Narrator - Dr. Abel 00:00 Welcome to HelixTalk, an educational podcast for healthcare students and providers, covering real life clinical pearls, professional pharmacy topics and drug therapy discussions. Narrator - ? 00:11 This podcast is provided by pharmacists and faculty members at Rosalind Franklin University, College of Pharmacy. Narrator - Dr. Abel 00:17 This podcast contains general information for educational purposes only. This is not professional advice, and should not be used in lieu of obtaining advice from a qualified health care provider. Narrator - ? 00:27 And now on to the show. Speaker 1 00:31 Welcome to HelixTalk episode 104 I'm your co host, Dr Speaker 2 00:34 Kane, and I'm Dr. Patel. And in today's episode, we are discussing what's the latest and the greatest and the greatest from the Global Initiative for asthma, 2019 guidelines. The title of our talk today is breathtaking updates from Gina 2019 Speaker 1 00:52 and just as a teaser for our audience, we'll get to it later, but one of the biggest changes in the Gina guidelines is actually challenging the role of albuterol as a rescue inhaler. So if you want to know more about that, stay tuned. We'll get there. But this is pretty groundbreaking recommendation from the Gina 2019 guidelines. Speaker 2 01:10 Yeah, so we will in depth talk about it. We have the references for the updated Gina guideline as well as not so updated 2007 and naepp guidelines too, which we practice in the United States. And then couple of primary literature that is associated with that change of albuterol (SABA) as the rescue inhaler. So you will find those links on our podcast as well. Speaker 1 01:36 Cool. Well, just to kind of you know, set the stage, if you will. So in terms of what is asthma, asthma is really characterized by three different characteristics, airflow obstruction, hyper responsiveness and inflammation. And those three characteristics are basically what make up the pathophysiology of asthma. Speaker 2 01:53 And we are looking at inflammation. We have a lot of different cells working in this pathophysiology. We had got the mast cell, the eosinophils, the lymphocytes, macrophages, neutrophages and epithelial cells too. And all of this results into you will hear patients complain of symptoms such as wheezing, chest tightness, breathlessness and cough, more so at night, but it could be early in the morning or during daytime as well. Speaker 1 02:21 And you know, if you globally look at the drug therapy that we use in asthma, it can be separated as controller medications that keep you from having asthma symptoms and then rescue medications that are used when you actively have symptoms of shortness of breath or wheezing. So controller medications, examples could be inhaled corticosteroids or ICSs. We have leukotriene receptor antagonists — the most common one is montelukast (Singulair). We have long-acting beta agonists that in asthma are always combined with an inhaled corticosteroid. An example of an inhaled corticosteroid–LABA combination could be fluticasone–salmeterol (Advair), and there's a number of others on the market. And then finally, we also have kind of a newer kit on the block for chronic asthma management, which is a long-acting muscarinic antagonist like tiotropium, which typically, historically, had been reserved for more COPD patients, but now in these more severe asthma patients may be used as a controller medication to prevent asthma symptoms from occurring. Speaker 2 03:21 And then summarizing the controller, flipping the switch to the reliever side, those will be the agents when patients have acute symptoms, they will be using to get some relief. Historically, SABA (short‑acting beta‑agonist) such as albuterol was used widely and recommended. We still recommend SABA for children <11 years, but the GINA 2019 update advises patients ≥12 years move away from SABA reliever and use ICS–formoterol PRN. Speaker 1 03:59 And we'll talk a lot more about this later on in the episode, but this is absolutely groundbreaking, if you think about it. For decades, albuterol was what we used as a reliever inhaler or rescue inhaler, and now the current guidelines are saying that is no longer the case in this 12 or older patient population. More on that to come. Absolutely. Speaker 2 04:17 I want to kind of briefly cover what guidelines are generally utilized by clinicians for the treatment of asthma. So if you're looking at the United States, we have the naepp, which is the expert panel report three guidelines. It's this