Time Stamps

  • 01:47 Evolving story of asthma management
  • 03:26 Pathophysiology of asthma management
  • 06:01 Key players & terms
  • 08:56 Story of asthma through the decades
  • 17:55 MANDALA Trial
  • 25:21 Recap

Show Notes

  • The Big Picture
    • Our understanding of the pathophysiology of asthma has evolved over time, and key trials have shaped our treatment strategies
      • The MANDALA trial answered the question: What is the right rescue drug for patients with moderate-to-severe asthma?
  • Key Terms
    • ICS (or IGS) = Inhaled corticosteroids or inhaled glucocorticoids
      • eg. budesonide, beclomethasone, mometasone
    • SABAs = Short-acting bronchodilators 
      • eg. albuterol, levalbuterol, terbutaline
    • LABAs = Long-acting bronchodilators
      •  eg. formoterol, salmeterol
    • “Rescue” medication 
      • Taken acutely during exacerbation
      • Relieves symptoms  
    • “Controller” or “Maintenance” medication: 
      • Taken daily
      • Controls symptoms
  • Asthma Physiology
    • What is asthma?
      • Chronic, inflammatory disorder of the airways leading to reversible airway obstruction 
        • Inflammation is both chronic and acute:
          • Chronic
            • Patients with asthma have an underlying degree of abnormal inflammation, even between exacerbations
          • Acute
            • Acute flares occur in the setting of over-exuberant immune response to a trigger, such as a virus or an environmental allergen
        • What causes the obstruction?  
          • Constriction of bronchial smooth muscle, airway edema, and mucus production
    • What treatments are available to help patients?
      • Bronchodilators → treat bronchoconstriction
      • Glucocorticoids → reduce inflammation
      • Many other classes of medications (including anticholinergics, leukotriene receptor antagonists, biologics, and more), not discussed in this episode!
  •  
    • What are the goals of asthma management?
      • Control symptoms
      • Reduce exacerbations
      • Minimize negative effects from medications used to achieve the first two goals 
  • Landmark trials over the years
    • BAGS Trial, 1996 – As-needed vs. scheduled albuterol (SABA)
      • Context: In the 1990s, most physicians were taught that albuterol should be used multiple times a day to control asthma 
        • “Like brushing your teeth”
      • Findings: For mild asthma, albuterol used only as needed as a rescue medicine was just as good for mild asthma control as using albuterol every day  
      • Implications: Albuterol shifted to as-needed usage for mild asthma
    • Several other trials in the next several years showed the efficacy of daily inhaled glucocorticoids for the management of asthma 
      1. Model shifted to include maintenance ICS + as-needed SABA for many asthma patients
    • STAY Trial, 2004 – Combining ICS and LABA in one inhaler
      • Context: Since inflammation is implicated in exacerbations, anti-inflammatory treatment may have a role as part of the rescue treatment during an exacerbation
      • Findings: Showed improved symptom control and lung function in patients with moderate to severe asthma by combining an inhaled glucocorticoid with a bronchodilator, when that combination inhaler was used for both daily maintenance as well as an as-needed rescue 
      • Implications: Brings attention to concept of SMART therapy (Single Maintenance and Reliever Therapy)
    • BEST Trial, 2007 – Do mild asthma patients need daily ICS?
      • Context: Inhaled glucocorticoids have side effects, so can patients with mild asthma get away with using less?
      • Findings: For patients with mild asthma, as needed (rescue) combined inhaled glucocorticoid and SABA (beclomethasone + albuterol) was as good as daily maintenance inhaled glucocorticoids plus an as needed SABA in terms of the outcome of peak expiratory flow 
        • The combined rescue inhaler group used less glucocorticoids overall
      • Implications: Maybe mild asthma patients didn’t need daily inhaled maintenance glucocorticoids – they could use ICS in their rescue medication with good results
    • PRACTICAL Trial, 2019 –  Rescue ICS-LABA is best for mild-moderate asthma
      • Context: This trial looked at ICS-LABA used just as a rescue medication, not as part of SMART therapy, to see if it was effective at preventing exacerbations. 
        • Compared ICS-LABA (budesonide-formoterol) as rescue to maintenance ICS (budesonide) with rescue SABA as needed in patients with mild-moderate asthma, in terms of the outcome of severe exacerbations per patient per year
      • Findings: Just using the combination med as rescue was better at preventing severe exacerbations
      • Implications: Reinforced that for mild-moderate asthma, ICS can be used as needed in combination with a bronchodilator to prevent exacerbations
    • NOVEL START Trial, 2019 – ICS does need to be in the rescue med, even for mild asthma patients
      • Context: Can we skip the ICS completely in mild asthma?
        • Compared budesonide-formoterol (Symbicort) as needed versus albuterol as-needed in patients with mild asthma
      • Findings: Symbicort as needed was better for preventing exacerbations in patients with mild asthma who weren’t on any daily inhaled glucocorticoids
      • Implications: Even patients with mild asthma need some ICS…it should be in the rescue med!
  • Corticosteroid Commentary
    • Even though inhaled glucocorticoids have fewer systemic effects than systemic glucocorticoids, they do not only act in the lungs…they are not “like water”!
