CEimpact Podcast

Is Enteric Aspirin Worth It?

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There are numerous formulations of aspirin available over-the-counter often advertised to decrease gastric issues. Join host, Geoff Wall, as he evaluates a new study to see if enteric aspirin is worth the extra money and effort.
 
The GameChanger
Buffered and coated aspirin are purported to cause fewer gastric adverse events. However, no efficacy or safety differences exist in the various formulations of aspirin.

Host
Geoff Wall, PharmD, BCPS, FCCP, BCGP
Professor of Pharmacy Practice, Drake University
Internal Medicine/Critical Care, UnityPoint Health
 
Reference
Sleem A, Effron MB, Stebbins A, et al. Effectiveness and Safety of Enteric-Coated vs Uncoated Aspirin in Patients With Cardiovascular Disease: A Secondary Analysis of the ADAPTABLE Randomized Clinical Trial. JAMA Cardiol. Published online October 04, 2023. doi:10.1001/jamacardio.2023.3364

https://jamanetwork.com/journals/jamacardiology/fullarticle/2809795?resultClick=1
 
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CPE Information
 
Learning Objectives
Upon successful completion of this knowledge-based activity, participants should be able to:
1. Discuss the history of various formulations of aspirin on the US market
2. Discuss the results and limitations of the ADAPTABLE study

0.05 CEU/0.5 Hr
UAN: 0107-0000-23-331-H01-P
Initial release date: 10/30/2023
Expiration date: 10/30/2024
Additional CPE details can be found here.

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Speaker 1:

Welcome to the Game Changers podcast, where we have clinical conversations that impact your pharmacy practice. Pharmacists by design members get 30 minutes of CE just for listening to this podcast and answering a couple of questions. Join Pharmacists by Design today and make getting CE easier. Let's listen in as our team discusses this week's clinical practice game changer.

Speaker 2:

Welcome to Game Changers clinical conversations. I'm your host, jeff Wall, professor of pharmacy practice at Drake University. Today we're going to talk about a subject that, okay, admittedly is not the most world-shaking subject in the world, but definitely falls into those. I've always wondered, I've always wondered about file. I think every clinician, you know pharmacist, provider, physician, whatever has always had a little and they're had a little file cabinet of. You know we do this and I've always you know we tell people this I always wondered if there was ever any research that showed that that was true or not.

Speaker 2:

And the problem with this is that most of the time and this is actually an exception in the study we're going to talk about that the question is interesting, but not so interesting that anyone is going to spend the you know tens or hundreds of thousands of dollars or even millions of dollars to actually do a randomized control trial to answer the question, and so it's one of those well, I guess we'll never really know sort of things. And you know this is what everybody says. I guess that's just what we're going to talk about. And so this is one of those very rare cases where, while it's not a true randomized control trial, it is a retrospective analysis or post-talk analysis of a retrospective study that I think may answer again not an earth-shattering question, but a question I get asked by patients and I'm sure you do too is I'm going to have to take aspirin? For you know my heart, should I take an entericoded aspirin or not entericoded aspirin? And I think most clinicians would, you know, kind of shrug their shoulders and say I don't care. Really, it stands to reason that giving entericoded aspirin would cause less direct irritation to the stomach lining and, you know, allow the drug to not cause so many GI side effects.

Speaker 2:

The flip side of that has always been with entericoded drugs that they especially aspirin is that their overall bioavailability may be reduced because, again, aspirin is primarily absorbed in the stomach and so when you have a coating that really basically makes it through the stomach into the first part of the small intestine, you might have a decrease in bioavailability. So even though there may be and again this is all kind of theoretical the you know, what makes sense certainly is that oh, I mean, this is coated, so it's going to be in the stomach and, you know, cause local irritation. It may decrease effectiveness as well and it's something I'm always telling my students is that you know we always like. Well, you know aspirin causes GI bleeds.

Speaker 2:

Well, it does, but it isn't because the drug itself burns a hole in the stomach, it's because, of course, it's blockade across the glands which breaks down defense mechanisms the stomach has against the very acid it produces. So you know, I'm not saying that you can't get direct stomach upset, and that absolutely is something that they get as direct irritation of tissues. But that's not the major way by which gastropathy occurs with aspirin or nods to ridals. So you know, when people would ask me a question, I think, like most clinics missions, I'd be like eh you know, whatever you want to do, I don't really care.