Napp, basically part of the National Heart Lung and Blood Institute, stands for National Asthma education program. Just as the audience knows, this was last updated in 2007 so pretty. Yeah, it's like 12 years too old, as we, you know, speak right now. And so if you kind of summarize what the NA PP recommendations are during all the steps there are recommending stab up. PRN as the rescue inhaler. Stage one, patients obviously are very mild asthma. They're not going to need a controller, but they can have this Saba PRN. Stage two, they could have Saba PRN, but then add low dose, you know, inhale corticosteroids. Stage Three, patients move on from low‑dose ICS and add a LABA (long‑acting beta‑agonist), or use medium‑dose ICS alone (preferred in some young children). Speaker 1 05:34 then kind of rinsing and repeating as you move forward from that: stage four—medium‑dose ICS plus a LABA; stage five—high‑dose ICS plus a LABA; stage six—high‑dose ICS+LABA plus systemic corticosteroids. There's plenty of other like biologics that are in there, other kind of alternative therapies that are in there. So clearly, we're kind of summarizing what is a 400 plus page document into something that takes about two minutes to talk about, but this is kind of setting the groundwork for what is a typical regimen. Earlier, more patients start on low‑dose ICS alone; as severity increases you add moderate doses and/or LABAs. At the advanced steps you escalate to higher‑dose ICS with a LABA. Speaker 2 06:22 and add one of those, you know, biologics or systemic corticosteroids, right? We're not here to compare the NAEP and Gina directly, but we do want to move on to the Gina, which is the focus of this podcast, right? So these guidelines are updated every year by a specific committee of Gina, which is their scientific committee. They meet to review literature twice a year, in conjunction with the American Thoracic Society and the European Respiratory Society. This frequent review is why the guidance is so up‑to‑date and widely used. The most recent version (2019) is comprehensive and covers non‑pharmacologic measures, exercise‑induced bronchoconstriction, acute exacerbation management, and asthma‑related comorbidities. Speaker 1 07:17 I'm going to be honest. Dr. Patel, you know, when I used to teach asthma. I really held on to those Napp guidelines because they were the US guidelines, as opposed to the global guidelines. But as we've kind of emphasized, the big deal with the Gina guidelines is that they do represent more modern, more updated literature, and making those recommendations so it's hard to ignore a guideline that is up to date. I think that that alone gives it some stance in terms of, should we be following that over some of these older guidelines, Speaker 2 07:49 older versus new? Yes, we want to consult the most updated literature. But the Gina 2019 has, you know, the scientific committee does have a disclaimer saying that they respect that, you know, the availability of these pharmacologic products, the availability of the interventions and the healthcare in general, in pockets of world, it's different. So while they're producing the latest and greatest from the literature, they are keeping in mind that we should individualize the approach with the resources that are available in whatever part of the world that they are trying to treat asthma. Speaker 1 08:19 And you'll see some recommendations reference products not available in the United States — GINA is a global initiative, not US‑specific. So these 2019, Gina guidelines, so they are really making some big changes that I think clinicians should be aware of who treat or see patients with asthma, right? Speaker 2 08:45 So let's kind of go over some of the brief recommendations that are updated in this Gina 2019, guidelines. The first and foremost is that for adults, or adults since greater than 12 years of age, the Saba PRN, the albuterol PRN, is no longer recommended as a rescue inhaler, and really the reason is because we've seen increased risk of severe exacerbation of asthma and asthma related deaths with this So kind of going back with the lab evidence we have in asthma too, and we know that adding an inhaled corticosteroid actually helps reduce this risk. So they're actually a proponent of introducing ICS earlier in these stages of asthma. Speaker 1 09:29 Number two is the preferred controller treatment for steps one and two, which would be mild asthma, is a low-dose inhaled corticosteroid with formoterol as needed. So the same