      • Glucocorticoids also have many mechanisms of action, many of which are not well understood 
        • Many opportunities for adverse side effects
    • Any treatment plan that results in a lower exposure to glucocorticoids overall while not sacrificing symptom control and/or exacerbation prevention is desirable
  • MANDALA Trial, 2022
    • The Basics:
      • Study Design
        • Multinational 
        • Phase 3 
        • Double-blind 
        • Randomized 
        • Event-driven trial 
      • Question: Tested the efficacy and safety of rescue combination albuterol-budesonide versus rescue albuterol alone in patients with uncontrolled moderate-to-severe asthma who were already on daily maintenance therapy (various ICS doses)
    • Population
      • Sample Size: 3132 patients 
        1. Mean age of participants = 50 years old
          1. 97% of patients were over age 12
      • Eligibility Criteria: Moderate-to-severe asthma 
        1. Definition: At least one severe asthma exacerbation in the previous 12 months (e.g. exacerbation requiring systemic glucocorticoids or hospitalization) 
        2. Exclusion criteria
          1. COPD or other major lung disease 
          2. Systemic glucocorticoid use within the last 3 months  
          3. Use of biologic asthma treatments
    • Interventions
      • 3 rescue medication groups:
        • Albuterol alone
        • Low-dose budesonide + albuterol
        • Higher-dose budesonide + albuterol 
      • All groups were continued on their home daily inhaled glucocorticoid maintenance therapy
    • Endpoints
      • Primary Endpoint: Time to the first event of severe asthma exacerbation using a time-to-event analysis
      • Secondary Endpoints
        1. Annualized rate of severe asthma exacerbations 
        2. Total systemic glucocorticoid exposure  
        3. Symptoms/quality of life
    • Results
      • Primary Endpoints:
        • Risk of severe asthma exacerbation was 26% lower in the higher-dose combination inhaler group than in the albuterol-alone group, with a hazard ratio of 0.74 with a 95% confidence interval of 0.62 to 0.89
        • The hazard ratio for the low-dose combination group, compared to the albuterol-alone group, was also below 1: it was 0.84, but the p-value was 0.052,  not statistically significant
      • Secondary Endpoints:
        • Patients in the combination higher-dose budesonide-albuterol rescue group had fewer annualized exacerbations on average 
        • The patients using the combination budesonide-albuterol inhalers received less systemic glucocorticoids 
          • Participants in the higher-dose combination group used an average of 84 mg of prednisone equivalents per year, while those in the albuterol-alone group used an average of 130 mg per year. A similar finding was observed in the lower-dose budesonide group vs. the albuterol-only group 
        • Patients on the higher-dose combined rescue medication also reported better quality of life in terms of asthma symptoms
        • Adverse Events were similar across all groups!
  • GINA Guideline and FDA Changes
    • Since 2019, Global Initiative for Asthma (GINA) Guidelines have recommended ICS-LABA as first line rescue medication for all adult asthma patients. Keep in mind, the only LABA that is fast-acting enough to be used as a rescue (or used in SMART therapy) is formoterol, which is what is recommended in these guidelines 
      • For patients with moderate-severe asthma, SMART therapy is best
        • If patients don’t have a combination inhaler, they can use ICS and their SABA or LABA at the same time
        • Again, the SABA or LABA must be fast-acting if it is going to be used as a rescue medication 
    • Despite these recommendations, until 2023, albuterol was the only inhaled medication approved by the FDA for asthma rescue
      • In January, 2023, the FDA approved AirSupra (high-dose budesonide-albuterol) as a rescue medication for asthma in patients 18 and older 
        • Based on the results of the MANDALA trial!
    • Of note, other guidelines, like those from the National Asthma Education and Prevention Program (NAEPP), which were last updated in 2020, still recommended as needed SABAs for adults with very mild asthma, but recommended that moderate or severe asthma should be treated with a rescue medication that includes an ICS and a bronchodilator 
  • MANDALA as a call to action
    • Old habits die hard…both patients and providers are used to thinking of albuterol as their go-to asthma rescue medication
    • In addition, even though SMART therapy has been recommended for years, combined ICS-LABA inhalers like Symbicort (ICS-formoterol) are only FDA-approved for maintenance use, not rescue use, so prescribing them for SMART therapy is technically “off-label”! 
      • This causes headaches with insurance and prior authorizations
        • For example, patients often can only receive one inhaler that is a 30 day supply/month, so if they use extra puffs as rescue doses, they will run out early…
    • But despite these barriers, we can do better for our patients and optimize their inhaler regimens!
  • Key Takeaways
    • Rescue inhalers for adult patients with asthma should include an inhaled glucocorticoid (combined with a fast-acting SABA or LABA)
      • Unless the patient is extremely well-controlled
    • For patients with separate ICS and fast-acting SABA or LABA inhalers, you can counsel them to take both at the same time during exacerbations!
    • To ensure medications are reaching the lungs, check and review how patients are using their inhalers and spacers, and make sure patients have an Asthma Action Plan
    1.  

