy. Len, do you have any other additional questions that interest you?

Leonard B. Bacharier, MD: I think Alan brings up many really essential points that we need, further clarity on over time. I think a couple others that we want to better understand is what really is mild asthma. How mild is mild? I think in many ways we've migrated away from the [00:20:00] distinction between intermittent and persistent asthma and are now starting to call that entire entity mild disease.

When is there enough disease that it's no longer mild? That you need more than AIR therapy, that you need some form of maintenance. I think these distinctions in the past have been relatively arbitrary, and I think we could stand a more evidence-based approach to better understand the gradations of asthma severity.

And I think the other one, in part because of my pediatric background, is really understanding are there long term consequences of the AIR approach? We've for long thought that daily ICS was the gold standard. Many studies examined its effect on lung function and lung growth and didn't find a tremendous disease-altering or disease-modifying effect. We're now migrating to a strategy where even less inhaled [00:21:00] corticosteroid is going to be used. We have moved more to an exacerbation-focused outcome than a lung function-focused outcome, because that's really what patients, especially with milder disease, are more interested in.

But I think we need to be cognizant and aware of an unintended set of consequences that could occur. Now, these are theoretical. I don't believe these are reasons to not adopt and embrace these strategies, because I think they are well-supported by very well-conducted research, but I think we all need to remain on the lookout for both the positive effects and any potential negatives that may come from these newer strategies that we are adopting.

Host: Len, Alan, wonderful thoughts. I'm so interested in the answers to those interesting questions. And at the end of this podcast, I encourage you to go to the website [00:22:00] to access some of the resources we'll provide to you to learn more about this. That website is college.acaai.org. This is the last episode of our three-part series, Shifting the Rescue Paradigm, from the ACAAI. Thank you so much for listening. My name is Gerry Lee. I appreciate your time. Have a wonderful day.