rescue inhaler for stages one and two. The preferred controller inhaler is also this as well, Speaker 2 09:45 and the recommendation for the exercise induced bronchial constriction is similar. There was no difference, but they are still recommending this combination be used before initiating an exercise as well. Speaker 1 09:58 And that formoterol is actually important. So note that we did not say inhaled corticosteroid plus LABA. It's specific to inhaled corticosteroid plus formoterol, and that deals with the fact that formoterol does have a very quick onset of action. We're talking just a couple minutes, whereas something like salmeterol does have a much, much more prolonged onset of activity. That would not make it a good rescue inhaler. So LABA means formoterol when talking about a rescue Speaker 2 10:23 inhaler, right? And this was the only one studied to support this recommendation. So we have two products with formoterol in it: budesonide–formoterol (Symbicort) and mometasone–formoterol (Dulera). We like to note that the SYGMA studies used the budesonide–formoterol combination (Symbicort), and that Symbicort is more widely used than Dulera. Speaker 1 10:52 Another recommendation was the use of azithromycin as a low-dose chronic therapy in this moderate-to-severe asthma patient category. The dose here is 500 milligrams taken three times a week. The patient population here is those that have persistent symptomatic asthma despite moderate-to-high doses of ICS plus LABA. So this is your later-stage patient with asthma, not your earlier, better‑controlled asthmatic. What they found was that azithromycin three times a week reduced exacerbations and improved asthma‑related quality of life. Speaker 2 11:31 In addition to those efficacy outcomes, they noted some safety issues. Diarrhea was the most common side effect; there were also risks of arrhythmia/QT prolongation and ototoxicity (hearing impairment). Those are important individual safety concerns, and there is also the public‑health concern of increased antimicrobial resistance with long‑term azithromycin use. Speaker 1 11:57 So tiotropium, which we mentioned in the beginning of the episode, and which is typically thought of as more of a COPD medication, has also made its way as an add‑on therapy for ages six and above. Speaker 2 12:09 And when we say this is add‑on therapy, as we summarized earlier, this is for patients with advanced stages of asthma (step 5). The GINA recommendation places tiotropium ahead of other biologics as a preferred add‑on controller in some patients because it produced modest lung‑function improvement and modestly increased time to exacerbation requiring oral corticosteroids. The dose used was tiotropium 5 micrograms daily delivered as a fine‑mist inhaler (Respimat), not the tiotropium HandiHaler. Speaker 1 12:52 And the difference with that is that the HandiHaler is the capsule device that is punctured and then you inhale the powder, as opposed to the Respimat, which uses a spring‑loaded device to push the fine mist into the lung rather than delivering a powder. Speaker 2 13:07 in Stage Four patients tiotropium add‑on garners as the other controller or secondary alternative option, because we don't have equivalency data comparing it directly with ICS+LABA combinations. Speaker 1 13:22 Not surprisingly, the guidelines do not recommend maintenance oral corticosteroids, even in step five, just because of the side effects that happen with chronic use of oral steroids. And there's a number that we can mention, including diabetes, weight gain, hypertension, edema, Moon faces, things like that, that if you take them long enough, you will experience some of those side Speaker 2 13:42 effects, yeah, and interestingly enough, they're coming out, as we mentioned earlier. These are comprehensive guidelines. They focus on non farm recommendations too, and one of the recommendation was like breathing exercises. What they actually found is that maybe it does help improve quality of life, but there is no improvement in these symptoms or exacerbation. So they're not recommending this overtly, but if the patient like to do so, it doesn't improve their Speaker 1 14:05 quality of life. Not going to hurt, right? Exactly. Then finally, transition of care. So after a very severe exacerbation, these patients should be seen on the outpatient side within two days, which makes sense, after a life threatening event, these patients really should get good follow up so that early action can be taken if it needs to be taken, but