Transcript

Dr. Greg Katz: Welcome to the fifth installment of Beyond Journal Club, a collaboration between Core IM and NEJM Group. 

Dr. Shreya Trivedi: The goal of Beyond Journal Club is to take landmark clinical trials and put them into context, telling the story of how we got to where we are and what it means for how we take care of patients. I’m Dr. Shreya Trivedi, an internist at BIDMC.

Dr. Greg Katz: And I’m Dr. Greg Katz, a cardiologist at NYU

Dr. Julie Barzilay: Hi, I’m Dr. Julie Barzilay! I’m a general pediatrician at Boston Children’s Hospital, as well as an Editorial Fellow at the New England Journal of Medicine. Today, we are talking about asthma, specifically the MANDALA trial, published in the June, 2, 2022 issue of the New England Journal of Medicine. 

Dr. Greg Katz: I’m so glad we are talking about asthma because when a disease is this common, it means we understand it pretty well. But I was surprised when we dug into the background research for this podcast, I learned that a lot of the traditional teaching that I was taught and a lot of my peers still reference about asthma is just either wrong or simply incomplete.

Dr. Julie Barzilay: Yeah and asthma is a disease I care about a lot, not just because I’m a pediatrician, but because asthma disproportionately impacts racial and ethnic minority groups, those from lower socioeconomic groups, and those living in areas with more pollution.

Dr. Shreya Trivedi: Yeah, this is such an important illness for so many reasons. 

Dr. Greg Katz: So the big picture question that MANDALA asked is – what is the right rescue drug in asthma? But to understand why that’s a question we’re asking, we need to first go through the history of how we think about the pathophysiology of asthma.

Dr. Shreya Trivedi: And with that grounding in pathophysiology, we’re going to discuss a few landmark trials that changed the way that we treated asthma before the MANDALA trial. And this was a little different for mild asthma versus moderate to severe asthma.

Dr. Julie Barzilay: Right! And finally, we’re going to take a deep dive into the MANDALA trial as the next step forward in how we manage asthma patients.

Evolving story of asthma management

Dr. Julie Barzilay: So I had the chance to sit down with Dr. Jeff Drazen, the former Editor in Chief of NEJM and a leader in pulmonary medicine, and I asked him about how asthma management has changed over the decades. I was shocked to learn that in the 1990s, most physicians were taught that albuterol should be used daily – actually, multiple times a day, to help control asthma. 

Dr. Jeff Drazen: So when I saw an asthma patient in 1988, I said to them, you need to take your beta inhaler four times a day. Think about it like brushing your teeth. You do that twice, three times a day because you know it’s the right thing to do.

Dr. Julie Barzilay: But that paradigm shifted from “brushing your teeth” with albuterol three times a day to using it ONLY as a rescue medicine and that shift started after the BAGS trial  in 1996.

Dr. Shreya Trivedi: Yes, BAGS, which stood for “Beta AGonist in mild asthma Study,” and was led by Dr. Drazen himself, showed that albuterol used only as needed as a rescue medicine was just as good as albuterol every single day for mild asthma symptoms.  

Dr. Greg Katz: And so it was in the 1990s that we started to conceptualize albuterol, a short acting beta agonist, as a rescue medication rather than a daily medication. What was the next big development in asthma management?

Dr. Julie Barzilay: The next big step was the understanding of asthma as a disease that benefits from using daily maintenance inhaled glucocorticoid dosing on top of the as needed rescue inhaled beta agonist therapy. 

Dr. Shreya Trivedi: And there is a good pathophysiological backing for the importance of  inhaled glucocorticoids in asthma. It is worth a bit of a detour as to WHY before we jump back to the evolving story of asthma mgmt.

Pathophysiology of asthma management

Dr. Shreya Trivedi: If we actually think back to what we were taught about in med school some time, broad strokes of the pathophysiology of asthma is that it’s a chronic inflammatory disorder of the airways leading to some degree of airway obstruction. And that airway obstruction is not just from constriction of bronchial smooth muscle, but also from airway edema and mucus production.

Dr. Julie Barzilay: Yeah! The way I think about asthma is almost as an over-exuberant immune response within the lungs that is happening in response to various triggers, like a virus or an environmental allergen. Over time, the lungs will even start to remodel in the setting of all this inflammation.

Dr. Greg Katz: Right! That is so important to point out that the lungs in asthma patients are thought to have some level of inflammation at baseline, even between exacerbations. 

Dr. Shreya Trivedi: So this pathophysiology gets really interesting when we juxtapose it to what we see in clinical practice. We see tons of patients with asthma only have albuterol as needed. So they’re not getting any medication directed at inflammation.

Dr. Julie Barzilay: Right, because if we said inflammation is a huge part of this disease process, then how can we just treat an acute flare-up with a temporary relief measure like albuterol that wears off after a few hours? 

Dr. Shreya Trivedi: Right, that albuterol, is just a bronchodilator, it dilates the bronchioles. Yes, of course it makes patients feel better in the moment, but it’s not really getting to the core of what’s going on, inflammation.

Dr. Julie Barzilay: Exactly. And this brings us to why glucocorticoids, which reduce inflammation, are such an important part of the treatment of asthma. 

Dr. Greg Katz: So having a medication that acts in the moment and another one that treats the underlying pathophysiological process fits with totally well my mental model of how we manage other chronic diseases. We don’t treat chronic angina just by giving anti-anginals, we also treat the underlying heart disease by treating the hyperlipidemia and hypertension.

Dr. Shreya Trivedi: Yeah, that’s a great analogy, Greg! So ideally in asthma we’d deliver an inhaled glucocorticoid directly to the lungs at the time of an exacerbation, right?

Dr. Greg Katz: Yeah! Right, so that way they can get some anti-inflammatory benefit before the patient gets so sick they need to come in for systemic glucocorticoids. 

Dr. Julie Barzilay: Yeah, so that all makes sense to us today, but in the early 2000’s this was not so clear. 

Dr. Shreya Trivedi: Yep, so let me summarize: in the 1980s to early 1990s, the teaching was that you treat an asthma flare with a short acting bronchodilator, but there’s a problem with that approach: it doesn’t match our understanding of the pathophysiology of asthma, because it doesn’t target the underlying chronic inflammatory component.

Dr. Greg Katz: Exactly! And that’s why the next couple of decades were spent figuring out: what is the best combination of maintenance inhalers and rescue inhalers for asthma 

Key players & terms

Dr. Julie Barzilay: Before we dive back into the story of outpatient asthma management over the decades, and why the MANDALA trial matters, let’s define three key players in the management of asthma: inhaled glucocorticoids, SABAs, and LABAs. These may be familiar terms for you, but honestly, in making this podcast, we sometimes felt like we were speaking in tongue-twisters, so we just want to make sure we start out all on the same page.

