Speaker 1 00:05 Lange, welcome to HelixTalk, a podcast presented by the Rosalind Franklin University College of Pharmacy. Narrator - Dr. Abel 00:11 This podcast is produced by pharmacy faculty to supplement study material and provide relevant drug and professional topics. Speaker 1 00:19 We're hoping that our real life clinical pearls and discussions will help you stay up to date and improve your pharmacy knowledge. Narrator - Dr. Abel 00:27 This is an educational production copyright Rosalind Franklin University of Medicine and Science. Speaker 1 00:32 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 - Dr. Abel 00:47 And now on to the show. Dr. Sean Kane 00:51 Welcome to HelixTalk. Episode 20. I'm your co host, Dr. King. I'm Dr. Patel, and I'm Dr. Schuman, and after a holiday break hiatus, we're back on with HelixTalk. And today we're going to be talking about landmark trial called the SMART trial. Speaker 2 01:05 And the SMART trial actually stands for Salmeterol Multicenter Asthma Research Trial, which was published in Chest in 2006, so Speaker 3 01:16 Just to give a little bit of background with this one, this is a study we knew some historical data that seemed to imply that LABAs, or long acting beta agonists, and what these refer to are either salmeterol or formoterol. These are a couple of medications that have been used for years for treatment of COPD and in this case, asthma. We found that they might be harmful in asthma due to increased mortality. So what they wanted to do with this trial is to determine whether salmeterol in particular increases the respiratory- or asthma-related life-threatening events or deaths. Speaker 2 01:51 So let me get this straight. This was not an efficacy trial, but it was actually a safety trial to see if this medication is causing adverse events. Speaker 3 01:59 Yes. I mean, why wouldn't you want to get enrolled in a study if you can go see if this drug could cause you to have mortality? That sounds reasonable. Dr. Sean Kane 02:07 So in all fairness to the drug, at this point, we did have evidence showing that actually got the drug approved for the indication of asthma. We had evidence that showed that Salmeterol and other long acting beta agonists reduced the usage of rescue inhalers like albuterol, and they had some modest benefit in things like spirometry findings. So we did have some evidence that they were beneficial, but like you said, Dr. Schuman, there was also some lower quality evidence that said that using these long acting beta Agnes could actually increase mortality in patients with asthma, and that was the impetus for the study. But as you alluded to, it's kind of a goofy study. Who would want to be enrolled in a trial to see if it causes death or not? Alright? Speaker 3 02:47 So, like, anytime we start to get into a study, I think one of the first things we can do is look at who was included in the study, who did they go for? And is that, you know, is that population somewhat unusual and is a representative of a larger population? Speaker 2 02:59 And so looking at the inclusion, you know, they included patients greater than age of 12 and any typical patient, if you can know, an asthma patient, mostly it's a prevalent disease in childhood. So we also know that 13 years shouldn't be treated similarly to a 50 year old or patient who has had asthma for two years shouldn't be treated similarly to patients who have asthma for 20 years. And so a typical patient in this study was about 40 years of age, had PEF, the peak expiratory flow rate of 80% had asthma for about 16 years. And interestingly enough, The study included more white patient compared to African American. 70% of the patient population was white and 18% African American. Dr. Sean Kane 03:49 We mentioned the peak expiratory flow is a mean of 80% so 80 to 100% of peak expiratory flow is what's called the Green Zone in asthma therapy. It's where you want to be with your spirometry finding, despite the fact that, as a mean, they were in the green zone, these patients in the study actually had pretty severe asthma. So within the past year, about one in four patients were seen in the emergency department for their asthma, and an eight person were actually hospitalized for an asthma exacerbation within the past year of therapy. So these were not patients that had exercise induced asthma that never really saw an emergency room or a hospital. These were patients that had good utilization of kind of rescue institutions, like an ED or a hospital for their asthma therapy. Speaker 3 04:33 And another interesting point about that is those these weren't though, these were individuals who did have a fair amount of presentation, a fair amount of use of those rescue inhalers, only about half, about 47% were using an inhaled corticosteroid. And