also things basic things like patient education, optimizing the chronic regimen that that patient will be on, deciding next course of action that has to happen fairly soon. Speaker 2 14:33 And now we're not gonna go over the different algorithms that GINA produces for children 6–11 or ≥12 years. What's more important is that GINA recommends assess‑adjust‑review: assess control, adjust therapy when needed, then review and de‑escalate if control is achieved. Speaker 1 15:04 So as we mentioned, one of the big things from GINA 2019 is that albuterol is no longer the preferred rescue inhaler for many adolescents/adults; instead the preferred reliever is ICS–formoterol. This recommendation was prompted by new evidence. Speaker 2 15:22 It does. Two key randomized trials (SYGMA 1 and SYGMA 2) were published in NEJM. SYGMA 1 was a 52‑week, double‑blind trial in patients ≥12 years with mild asthma; SYGMA 2 used a similar population. SYGMA evaluated arms including terbutaline PRN, budesonide–formoterol PRN, and scheduled budesonide plus terbutaline PRN. Speaker 1 16:46 We should mention terbutaline is not a commonly used agent in the US. This would be equivalent to an Albuterol or a beta two agonist here in the US. And the Speaker 2 16:54 The primary objective was to establish superiority of PRN budesonide–formoterol over PRN terbutaline (SABA) for weeks with well‑controlled asthma; control weeks were tracked by electronic diary. Speaker 1 17:15 So just to give a concept of who was included in the trial, we had just shy of 4,000 patients. Mean age was ~40 years and slightly more than half were female. Mean duration of asthma was ~6 years and about 20% had an exacerbation in the prior year. The mean baseline FEV1 was 84%, so this was not a very severe population overall. Speaker 2 17:57 And then looking at the outcomes, the first primary outcome was, you know, weeks with well controlled asthma. And what they found is that the budesonide–formoterol PRN combination was indeed superior to terbutaline. Weeks with well‑controlled asthma were 34.4% with the combination versus 31.1% with terbutaline (OR 1.14; P = 0.046). Speaker 1 18:27 And they also looked at budesonide–formoterol PRN versus scheduled budesonide maintenance. They found scheduled budesonide was slightly better for symptom control (44% of weeks well controlled versus 34% with budesonide–formoterol PRN). That makes sense — scheduled dosing provides more steroid exposure than PRN dosing. Speaker 2 19:07 Some secondary endpoints looked at annual rates of exacerbation: 0.20 with terbutaline, 0.07 with the budesonide–formoterol PRN combination, and 0.09 with budesonide maintenance therapy. The relative reduction for budesonide–formoterol versus terbutaline was significant (RR ~0.36), but the difference versus budesonide maintenance was not statistically significant. Speaker 1 19:42 This is where the trial shone: albuterol PRN was inferior to PRN ICS–formoterol for reducing exacerbations. Using ICS–formoterol PRN reduced annual exacerbation risk compared with SABA PRN. Speaker 2 20:22 And as discussed earlier, the GINA update reflected evidence that excessive SABA use is associated with worse outcomes — SYGMA showed PRN ICS–formoterol reduced exacerbations compared with SABA PRN. Speaker 1 20:39 And one thing that is interesting is that, prior to these trials, we lacked strong RCT data supporting SABA PRN. It had been assumed to be appropriate because it relieves symptoms, but observational data suggested higher SABA use linked with worse outcomes. The SYGMA trials challenged that assumption and helped prompt the GINA change. Speaker 2 21:27 yeah, and especially, like I said, we didn't have good data, and patients who have are defined as mild asthma patients. So this evidence really solidifies that some of the worries that we have for exposure to like inhaled corticosteroid is the long term side effect of that inhaled corticosteroid, right? We know that, but looking at this combination therapy, the study also looked at what corticosteroid sparing we achieved, and obviously, in the combination PRN group, patients received less exposure to inhaled corticosteroids. We observed steroid exposure of ~57 µg in the PRN group versus ~340 µg in the scheduled budesonide group (scheduled budesonide = budesonide twice daily). Speaker 1 22:14 And that's relevant, because again, the kind of scheduled corticosteroid regimen did slightly better when it looked at asthma symptoms, but it was at the expense of more steroid exposure. You know, you could give