Dr. Shreya Trivedi: Yes, yes! Let’s go through these key players. First, we have inhaled glucocorticoids, also known as inhaled corticosteroids, often abbreviated “ICS”: these are meds that end -one, so beclomethasone, fluticasone, mometasone, or ones that end with -ide like budesonide. I have a fun way to remember this. When we think of glucocorticoids, they really own asthma management, they really “own” asthma management so you’re going to have meds that end in -one like beclomethasone, fluticasone, mometasone. And then you have meds like budesonide that just “come along for the ride.” And end with -ide. I don’t know if that sticks better, but I like it!

Dr. Greg Katz: I’ve heard worse.

Dr. Shreya Trivedi: I thought you’d like it!

Dr. Greg Katz: I can live with it. And then the other two are bronchodilators that open up the airways. These are either short acting bronchodilators aka “SABAs,” and long-acting bronchodilators or “LABAs.” 

Dr. Shreya Trivedi: For the purposes of our discussion today, in terms of keeping the SABAs and LABAs straight, anytime you hear one ending with an -ol that’s not albuterol or levalbuterol, we are talking about a long-acting beta-agonist aka LABA, so examples of LABAs are formoterol or salmeterol. 

Dr. Julie Barzilay: Right, and just to say, of course there are many other types of asthma meds, including some exciting new biologics, that we are not talking about today, but are an important part of asthma care.

Dr. Shreya Trivedi: Just a couple more terms we are gonna throw around today- when we say “rescue” inhaler, we’re talking a medication that a patient takes acutely in the moment of an exacerbation, to relieve symptoms. That’s as opposed to a “controller” or “maintenance” medicine they’re meant to take daily to control symptoms. It can be a mouthful, but we’ll do our best it straight. 

Dr. Julie Barzilay: And we haven’t even mentioned any brand names yet, which is what our patients and nursing colleagues refer to these meds as! You know,  Symbicort, Pulmicort, Atrovent, Asmanex, Qvar…the list goes on and on. 

Dr. Shreya Trivedi: So many!

Dr. Greg Katz: And you didn’t even mention the way I think about inhalers – the red one the orange one and the blue one. So if it’s this hard and complicated for clinicians who do this everyday to keep these medications and labels straight, it must be hard for patients, too. Maybe asthma medications just need a bit of a marketing intern to come in and help out with meds.

Dr. Shreya Trivedi: Amen! And listeners, we spent hours and hours trying to think of how to best present the story of the trials and keep these different meds, regimens, and endpoints straight. We really tried our best! And don’t worry if of it goes over your head, we will keep recapping the high level points for you!

Story of Asthma through the decades

Dr. Greg Katz: They way I see it, the story of asthma management over the decades has been trying to figure out the best way to do three things: 1) control symptoms, 2) reduce the risk of exacerbations, and 3) minimize negative side effects from medications to do the first two. 

Dr. Shreya Trivedi: And, and in doing so, that required a lot of trials testing different versions of outpatient daily maintenance inhalers and as well as rescue inhalers.

Dr. Greg Katz: So Julie, what was the next big leap after the BAGS trial showing that albuterol as a rescue, and not around the clock was enough to treat asthma in some mild cases. What was the next big leap in asthma management after the BAGS trial? 

Dr. Julie Barzilay: Yeah! There were a bunch of RCTs over the next couple of decades looking at different SABAS and LABAs along with inhaled glucocorticoids. And it’s hard to compare these studies directly because they studied different patient populations and had different endpoints, but I think the overall message was that inhaled glucocorticoids help treat asthma – and the amount and frequency required depended on the severity of disease.

Dr. Shreya Trivedi: Yeah! So we are going to try to summarize for you 4 trials from the last two decades: STAY, BEST, PRACTICAL, and NOVEL START. Obviously, this is not the whole story, but we think this will help set the stage to talk about MANDALA.

Dr. Greg Katz: Let’s start with the The STAY trial from 2004. This is a trial that showed that combining an inhaled glucocorticoid with a bronchodilator and using that combination inhaler for both daily maintenance as well as an as-needed rescue improved symptom control and lung function in patients with moderate to severe asthma. 

Dr. Shreya Trivedi: Okay so this, along with other trials, is where the SMART or MART therapy comes from. SMART stands for Single Maintenance and Reliever Therapy, which basically means using daily inhaled glucocorticoid and a LABA TOGETHER in single inhaler, and then that same inhaled glucocorticoid and LABA inhaler used on top of that as needed as rescue medicine. 

Dr. Greg Katz: And just to keep things clear, formoterol is the only current LABA that can work in SMART therapy since formoterol acts faster than the other LABAs, and it can be used multiple times per day. It’s considered a win-win LABA since it has both a rapid onset and prolonged duration of bronchodilation. 

Dr. Julie Barzilay: Right. But then people started to wonder, maybe not everyone needs to take a daily maintenance inhaled glucocorticoid at all? Like what about patients with mild asthma?

Dr. Shreya Trivedi: And just to say, what is mild asthma? Of course different studies define had defined it differently. But I think overall one way to think of mild asthma is by the “rule of 2s” – mild asthma should not have day symptoms more than twice a week, or night symptoms more than twice a month, or need systemic glucocorticoids more than twice a year.