part of that may be just a changing or progression in the time zone what's used, because in today's era, those inhaled corticosteroids or ICS as shorthand, those are considered the cornerstone of asthma therapy. Dr. Sean Kane 04:57 And to be honest, at this point in time, the use of an inhaled corticosteroid like fluticasone or Flovent was important, and you can see about half the patients were on it, but it wasn't to the point where it was a standard of care where everyone should be on it, regardless of whether they're on a long acting beta agonist or not. So this trial, the SMART trial, is so pivotal, because it really changed the practice of asthma and changed how we treat patients with asthma, absolutely. Speaker 2 05:25 So the treatment in this particular study involved two groups, obviously the control group, which was the placebo group, and the active group, which was salmeterol or the brand name Serevent, which was taken twice a day over the 28 weeks, which was about seven months. Dr. Sean Kane 05:41 And of course, this was in addition to whatever the patient was taking at home. So if they were on Fluticasone and inhaled corticosteroid, they could continue it. The only thing is that they couldn't be on a different long acting beta agonist. So this was truly an add on of ceravent or Salmeterol versus placebo on top of whatever you were taking for your asthma therapy at home. So thinking about how the trial was designed, then their primary endpoint was a composite meaning that a patient could meet the primary endpoint if they had one or of two things happen, either they died or they had a life threatening respiratory event. Usually this meant that they had to be intubated and put on a mechanical ventilator to help them breathe. So they either died or they were basically intubated, and that was the primary endpoint of the trial. Speaker 2 06:24 So interestingly enough, you know, whenever we were looking at a study, we emphasized the fact of the power, whether the study meets the power or not. Initially, the study was powered to detect 40% increase in composite endpoint, assuming the baseline increase of about point 8% considering this ground condition, they wanted to enroll about 30,000 patient. However, the actual incident rate was actually only point 4% of the patient enrolled either diet or had life threatening respiratory event within the 28 week period. So based on this, they doubled their enrollment to 60,000 however, the interim analysis showed a harm. That's why they kind of stopped the enrollment at 30,000 patients. So if you can think about they needed 60,000 patients to meet that power, pre stated power, however, they only had 30,000 patients. So they only had half the intended patient population enrolled in this study. Dr. Sean Kane 07:19 So Dr. Patel, what you're saying then is that initially the study wanted 30,000 people. Then they realized, uh oh, our incidence rate of the primary endpoint was half of what we thought. So then they doubled the intended population to 60,000 and then they stopped the trial at 30,000 their initial power, although that was half of the power that they needed because the incident rate was so much lower than they had anticipated, absolutely correct. It's pretty confusing. So the long story short is they weren't powered for the primary endpoint, but they stopped it early because they were seeing some concerning things in the results Speaker 2 07:52 correct, and considering the ethics behind the study design and stuff, they've had to stop the trial at interim analysis. Dr. Sean Kane 08:00 So Dr. Schuman, what were some of these concerning findings, and what was the actual finding of the study with regards to the primary endpoint? Speaker 3 08:07 What they found is that within the total population, salmeterol did not increase the composite endpoint of mortality plus life-threatening event. What they did find, though, is harm in the African American group. So that was 18% of the total study who were African Americans, and they didn't see harm with a relative risk of 4.1 — so patients here were about four times more likely to have reached that endpoint if they were receiving salmeterol than if they were receiving placebo. Dr. Sean Kane 08:34 So that sounds horrible. You're quadruple the risk of having either dying or having a life threatening respiratory event. Speaker 3 08:41 It is something when you first look at those numbers, and like anything, we have to go a little bit deeper into what it means. So one of the things we do is, once we know relative risk, we also have to look at what is the absolute risk in the population. So what we see is that there is an actual risk of about 0.845% so less than 1% on salmeter, all versus point two, one, 6% with placebo. So even though there was that