an asthmatic patient 60 milligrams a day of prednisone, and they probably wouldn't have that many asthma exacerbations, but you're giving them the steroid exposure that maybe you don't need to give them, and get a similar benefit, or an almost similar benefit. Speaker 2 22:41 So that was SYGMA 1. SYGMA 2 was done at the same time and in a similar population but with two arms: placebo twice daily plus PRN budesonide–formoterol, or scheduled budesonide twice daily plus terbutaline 0.5 mg PRN. The primary objective was annual rates of severe exacerbation. Speaker 1 23:21 They enrolled just above 4,000 patients (mean age ~41 years, ~62% female). Baseline FEV1 was ~85%. Budesonide–formoterol PRN was non‑inferior to budesonide maintenance for severe exacerbations. Speaker 2 23:56 Annual incident rates were ~0.11 for the PRN combination group versus ~0.12 for the budesonide maintenance group — essentially not different. Speaker 1 24:13 And of course, they demonstrated an ICS‑sparing effect: patients randomized to PRN ICS–formoterol received less total inhaled steroid exposure than those on scheduled budesonide. Speaker 2 24:31 the secondary outcome also looked at time to the first exacerbation. Again, this was not statistically significant finding, and Speaker 1 24:39 that really wraps up what has prompted the Gina guidelines to have this change from albuterol to ICS formoterol. This is not going to be a change that happens overnight, but when we start seeing ICS–formoterol inhalers used PRN, a product that was historically a controller could also serve as a rescue inhaler. Over time many patients may carry a single inhaler (ICS–formoterol) instead of separate rescue and controller inhalers, with implications for copays and regimen simplicity. Speaker 2 25:19 And I also hope that the National Asthma education program, you know, puts together their updated version of guidelines soon, so the evidence based therapy can be utilized in United States widely. I check every year. Dr. Patel, I bet you do every month. Speaker 1 25:38 So the other thing that you mentioned, Dr. Patel, was tiotropium for severe asthma (not just COPD). There is evidence supporting tiotropium as an add‑on in some asthmatic patients. Speaker 2 25:51 That's correct — one of the LAMAs with evidence is tiotropium. We were referring to the tiotropium Respimat (fine‑mist inhaler) versus the tiotropium HandiHaler (capsule). The Cochrane review (2016) looked at ~48–52 weeks of tiotropium 5 µg daily in patients with severe asthma (baseline FEV1 ~55%); it showed some reductions in oral‑steroid–requiring exacerbations but not consistently significant. Quality‑of‑life differences were small, and safety event rates were too low to draw firm conclusions. Speaker 1 27:10 A JAMA meta‑analysis (2018) found adding a LAMA (tiotropium) to ICS reduced exacerbation risk versus placebo (RR ~0.67). Adding a LAMA was not clearly superior to adding a LABA, and triple therapy (ICS+LABA+LAMA) showed modest/non‑significant benefit over ICS+LABA. Speaker 2 27:46 and then the triple therapy (ICS+LABA+LAMA) versus ICS+LABA was also not statistically significant (RR ~0.84). So the evidence is modest. Speaker 1 28:00 This is somewhat lukewarm evidence for tiotropium, but tiotropium may be reasonable to try before moving to biologics in some patients. Speaker 2 28:24 that you pointed that out, because the Gina Scientific Committee, the reason for tiotropium meriting that stage five add on therapy was exactly preferred over the biologics, was exactly this because, you know, it's it's less invasive. Type of a treatment requires less monitoring, has perhaps less side effect, you know, profile as well, and it's it's easier for patients to use at home versus having to inject that. Oh, yeah for sure. Speaker 1 28:51 Or last kind of big update dealt with azithromycin as a chronic medication to help prevent future asthma exacerbations. And again, we do have evidence of this in COPD. It is recommended in certain patients with COPD as a chronic medication as well. So we are seeing some overlap, kind of interesting overlap here, between COPD evidence and asthma evidence, kind of trying each other's regimens to see if it may be effective for the opposite disease, which is interesting, given that the pathophysiology is pretty different between the two, right? Speaker 2 29:23 And I think here we are looking at probably that immunomodulatory effect of the azithromycin that you know, has on inflammation part of the asthma pathophysiology. So the trial that put the