Dr. Greg Katz: I think that’s such a good way to summarize inclusion criteria for a half a dozen trials. So the next trial we’re going to look at is the BEST Trial in 2007. This trial looked at patients with mild asthma, and it found that as needed, rescue combined inhaled glucocorticoid and SABA (this combination was beclomethasone + albuterol) was as good as daily maintenance inhaled glucocorticoids (specifically beclomethasone) plus an as needed albuterol inhaler. And the outcome they studied in  BEST was peak expiratory flow. 

Dr. Julie Barzilay: This idea of using inhaled glucocorticoids only as needed was reinforced again in 2019 with the PRACTICAL trial, which looked at patients with mild-moderate asthma. 

Dr. Shreya Trivedi: Yeah, so in PRACTICAL, one group got budesonide and formoterol, which we know as Symbicort, to use just as a rescue medication. Another group got maintenance budesonide, which we know as Pulmicort, and then on top of that a rescue short acting beta- agonist as needed.

Dr. Julie Barzilay: That’s right! And they found that using the combination med – budesonide-formoterol together –  just as needed was better at preventing severe exacerbations, even though that other group was using an inhaled glucocorticoid every day.

Dr. Greg Katz: Wow! And so arguably the most important takeaway from the BEST and PRACTICAL trials is that we could get away with giving less inhaled glucocorticoids overall to these patients with mild asthma. We can just give these inhaled glucocorticoids as part of their rescue therapy – at least for the outcomes we looked at in these trials.

Dr. Shreya Trivedi: Yep, so it sounds like mild asthma patients didn’t need daily maintenance inhaled glucocorticoids. 

Dr. Julie Barzilay: Right! And I love to hear that, because minimizing the side effects of medications like glucocorticoids is one of the major goals that we have for asthma treatment. Dr. Drazen had a really good story that reminded us that while inhaled glucocorticoids are less harmful than systemic glucocorticoids, they don’t just act in the lungs.

Dr. Jeff Drazen: I distinctly remember, I had an older patient, I started on inhaled glucocorticoids, and she says to me, ‘Doctor, this is the best medicine ever. It makes my asthma better and it’s good for my arthritis.’ Now, I knew what was happening, the steroids we’re getting in there and helping her arthritis. So we know that there are systemic effects of inhaled glucocorticoids. They’re not like water. They do have side effects. And if you can get away with less, you’re better off!

Dr. Shreya Trivedi: So we certainly had evidence to support that we can get away with less inhaled glucocorticoids from the BEST and PRACTICAL trials, but I’m so curious now, can we get away with no glucocorticoids in mild asthma? 

Dr. Greg Katz: That’s where the Novel START trial came in. Novel START is a trial from 2019 that compared budesonide-formoterol (aka Symbicort) as needed versus albuterol as-needed, and found that Symbicort was better for preventing exacerbations in patients with mild asthma who weren’t on any daily inhaled glucocorticoids. 

Dr. Julie Barzilay: Yeah! So honestly the Novel START trial showed us we can’t really get away with no inhaled glucocorticoids in patients with mild asthma. Inhaled glucocorticoids should be in the rescue medication at least. 

Dr. Shreya Trivedi: Oh man, this just makes me feel for clinicians and researchers who have to juggle the multiple end points of managing asthma. It’s a balancing act between what combinations are best for daily symptom control, preventing exacerbations, and reducing excess harms from the glucocorticoids. 

Dr. Julie Barzilay: Exactly. Okay, so if you guys have made it this far through the tongue-twisters of asthma medication names and trial acronyms, the worst of the alphabet soup is over! Let’s move to how guidelines started to change after some of these trials.

Dr. Greg Katz: So a lot of the most important guidelines in asthma come from the GINA initiative, or Global Initiative for Asthma. 

Dr. Shreya Trivedi: So it was in their 2019 guidelines that albuterol was no longer recommended as a first line for rescue in adults.

Dr. Greg Katz: Rather, we are supposed to be using rescue treatment that combines both a bronchodilator and an inhaled glucocorticoid.

Dr. Julie Barzilay: That’s right. This is so important so I’ll say it again – the 2019 guidelines essentially recommend for adults with all types of asthma, the first line rescue medication should be an inhaled glucocorticoid combined with a LABA (for example, budesonide-formoterol  together- which is called Symbicort – or mometasone-formoterol together which is called Dulera). 

Dr. Greg Katz: And for patients with moderate or severe asthma, the guidelines say to use the same combination of inhaled glucocorticoids and bronchodilator as their daily maintenance therapy as well as their rescue medication. 

Dr. Shreya Trivedi: So in moderate to severe asthma, we can’t get away with just a combination rescue medication only. We still need a daily maintenance combination of inhaled glucocorticoids and LABA on top of the combo rescue med. 

Dr. Greg Katz: That’s exactly right, and I want to point out, these guidelines change five years ago and so one of the questions I’m asking now is, is that what clinicians are really doing? 

Dr. Shreya Trivedi: You know, Greg, I think there still a huge practice gap. I know for me before working on this episode, I remember having a patient in the hospital using his albuterol as needed. And I was being like shh don’t tell anyone. I don’t want to bother the nurses. And pulling it out from his fanny pack. And I didn’t even bat an eye that he was using rescue albuterol and it was completely outdated in asthma management. 

Dr. Greg Katz: Bat an eye at the rescue albuterol or the fanny pack?

Dr. Shreya Trivedi: Haha, neither one! I’m a non-judgmental doctor. But bad when it’s outdated management,

Dr. Julie Barzilay: Well, give yourself some grace, Shreya, because it’s not always easy to make these changes happen in real life! One very real barrier is that, combination ICS/LABAs like Symbicort and Dulera, are only FDA-approved for use as maintenance therapies in the US, NOT rescue medications. 