four times the risk, we're still talking about two fairly uncommon percentages. And so it's, you know, somewhat unlikely in both cases regardless. Speaker 2 09:15 And so this leads us to discuss what was so special about this African American patient. Why did the results differ in African American patient compared to the Caucasian patient? And one of the reason was because African American patient had lower PEF to begin with, 85% worse than 78% in the African American patient also due to some ethnic or cultural reason, they were less likely to use an inhaled corticosteroid. So the use of inhaled corticosteroids in African American patient was 38% compared to 49% of that in Caucasian patient. And as Dr. Schuman mentioned earlier, this needed to be looked at, just because we could not rule out the usefulness of inhaled corticosteroids being obviated compared to just LABA alone. Speaker 3 10:02 So then this brings up a few different points, and are at least some explanations for that. Because when you look at that, it definitely does seem that there's difference between African Americans and the rest of the population. I believe Dr. Kane looking it could be, we could be looking at genetic variations. It may be in the beta receptor. Adrenergic receptors is one potential reason Dr. Sean Kane 10:20 for that? Yeah. So the thought could be that maybe either they have poor efficacy of the beta receptor in the lung, where the drug doesn't work very well in the lung, or they have some kind of mutation on the heart beta receptor where they're more prone to, let's say, a sudden cardiac death from overstimulation of the beta receptor. We don't really know, and at this point, the risk is so low, it's really hard to study the true effect. All we know is that there does seem to be this risk, but why we have the risk is really unknown. Speaker 3 10:48 And then, as Dr. Patel mentioned, there could be a social or an ethnic factor relating to it, and some sort of a difference in patient behavior, maybe those you know using it, either you know, less likely to present to a hospital, or changes in staying in or out, or more likely to go in as delayed in care, difference in compliance rates, or even Speaker 2 11:07 using a LABA as their rescue agent, instead of using, you know, a short acting beta agonist as their rescue Speaker 3 11:13 agent, certainly, and then aparthemogenetic factors, it may just simply be that it was the severity of the asthma itself and not the reason may have just been that this population just happened to be more sick than those other ones, and thus, if they're more sick, then we're lucky to get some of these worse outcomes. Absolutely. Dr. Sean Kane 11:31 The thing here is that we really don't know why African Americans did worse. It could be a true effect of being African American. It could be some other thing that was that was just associated with their ethnicity that had nothing to do with genetics or ethnicity, but dealt with some other factor that we're not capturing with our data analysis. Again, the risk is 0.8% versus 0.2% it's very, very difficult to tease out the true effect when the incidence rate is so low, to really distinguish what the problem was. Speaker 3 12:01 And I think to further emphasize this is to come out of this study a look at some of the newer data. The Cochlear group does these reviews, and they've been actually reviewing the use of these medications every year due to this as an important safety signal. They've gone every year and reviewed this, and most recently, in 2014 they went back and looked at all the studies, and they found a total of 10 trials that enrolled a total of 29,128 adults. And what they did is they looked at the number of deaths in cell meter all and a placebo in that group, and they found 44 deaths in the cell meter all group, and 33 in the placebo group. And that was a difference of about 10 per 10,000 patients. That was an increase of eight, so eight per every 10,000 patients. So even again, once again here in a larger portion, we're still talking about very, very small numbers. And so even though that odds ratio what was fairly large, and we're still talking infinitesimal changes in that overall population. So you just have to kind of think of that when you're changing your practice based upon a study such as this, Dr. Sean Kane 13:01 and really the biggest question that probably comes out of the smart trial before we kind of get to the conclusions, is, what was the effect of having the inhaled corticosteroid like a Fluticasone on board? Was that protective from the increased risk of mortality or a life threatening event, or did it not matter at all? Is getting long acting beta agonist alone, regardless of your background, asthma therapy, going to increase your risk of this primary