evidence forward was AMAZES. It was a 48‑week, double‑blind, placebo‑controlled trial in patients with persistent asthma despite ICS+LABA; the trial excluded patients with hearing impairment or QT prolongation. Speaker 1 29:58 That's relevant, because in the COPD. Trial equivalent of this, where they looked at azithromycin and COPD, they did observe that as a side effect, that was a significant side effect in the trial, that it did cause some hearing impairment, and typically this older patient population, but still relevant. So it makes sense that they would want to get rid of those patients, and a trial looking at this as well. Speaker 2 30:19 Yeah, makes sense again. The intervention, as you summarized earlier, Dr. Kane, was using azithromycin, 500 milligram three times a week, or placebo, and the primary outcome was looking at the exacerbation of asthma, and then this was combined between moderate and severe exacerbations and looking at the asthma quality of life as well. Speaker 1 30:38 They enrolled just over 400 patients (mean age ~60 years, ~60% female, ~20 years of asthma). Baseline FEV1 was ~72% and most patients were on ICS+LABA — consistent with an older, more severe asthma cohort. Speaker 2 31:07 The study found azithromycin reduced exacerbations versus placebo: 1.07 per patient‑year in the azithromycin group versus 1.86 per patient‑year in the placebo group — a statistically significant difference. Speaker 1 31:27 Then they also looked at the asthma related quality of life, and azithromycin improved it with an adjusted mean difference of point three, six points that was statistically significant. Typically, the clinically meaningful difference for this kind of a scale is point five, and again, it was point three six. So it didn't quite meet that, but it did demonstrate this numerical difference that reached statistical significance, and depending on the patient, it may or may not have implications for quality of life for that patient, Speaker 2 31:56 and because patients with QT prolongation or any type of hearing impairment were excluded. The most common adverse event was diarrhea (azithromycin 34% vs placebo 19%). So kind of summarizing what we discussed today in the podcast is for our audience to know that there are a couple different guidelines available for the treatment or management of asthma. The naepp National Asthma education program. It's widely practiced in the United States. However, it needs a major update, because last update was in 2007 while the Gina guideline is global guidelines, they're updated every year with twice the yearly literature review, and the most recent version we have available is the 2019 guideline. Speaker 1 32:48 And for me, one of the big changes in GINA 2019 was that albuterol is no longer the preferred rescue inhaler for patients ≥12 years — inhaled corticosteroid plus formoterol (specifically formoterol, the LABA with rapid onset) is preferred as the reliever. This can also be used as a controller in early steps (1–2). The recommendation is limited to ≥12 years because that was the studied population. Speaker 2 33:26 So for younger patients (<12 years) we will still use SABA PRN as the rescue inhaler. The other focus was tiotropium (Respimat, fine‑mist inhaler) as an add‑on; it is a preferred, less‑invasive option ahead of biologics for some step‑5 patients. Speaker 1 33:51 Then finally, the concept of using low‑dose azithromycin chronically (500 mg three times weekly) is recommended for some patients who remain symptomatic despite moderate–high ICS+LABA; data show reduced exacerbation risk but safety concerns (diarrhea, hearing loss, QT prolongation, antimicrobial resistance) limit broad use. So that wraps up episode 104. If you'd like to see the references for this episode (including the 2019 GINA guidelines), visit HelixTalk.com and click on episode 104. We're also on Twitter @HelixTalk — we appreciate five‑star iTunes reviews so other health‑care providers can find our content. So with that, I'm Dr. Kane. Unknown Speaker 34:54 I'm Dr. patal. Deep breath and study hard. Narrator - Dr. Abel 34:58 If you enjoyed the show, it's. Please help us climb the iTunes rankings for medical podcasts by giving us a five star review in the iTunes Store. Search for HelixTalk and place your review there Narrator - ? 35:09 to suggest an episode or contact us. We're online at HelixTalk.com thank you for listening to this episode of HelixTalk. This is an educational production copyright Rosalind Franklin University of Medicine and Science.