Dr. Shreya Trivedi: Wait, what?! Really? Despite the guidelines having combination med as maintenance and rescue as SMART therapy, it sounds like clinicians technically using that combined inhaler as a rescue “off-label”!? That is infuriating!!

Dr. Julie Barzilay: I know! Until last year, the only inhaled medication approved for asthma rescue treatment was albuterol. So when a provider tries to prescribe, let’s say, Symbicort for both maintenance and reliever as per the guidelines, insurance companies will say, hmm, no, that’s not approved as a rescue inhaler, which can mean extremely high co-pays and insurance headaches for everyone involved. But since the MANDALA trial, a new combination rescue inhaler has come onto the scene.                         

MANDALA Trial

Dr. Julie Barzilay: The 2022 MANDALA Trial looked at patients with moderate to severe asthma who were already on daily maintenance inhaled glucocorticoids and tested two different rescue medications for them. They compared a combined inhaled glucocorticoid and SABA (so budesonide plus albuterol together in one rescue inhaler) vs. just rescue albuterol alone.

Dr. Greg Katz: One of the reasons this study was very important was that it was the first to ask which rescue inhaler is better in a population of sicker patients with moderate to severe asthma. 

Dr. Julie Barzilay: Yeah and it was also the first to study this specific combination inhaler of an inhaled glucocorticoid plus albuterol. Remember, the other ones looked at a combo of inhaled glucocorticoid and LABAs.

Dr. Shreya Trivedi: You know, when I first heard this, I was confused about why the authors chose albuterol, a short acting bronchodilator, to mix with budesonide rather than LABA like formoterol? I mean, didn’t the GINA guidelines in 2019 recommended combined inhalers containing formoterol? Why not just study the LABAs?

Dr. Julie Barzilay: I had the same thought, Shreya. I actually sat down with the first author of the MANDALA study, Dr. Alberto Papi, Head of Respiratory Medicine at the University of Ferrara and head of their research center on asthma and COPD, to ask him that exact question.   

Dr. Shreya Trivedi: Oh, yeah what did he say?

Dr. Julie Barzilay: The guidelines didn’t recommend combined inhaled glucocorticoid-albuterol inhalers not because they felt it wouldn’t work – but because it hadn’t been studied yet. Basically, guidelines recommend things we have RCT evidence for, and what we had evidence for was inhaled glucocorticoids plus formoterol, so all of the guidelines recommended that. Even though albuterol is the most widely used rescue medication worldwide.

Dr. Greg Katz: So in other words, the absence of evidence is not evidence of absence.

Dr. Shreya Trivedi: Right, and this got me thinking about the previous studies we just mentioned, right? I’m so curious. How much of that benefit we were seeing was from inhaled glucocorticoids decreasing airway inflammation, and who is to say that a combination inhaled glucocorticoid with short-acting albuterol won’t work also? 

Dr. Julie Barzilay:  Yeah, exactly. Dr. Papi also mentioned that he felt an albuterol-containing rescue inhaler would be more easily adopted by patients.

Dr. Shreya Trivedi: Right, at the time of his trial, the only approved class of rescue medication for asthma in the United States was albuterol. So patients and clinicians are pretty used to using it for that purpose.  

Dr. Greg Katz: And understanding the patient perspective – in addition to just the researcher perspective – helps bring context to a trial just like this. Let’s get into what MANDALA evaluated. This was a multinational, Phase 3, double-blind, randomized, event-driven trial to evaluate the efficacy and safety of rescue combination albuterol-budesonide versus rescue albuterol alone. They studied patients with uncontrolled moderate-to-severe asthma who were already on good daily maintenance therapy.

Dr. Shreya Trivedi: And for our med-peds friends listening, did the MANDALA trial include children?

Dr. Julie Barzilay: Great question – it did, but not very many. The trial included patients aged four and up, but 97% of the patients ended up being over age 12. The mean age was 50 years old. So the trial doesn’t tell us too much about pediatric patients – unfortunately! Definitely an area for future research.

Dr. Shreya Trivedi: So then we mentioned this was the first trial to really ask these specific questions in the moderate to severe asthma population. Which then begs, how did they define moderate to severe asthma?

Dr. Julie Barzilay: So patients needed to have had at least one severe asthma exacerbation in the previous 12 months – basically anything requiring systemic glucocorticoids or hospitalization. 

Dr. Shreya Trivedi: Got it, so then, who did they exclude?

Dr. Julie Barzilay: They excluded patients who had COPD or other major lung disease, patients who had used systemic glucocorticoids within the last three months, and patients who had recently used biologic asthma treatments.

Dr. Greg Katz: And then they took the adult participants who had a severe asthma exacerbation in the past year and divided them into three groups. One group used albuterol only as a rescue inhaler, another group used a rescue combination of albuterol and lower-dose budesonide. And the last group used a rescue that combined albuterol with higher-dose budesonide. 

Dr. Julie Barzilay: And remember, all the patients were already on some form of inhaled glucocorticoid daily as a maintenance medicine, since they had moderate to severe asthma, and they continued these throughout the trial.

Dr. Shreya Trivedi:Yep. So then it looks there were about 3100 patients, they underwent randomization, and the primary endpoint was the time to the first event of severe asthma exacerbation, using a time-to-event analysis. 

Dr. Greg Katz: Julie, do you want to do the honors of telling us what the MANDALA study found?

Dr. Julie Barzilay: Yes, definitely. The study found that the risk of severe asthma exacerbation was significantly lower, 26% lower to be exact, in the higher-dose combination rescue inhaler group than in the albuterol-alone group. The hazard ratio was 0.74, and the result was statistically significant.