Speaker 2:

You know, I suppose if you're having stomach upset right after you take an uncoated aspirin, I guess go ahead and take a coated aspirin you know, and I think that was kind of the you know it doesn't, I don't really care what I wear the other.

Speaker 2:

So you know, basically, you know, do what you want to do, sort of thing. It is worth noting that when I came out of school, buffered aspirin was kind of the big thing and the thought was again that when you gave aspirin in a, in a, in a buffered aspirin you know it was a a a formulation that it would. It would basically cause less stomach irritation and and allow the patient to take the drug more. And, interestingly, those there were some retrospective studies with buffered aspirin that actually thought it was less effective and so most people kind of abandoned the use of buffered aspirin in patients who were taking and then, you know, aspirin for cardiovascular purposes. So you know that that. You know that did show that formulation of aspirin may be and not the most thrilling subject in the world, but it's definitely one of those. Hey, maybe I can take this piece of paper out of the file cabinet in my brain about. I've always wondered why, and we can answer the question of the efficacy and safety of entericoted versus uncoded aspirin in patients with cardiovascular disease. Now, this is a secondary analysis of the adaptable randomized control study and, and the randomized control study that was known as adaptable its big job was to take a look not at formulation of aspirin, but at dose of aspirin. So, in other words, if you were to, you know, send somebody home after they've had a heart attack or a stroke, what dose of aspirin should you send them out on? Should you send them out on 81 milligrams if you're in the United States, in Europe and other places, it's 100 milligrams, or the full 325, what's called full dose aspirin? Which of those you know should, should you do? And is there a difference in efficacy and safety? And the adaptable study itself had. It was a fairly large study and it was completed in 2021.

Speaker 2:

And the study itself again, this is just a retrospective analysis of the study itself is that patients, to be in the full adaptable study, had to have known cardiovascular disease, which meant an MI, or they had to have cardiac catheterization that showed a greater than 75% synosis of greater than one epicardial vessel, or they had a history of PCI or cabbage. And then they also had to have other at least one other criteria of being age over 65, having chronic kidney disease or diabetes, having history of cerebral vascular disease or peripheral vascular disease or having EF of less than than than 50% or be a current smoker. So they'd have one of those things on top of the known cardiovascular disease. And that was a way, I think, to increase patients who were going to be at risk for recurrent events that may have may show a benefit to aspirin, depending on the dose. These patients were identified through EHR and then the contacted to see if they'd be interested in being in the study and then again randomized to aspirin 81 milligrams a day versus aspirin 325 milligrams a day. They did not specify that. The patients were basically allowed to take the tablets they want because it was a pragmatic study. They did not in fact dictate if it should be coded or uncoated. That's kind of interesting.

Speaker 2:

They did do electronic follow up and then they looked over 24 months with a max follow up of 30 months. The primary endpoint of the overall adaptable study was a composite of all cause mortality, not fatal MI and not fatal stroke and the composite safety endpoint was major bleeding complications, which then they split into all sorts of different things. The main adaptable study had a total of about 15,000 patients who were followed for about two years. Before animaization. Almost everyone was already taking aspirin, so that's important to note, and that most of them are taking baby aspirin or 81 milligrams. But after they randomized patients to these two different doses, they found that death, hospitalization for MI or hospitalization for stroke occurred in 7% of patients in the 81 milligram group and 7% of patients in the 325 milligram group, and so there was no statistically significant difference in efficacy between the low and high dose.

Speaker 2:

And then when I took a look at major bleeding in particular, the safety outcome they were interested in was hospitalization for major bleeding, which occurred in 0.63% of patients on the 81 milligram group, page 12 of 12. 0.6% of patients in the 325 milligram group, so again, not statistically significant. They do note that in the study, though, that a lot of patients with 325 had a higher incidence of stomach local stomach dyspepsia type symptoms and were switched to the 81 milligram tablet as well. So in this pragmatic study called the Daptable, they did not find a difference between 81 and 325 as far as efficacy or major bleeding events, with the exception of more dyspepsia with the higher dose and that a lot of people ended up switching to the lower dose. So that was the overall study.