endpoint. So they did do an analysis of this, but if you recall, we were about 50% of the power that we wanted to have in terms of enrolling patients, and of that, only half of the patients were on an inhaled corticosteroid. So now we're at a quarter power. We didn't see an effect, but we probably wouldn't see an effect because our power was so low, because the incidence rate was so low. So this is truly an unanswered question of whether something like Advair Salmeterol with Fluticasone, whether that also has the same effect, or if it's a sole drug effect of Salmeterol, and it can somehow be prevented by having Fluticasone on board as well. We don't know the answer to that correct. Speaker 2 14:04 And you know, even before going over the study conclusion, if you look at the practice norm, the recommendation is to not use LABAs solely to treat patients asthma, but always use as an add-on therapy to inhaled corticosteroids. Speaker 3 14:17 Yeah, there's actually again that that's quoted right out of the FDA recommendations in this guideline: if the addition of formoterol or salmeterol to an inhaled corticosteroid is found to improve symptomatic control, it is safer to give in the form of a combination inhaler. This prevents and then one other argument they made is that it prevents the substitution of the LABA for inhaled corticosteroid if symptom control is improved. And that's one other thing that could be thought of — if you are doing separate versus combination, maybe there's this instinct to add one drug and remove another one. Dr. Sean Kane 14:48 So to kind of wrap up the SMART trial where this might come into clinical practice, if a patient ever reads any of the documentation that comes with Advair, with Serevent, with Symbicort, all of these have a boxed warning as a result of the SMART trial and other analyses, saying you will die more often if you take this medication, or you're more likely to have a life-threatening event. That sounds really, really scary, and if you're a patient that reads the packaging, you're probably not going to want to take the medication unless your health care provider sits down with you and talks to you about where that warning came from, and what is the actual Speaker 2 15:23 risk, right? So again, looking back at the statistics that we discussed, you know, the conclusion from the trial was that, yes, in African American patient, use of lab up, quadrupled the risk of mortality, or like threatening respiratory event. But we looked at the actual risk, it was point 8% versus point 2% so again, this risk is even less than 1% Dr. Sean Kane 15:45 and keep in mind, though, because this was an underpowered trial, we've really focused on African Americans, but the Caucasian group was underpowered. So Caucasians may also be at an increased risk of mortality, but we didn't detect that, probably because we're an underpowered trial. So had they had adequate power, we'd be able to know whether this is an African American effect only or everyone effect. We just didn't see it with the entire cohort, and we didn't see it with Caucasians alone. It was definitely seen with the African Americans. Speaker 2 16:16 And following this trial, FDA also looked at a trial called SNS, as well as they looked at a meta-analysis and published in 2008 that, yes, we do not have enough data to conclude whether using LABAs with or without inhaled corticosteroids would reduce the risk of asthma-related death or hospitalization. However, FDA is requiring clinicians to individualize therapy, assess the patient's severity of asthma, the level of asthma control, and the risk of exacerbations as well as hospitalization, and provide care accordingly. Dr. Sean Kane 16:55 So Dr. Schuman, in your practice, do you see a lot of Advair in patients who have asthma. Speaker 3 17:01 Certainly we use either Advair or another combination product, depending upon formulary restrictions, but more commonly than using it on its own, we definitely see the LABA and ICS combination versus something like Serevent on its own. Dr. Sean Kane 17:16 Do you think Dr. Patel that providers are less likely to give a long acting beta agonist as a combination product to an African American versus a Caucasian patient. Or do you think that crosses the mind of most practitioners? Speaker 2 17:29 I think at this point, if I can recollect what's happening in my clinic itself, I don't think providers are making distinction between African American versus Caucasian, but they do make sure that they're not utilizing a LABA on their own; they're always adding it to an ICS therapy, which is, again, a very Dr. Sean Kane 17:44 important part. So for yourself, if you had asthma and you were not well controlled on Fluticasone alone, would you be adding that long acting beta agonist in the