Dr. Greg Katz: Just to be on the same page, hazard ratios basically compare the risk of an outcome happening in one group compared to the other, and if the hazard ratio is below 1, it usually means the treatment group has less “hazard” of reaching the outcome first – which in this case, means a lower risk of a severe asthma exacerbation. 

Dr. Shreya Trivedi: Nice! So the risk of severe asthma exacerbation was significantly lower with as-needed use of higher-dose budesonide combined with albuterol compared to as-needed albuterol alone. What about the lower-dose budesonide group with albuterol?

Dr. Julie Barzilay: So actually, the hazard ratio for the lower-dose combination group, compared to the albuterol-alone group, was also below 1 – it was 0.84, but the p-value was 0.052, so technically that result was not statistically significant.

Dr. Shreya Trivedi: Okay, interesting! What about our secondary endpoints? I know one of them was looking at annualized rate of severe asthma exacerbations.

Dr. Julie Barzilay: Yeah. The patients in the combination higher-dose budesonide-albuterol rescue group had a lot fewer exacerbations on average than the albuterol rescue alone group. 

Dr. Shreya Trivedi: Nice, okay. So now on to the secondary endpoint that I think I’m most interested in, especially after all that discussion we had with Dr. Drazen – so about how much total systemic glucocorticoid exposure did each group have? 

Dr. Julie Barzilay: Yeah, Shreya, I was really interested in this question, too. The patients using the combination budesonide-albuterol inhalers ended up getting exposed to less systemic glucocortidoids overall. Participants in the higher-dose combination group used an average of 84 mg of prednisone equivalents per year, while those in the albuterol-alone group used an average of 130 mg per year.

Dr. Shreya Trivedi: Ah! So it sounds like if we use a combined inhaled glucocorticoid-bronchodilator, like budesonide-albuterol, as a rescue instead of just albuterol in these patients with moderate to severe asthma, we can not only prevent more exacerbations, but also sparing them the equivalent of something like 50 milligrams of prednisone per year? Awesome!

Dr. Julie Barzilay: Yeah, exactly. And a similar finding was observed in the lower-dose budesonide group vs. the albuterol-only group. In terms of the glucocorticoid exposure alone. 

Dr. Shreya Trivedi: Nice, nice!

Dr. Julie Barzilay: On top of that, patients on the higher-dose combined rescue medication also reported better scores on various scales that measure quality of life with asthma, which was another secondary endpoint. Plus, adverse events were similar across all groups.

Dr. Greg Katz: So I’m hearing fewer exacerbations, feeling better day to day, less glucocorticoid exposure overall, and no increase in adverse events? This sounds like a pretty decent amount of wins across this population

Dr. Shreya Trivedi: Yea, I agree!

Recap

Dr. Shreya Trivedi: So let’s step back, and maybe we can recap the journey of what we knew about asthma management and how the results of the MANDALA trial really add to the conversation?

Dr. Julie Barzilay: So we already knew that for adults patients with mild asthma, the first-line rescue medicine should be a combined inhaled glucocorticoid with a LABA, and all the data we had basically looked at inhaled glucocorticoids combined with formoterol, so that’s what was recommended as a rescue. Ironically that is still an off-label use of that medication. 

Dr. Shreya Trivedi: Pains my soul. Anyway, and then in the moderate-severe asthma group, we knew that the budesonide-formoterol or other similar combo inhaler with ICS and LABA were effective when they’re both a maintenance medicine, as well as, a rescue medicine. 

Dr. Greg Katz: And so MANDALA gave us new option for a combination rescue inhaler (this time using a SABA) that really had never been tried before. This combination of albuterol-budesonide seems to work really well for adults on who continued on their various daily inhaled glucocorticoid controller medications.

Dr. Julie Barzilay: Right, and because of the MANDALA trial the FDA approved a new high dose budesonide-albuterol rescue inhaler in January 2023, which is for patients 18 years or older. If you’re looking for it in your patient’s charts, the brand name is AirSupra.

Dr. Greg Katz: One thing I found really exciting about these results was something I observed about the Kaplan-Meier curves in the MANDALA trial. 

Dr. Shreya Trivedi: Oh, man! It wouldn’t be a Beyond Journal Club if Greg doesn’t being up the Kaplan-Meier curves! 

Dr. Greg Katz: My favorite curve and what I see at night before I go to sleep!

Dr. Shreya Trivedi: I wonder that sometimes, Greg! But yeah, lay it on us.

Dr. Greg Katz: The Kaplan Meier in this study is very interesting because it shows the biggest change in the trajectory up front. And so what that says to me is when you find these patients who are vulnerable with uncontrolled moderate-to-severe asthma, getting them on the right medications sooner has an upfront benefit in preventing exacerbations in this group of patients.   

Dr. Julie Barzilay: Right and just to hammer home the point about pathophysiology, this does make sense. When patients have asthma symptoms, they do better when they get an inhaled glucocorticoid as well as a bronchodilator in their rescue inhaler, because the glucocorticoid can reduce underlying inflammation while the bronchodilator provides relief in the moment. 

Dr. Shreya Trivedi: So this all sounds great. I’m kind of sold. And I’m wondering should we stop prescribing albuterol rescue inhalers completely in our adult patients?

Dr. Julie Barzilay: That’s a great question. The answer is – probably honestly yes – but of course, in medicine it’s never a one size fits all answer. 