Speaker 2:

This study again was a post-doc analysis of that, and so what they wanted to do is dig a little deeper. When the patients did be enrolled in the study and they were looked at in their clinic visits and stuff like that, they were asked are you taking coded aspirin or non-coded aspirin, and stuff like that. So in this study, this analysis, the participants were divided into subgroups, based both on the randomized aspirin dose and then self-reported aspirin formulation. So entericoded aspirin versus un-coded aspirin. At the time of randomization there were patients who did not fill out that part of the questionnaire related aspirin formulation or didn't remember what it was. If those patients were excluded from the analysis, it was assumed those patients remained on the same aspirin formulation throughout the entire study, as information on entericoding was not collected after the baseline. So all they looked at was baseline were they on a coded or un-coded aspirin? They wanted again to take a look at efficacy and safety. So I think the outcomes were fairly similar between the overall adaptable study and this post-doc analysis. And they looked again at primary safety efficacy and points we've talked about. I think they dug a little more into the primary safety end points Because again, that's the point of coded versus un-coded.

Speaker 2:

They did do some pretty complex statistics and I think the reason for this is they really wanted to try and capture covariates and confounders that may make up the difference or show some of the differences they were going to see, and so they did. Do you know, get tox proportional hazards. They came up with a model that took a look at about 12,000 different potential confounders. It was fairly in-depth and something that I wouldn't have even considered. So, for example, stuff I would have thought you'd see as far as confounders in this model would be current smoking, gender, age, presence of hypertension, hyperlipidemia, atrial fibrillation, heart failure, that all kind of makes sense. But they even looked at things like whether the patient had any access to the internet at use of randomization. So I would assume that has something to do with health literacy, but I thought that was kind of interesting.

Speaker 2:

They looked at baseline P2Y drug and they also looked at BMI, which I thought was really good because there has been some question about, you know, in very obese patients, is 81 milligrams of aspirin truly enough for those patients?

Speaker 2:

So anyway, you know this very, very complex statistical model where they tried to really do, I think, a pretty good job of accounting for a lot of the confounders that you might see in a study like this.

Speaker 2:

And of course, the other problem with this study is, since it was a pragmatic study and they didn't give the pills to the patients, there is no real way in the study to assess for adherence except just asking patients and so to account for non-inherence.

Speaker 2:

In the study they conducted a sensitivity analysis to assess if aspirin formulation modified the association of the participant reported aspirin dose or aspirin.

Speaker 2:

The formulation had an association with the participant reported aspirin dose and then went downstream and took a look at the safety end points again primarily bleeding that we talked about. They also looked at some of the efficacy end points as far as all cause death as well and from that information they conducted yet another model with Cox proportional hazards that looked at trying to put in adherence as one of the confounders. And again it was pretty complex and I applaud the authors for trying to do this though, in all honesty, not being an absolute master of statistics, I had to read the paper two or three times to kind of really okay, this makes sense, and I'd kind of look at what was going on and it all did just again ended up being, you know, again, as you might imagine, a very, very complex model that dealt with not only a wide, wide variety of confounders but even trying to take a look at adherence in a study where patients were just basically expected to take their own pills.

Speaker 2:

They also did one last analysis where they took a look at patients on acid reducing medications because, again, the thought would be, if coded aspirin really primarily decreases dyspepsia and you're on a proton puff inhibitor or a H2 blocker, what would that kind of decrease that as well? And so, again, you know, I applaud that the authors are really trying to come up with a model that pretty much took up everything as they could basically. So what did they basically find? Of the 15,000 patients that were enrolled in the overall adaptable trial, 10,000 of them, or about 70,000, did report the aspirin formulation used. In that cohort the average age was 60 years. About 68% of patients were men.