form of Advair? Would you be doing something different for your asthma therapy? Speaker 2 17:58 I think I would go ahead and add Advair, because we know that, you know, adding a LABA can, in addition to ICS, be beneficial. Even the guidelines recommend that instead of intensifying ICS therapy, we should go the route of adding a LABA on board, because of additional benefits, not just the respiratory peak flow numbers, but additional benefits in terms of exacerbations and hospitalization due to pneumonia. Speaker 3 18:23 And I would certainly counsel again, if it was myself or another, another patient, I would recommend that we still encourage and reinforce the use of a short acting beta agonist as your albuterol rest inhaler as well, that though we are that, you know, it sounds like albuterol, the name looks like albuterol, that this does not replace albuterol as that rescue inhaler. And so to give that extra piece of information so that we're not going to that disc as our sole treatment for somebody who's having an acute exacerbation, and hopefully information like that, as well as the ability to then track the use of it, I think was something I would also recommend to make sure that we're keeping track of whether, how little or how much use of those beta agonists we are using to make sure that as a net effect, we're not just overloading those beta receptors Absolutely. Speaker 2 19:08 And you kind of have to look at the patient's comorbidities as well, you know, if they have baseline cardiac conditions or arrhythmias, and we're adding this, you know, beta agonist on top of that to exacerbate those conditions, then we kind of have to individualize the patient, whether certain patients are going to benefit from LABA therapy versus the other. Dr. Sean Kane 19:27 And I'd really second the idea that probably the most critical point here is helping the patient distinguish a rescue inhaler versus a controller inhaler. If you're a little bit of a conspiracy theorist, you can look into the smart trial, and it was actually split into two different phases. Phase One was a radio ad, or other media ads, where patients listened to an ad and then went to a healthcare provider that enrolled them in the trial. Phase two was they actually had a healthcare provider already, and that was the person who enrolled them most of the deaths. Is in the smart trial occurred during phase one, and some people think that because these patients may not have had a primary care physician who is managing their asthma, but this was a patient who was seeking a researcher, basically to give them the study drug, perhaps they didn't have the appropriate counseling regarding medication therapy, specifically, if they're having an asthma exacerbation to educate them, don't reach for the steady drug that we're giving you. This is for your asthma control, but it's not for acute asthma exacerbations. When you have acute asthma exacerbations, this is to help you reduce the need for your albuterol, and potentially that was one of the reasons that we saw the effect in the trial. And if that was the case, that really exemplifies the importance of patient counseling as opposed to the selection of drug therapy, meaning that maybe the LABA isn't bad on its own; it's only bad if misused by the patient. Speaker 2 20:47 Absolutely, and I think that's where pharmacists come and play a great role in explaining not only how to properly use the medication, but what are the differences between the different medications that they will be rather using at this point or future when they have add on therapies. Speaker 3 21:04 It also reinforces to anyone who's looking at study design or conducting a trial, what the importance of not just looking at the patients you enroll, but how you enroll them, to look at some sort of a bias that may be incurred Dr. Sean Kane 21:16 absolutely especially when you have this dual enrollment, where you get some people who already have a relationship with a healthcare provider, and then other patients who, perhaps due to socioeconomic reasons or for whatever reason, they're more likely to see a radio ad and not have an established healthcare provider that helps treat their asthma, maybe they're more likely to seek primary care in an emergency department, as opposed to in a primary care office. So if you haven't done so already, we really appreciate a five star review on iTunes. We're still accepting any suggestions for future podcast episodes. You can visit us at HelixTalk.com with that, I'm your co host, Dr. King, Unknown Speaker 21:52 Dr. Patel, and I'm Dr. Shuman. Unknown Speaker 21:54 And as always, study hard. Narrator - Dr. Abel 21:58 Thank you for listening to this episode of HelixTalk. For more information about the show, please visit us at HelixTalk.com you.