Dr. Greg Katz: So, I think if you’re taking the literature seriously, it definitely means that albuterol inhalers don’t really have much of a place. But in talking to pulmonologists in preparation for this episode, I think it’s worth noting that there’s a big difference between a patient who is well controlled on maintenance therapy and uses as needed albuterol once or twice a year compared to the patient who needs their albuterol all the time and doesn’t leave home without it – that’s the patient who should be switching. For the patient who is well controlled, I’m really not sure we need to convince that well controlled patient to spend money on a new inhaler or to adjust the routine they’ve gotten used to.

Dr. Shreya Trivedi: Yes, especially because some patients have limited access to certain medications based on insurance, geography, or personal preference. So much. 

Dr. Julie Barzilay: That’s so true – but even if our patients can’t get the combination rescue inhaler for one reason or another, we can still optimize our patient’s care just by changing how we counsel them. If a patient has two inhalers – an inhaled glucocorticoid and a SABA. the clinicians can tell them to take both of their inhalers together when they feel sick  That kind of simulates the combined inhaler effect.  

Dr. Jeff Drazen: Dump your albuterol inhaler or your short-acting beta agonist for an inhaler that has both. And if you can’t get both, carry with your albuterol inhaler, an inhaled glucocorticoid of your choice; and when you use one, use the other. Don’t leave home without them. You’ll be better off.

Dr. Shreya Trivedi: Yep, that is the new message! 

Dr. Greg Katz: That workaround – using both inhalers at the same time – is exactly what the GINA guidelines actually recommend.

Dr. Shreya Trivedi: It’s wild to me that the guidelines have explicit recommendations on workarounds of insurance madness— I hope people listening from other countries have much fewer barriers than we do in America.

Dr. Julie Barzilay: I sincerely hope so, too! 

Dr. Jeff Drazen: So now we have to change the behavior of almost all the doctors in the world. Because most doctors have been educated, up until 2015, were taught that when someone has a little breathing problem, you give them albuterol alone.

Dr. Shreya Trivedi: You know, this makes me so glad were spending time doing this episode, and making a small but hopefully mighty dent towards that goal. We should be using a trial like MANDALA as a call to action, right? Any of us prescribing albuterol without understanding the disease is not doing right by our patients.

Dr. Greg Katz: So, Shreya, I so admire you for the idealistic take on MANDALA which is to use it as a call to action that we need to do better by our patients. The cynical take here is that anyone who’s been paying attention to the asthma literature for the past couple of decades, knows that combined therapy in the setting of the need for a rescue inahler is better than just albuterol alone. And AstraZeneca was able to capitalize on this hole in the FDA approval process to make a lot of money by getting AirSupra approved and, you know, it’s probably a combination of the two and the cynical read isn’t entirely the correct one. But I wouldn’t be able to sit on my hands and be quiet and point out there is a cynical view of a trial like this too. 

Dr. Shreya Trivedi: You know, I appreciate that realism. And sure, that is probably very much the story! But I very much agree with you. We have known this for decades. Right? Wasn’t it 2004 with that SMART trial that we learned about maintenance and combination and it’s been 20 plus years now. So it makes me really sad. Maybe as a society we have accepted that patients with asthma will not feel great from time to time, and even patients and clinicians are like ‘oh well at least they’re getting some relief from the bronchodilators they have.’ But it’s clearly not enough.

Dr. Julie Barzilay: Yeah, but I don’t think we should settle for just “some relief” for our patients. We have evidence now we can prevent exacerbations and get patients to feel better day to day if their rescue inhaler has an inhaled glucocorticoid in it. 

Dr. Shreya Trivedi: And since it’s a rescue med, we are basically using the patient’s symptoms to guide how much glucocorticoid therapy they need. And, hopefully, in that process use less systemic glucocorticoids! Which I think a lot of people can get behind.

Dr. Julie Barzilay:Really quick, I feel the need as a pediatrician to quickly remind everyone that before you decide a patient’s asthma is poorly controlled, just make sure they are using their inhalers and spacers correctly – none of these medications will do any good if they don’t reach the lungs!

Dr. Shreya Trivedi: Oh so true! I actually learned this from Pearl 3 in COPD episode that the most important thing we can do is to observe, and if needed, correct how our patients and its different for each inhaler delivery system. I also learned from that episode that pharmacists are actually very trained in this and can help us out. So I love that we can also use our inter-professional colleagues in this mission.

Dr. Julie Barzilay: Yeah! That’s exciting. Another thing I’m excited about is the graphics that Dr Jimin Hwang did for this episode. 

Dr. Shreya Trivedi: Yeah, I think visuals are so important and I’m certainly gonna be pulling this up in my counseling conversations to show the difference in, hey this is your lungs when you’re using a bronchodilators versus a here’s what your lungs look like when using combination inhaled glucocorticoid and a bronchodilator. I think we just really need all hands on deck when with trying change this practice gap we have. And I welcome listeners to write in and let us know what tips they have to have clinicians and patients be using these evidence-based inhalers? 

Dr. Julie Barzilay: Yeah! And please also write in to tell us how you keep all these meds and brand names straight…do you have better mnemonics than us?!

Dr. Greg Katz: I sincerely hope you do! And so there you have it. This has been the fifth edition of Beyond Journal Club with NEJM Group. 

Dr. Julie Barzilay: And that is a wrap for today!. If you found this episode helpful, please share with your team and colleagues and give it a rating on Apple podcasts or whatever podcast app you use! It really does help people find us! 

Dr. Shreya Trivedi: Thank you to Dr. Yichi Zhang for audio editing. If you have any feedback, please email us at hello@coreimpodcast.com. Opinions expressed are our own and do not represent the opinions of any affiliated institutions. Thank you!

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