Speaker 2:

The overwhelming number of patients in this study were white, though there were other races as well. Of that group, about 331 patients had missing data in the demographics. So they included those people in the overall analysis but noted that they did not have all the data when it came to some of the demographics. Most of this was based on where patients prefer not to say, for example, what the race was, or more what their gender was and stuff like that. After they divvied things even more, they found that that aspirin formulation was reported by 5,374 patients and the 81 milligram cohort and 5,304 patients in the 325 milligram cohort, with intercorner and aspirin used by about half in those patients and, as you might imagine, about 70% of patients in the study did preferentially use entericotid aspirin versus uncoded aspirin. At the time of enrollment, about a quarter of those patients were taking a P2Y drug, so either tachycagrelor or clopidogrel, and the number of patients taking uncoded aspirin was higher than patients who were taking in-coded aspirin.

Speaker 2:

Among current smokers, individual with diabetes or a history of bleeding, which I would think would be kind of surprising, wouldn't you recommend a coded aspirin patient who might have a distant history of GI, of bleach? I thought that was kind of surprising. So what did they find? Is coded better or worse than uncoded when it comes to efficacy and safety? We will answer that question when we hear from our sponsor, ce Impact.

Speaker 1:

Are you a pharmacist by design? Since we hold a vital position on the health care team, it is our responsibility to advance our knowledge and skills so we can provide the best possible care to our patients. Being a pharmacist by design means striving to be the best version of ourselves, not just as professionals, but as individuals dedicated to improving patient outcomes. Learn more about pharmacists by design at ceimpactcom. Join us and begin your journey to being the best version of your pharmacist self.

Speaker 2:

So we are back answering the first shattering question that will change medicine forever. No, it's kidding, but an interesting question nonetheless about is enteric-coated aspirin truly safer than uncoded aspirin or is it truly less effective than uncoded aspirin? Based on this retrospective, post hoc analysis of the adaptable study, what did they find in this study? The primary efficacy endpoint again, which was, you know, similar to the overall study death, hospitalization for MI or revascularization. That endpoint occurred in 6.6% of patients in the 81 milligram group in this smaller cohort, and 7.2% of patients in the 325 milligram cohort, and that wasn't statistically significant. But when you drill down to take a look at coded versus uncoded in those in those groups, similar results were observed with the uncoded aspirin and the coded aspirin. So it did not look like there was a difference whether the patients had coded or uncoded aspirin at either 81 or 325 milligrams. It seemed like the numbers were almost identical to each other and there didn't seem to be a big difference between all of them. And when they broke it down and looked at all cause mortality, that also did not significantly differ across the full cohorts and the overall hazard ratio for inter-coded aspirin was 0.88 compared to 0.9 in the uncoded aspirin. So basically no difference between at either dose or coding and non-coding. So that was, I think, kind of interesting. And so efficacy there was really no difference. Now let's talk about safety, which again I think is the more important thing. I don't think anyone's ever really accused inter-coded aspirin, even though it has lower bioavailability, of not being particularly effective, right.

Speaker 2:

So when they took a look at overall bleeding and one of their definitions was overall bleeding that required any blood product transfusion, which they defined as major bleeding they noted that overall inadaptable, that number was pretty low. But when they took a look at the four cohorts, there was no significant interaction of major bleeding by either aspirin dose or formulation within the inter-coded aspirin group. Interestingly, there was a small but significant increase in major bleeding with the higher dose, but no difference in major bleeding with the uncoded aspirin cohort. So in this study and again, you always want to be careful when you take a look at a study whose overall results were negative but the post-doc analysis finds a positive they did find that higher doses were associated with a slight increased risk of major bleed. Again, I'm not saying that's the case, but it is kind of intriguing that that's something that they found.

Speaker 2:

Again, all GI bleeding, there was no difference in the four formulations and so overall hazard ratios were similar between the four groups, depending on dose and the coded versus inter-coded. They didn't find any difference in other safety outcomes and there was no significant difference between inter-coded aspirin or uncoded aspirin on major GI tract bleeding. And so, interestingly, the other big difference they did not find was an increase in rates of dyspepsia. And so, even though we tell patients routinely to take a coded aspirin if they have stomach upset, it didn't look like there was a change in this analysis of risk of stomach upset whether you had coded or uncoded aspirin. So, basically, this post-doc analysis of the adaptable study again which the overall adaptability of the adaptable study was a large multi-center pragmatic randomized control trial when they dug down with this data to try and look at the intersection between dose and coded versus uncoded aspirin, they essentially did not find any difference, and so you know both formulations and both doses seem to be about equal to each other as far as rates of MI, rates of death, rates of hospitalization for MI, but also were very similar in rates of GI bleeds, major bleeds, and, unlike the original adaptable study which found that lower doses had a decrease of dyspepsia. This study didn't even find that. This study didn't find that there was a positive increased risk in patients who had a coded aspirin versus uncoded aspirin on the risk of dyspepsia. So you know, what I kind of walked away from this study showing is that, despite kind of the theoretical advantage is a coated aspirin that you know it's that you've coated it so it's not gonna, you know, irritate the stomach, you're gonna get less dyspepsia, but that you know the flip side of that is, because of its decreased bioavailability, like buffered aspirin before it, it may not be as effective as uncoated aspirin. Really, this study basically refutes all of that. It suggests that it really doesn't matter what aspirin formulation you use and almost really what dose you get.

Speaker 2:

As far as either efficacy of aspirin and cardiovascular disease or safety in aspirin and cardiovascular disease. Now, keeping in mind this was a secondary prevention population, right? So you know these patients already had a history of cardiovascular disease and should be on sort of anti-platelet agent, would this data be translatable to primary prevention? My tip of the tongue is no, because I think the pendulum is kind of swinging away from most patients getting primary prevention for aspirin anyway that we're starting to realize that the risk of GI bleed or head bleed in most patients for primary prevention is just about as high as the risk of having a heart attack. So you're really just trading one problem for another in those patients.

Speaker 2:

So I'm not sure I would translate this information to primary prevention, but I think for secondary prevention, when a patient comes to you and says, hey, I heard I'm supposed to take, you know, coded aspirin, you know, is that reasonable to do? I think it's reasonable to do. But I think if they come to you and say you know, I've been having a lot of stomach upset in the morning when I'm taking my aspirin, should I go to a coded aspirin? Again, you can certainly recommend it because it's certainly not harmful for the patient. But I think it's worth noting that at least based on this post-doc analysis, they're not probably gonna get a lot of benefit from going to a coded versus un-coded aspirin.

Speaker 2:

Now I did note that they did do a final analysis, taking a look at acid reduction medications, and found probably not to a big surprise that patients who receive either proton pump inhibitors or H2 blockers actually had a much less incidence of both dyspepsia. And then the numbers were so small they weren't really able to look at a difference in major bleeding. Numerically it was smaller, but again, what been recetitical significance? But I think what you can say is that if someone's having persistent dyspepsia after they're taking their morning aspirin, it's certainly reasonable for them to consider an H2 blocker. I think that would be the easiest and cheapest way to do it.

Speaker 2:

And so famotinine might be a good drug as long as there's not any other issues with that medication that might help. I'm never a fan of proton pump inhibitors being used long-term in patients unless there's a real reason to. Now, certainly if you had somebody who had was on an aspirin a day and on a DOAC or on a dual-ioniplatelet therapy and had other risk factors, that's a whole nother kettle of fish and I think the risk of GI bleeding those patients is a little bit higher. So I think that my a proton pump inhibitor might be the way to go with those patients. But I think just taking a baby aspirin a day and they're having just plain old dyspepsia. Based on this study there's no increase or decrease risk of efficacy or safety. So they're not more likely to have GI bleeds with coated or uncoated aspirin and if they have dyspepsia I think just symptom relief of dyspepsia with acid-relate reducing medication seems to make sense.

Speaker 2:

So again, a question I've thought about most of my career is kind of finally answered that it doesn't really matter and you can really tell your patients to take just about any dose of commercially available aspirin, and coated or uncoated, and it seems to me that that you know any of them is reasonable. So what's the easiest, cheapest way they can get? It is probably the most important thing of all. So that's it for this week's version of Game Changers. Thanks for listening. We will see you next week, but until then, remember time flies. I don't know where it's going, but the most important day is today.

Speaker 1:

Jen here. Be sure to check out our education at cempackcom. You'll find it to be your one-stop shop for all the CE resources you need. Become a pharmacist by design member today to access it all for free, including CE for this podcast. Thanks for listening. We'll talk to you next week on Game Changers Clinical Conversations.