Multiple studies highlight the benefits of direct oral anticoagulants (DOACS) with lower incidence of side effects and non-inferiority to warfarin. Join host, Geoff Wall, and guest, Mathew Boyd, as they discuss the FRAILE AF study and whether warfarin may be the best bet in older adults.
DOACs are recommended by nearly all relevant major medical guidelines as the anticoagulant of choice in atrial fibrillation. A new study has found that in frail elderly patients, warfarin may be associated with fewer bleeding episodes.
Geoff Wall, PharmD, BCPS, FCCP, BCGP
Professor of Pharmacy Practice, Drake University
Internal Medicine/Critical Care, UnityPoint Health
Mathew Boyd, PharmD
Joosten LPT, van Doorn S, van de Ven PM,et al. Safety of Switching from a Vitamin K Antagonist to a Non-Vitamin K Antagonist Oral Anticoagulant in Frail Older Patients with Atrial Fibrillation: Results of the FRAIL-AF Randomized Controlled Trial. Circulation. 2023 Aug 27. doi: 10.1161/CIRCULATIONAHA.123.066485. Epub ahead of print. PMID: 37634130.
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Welcome to the Game Changers podcast, where we have clinical conversations that impact your pharmacy practice. Let's listen in as our team discusses this week's clinical practice game changer.Speaker 2:
Hello and welcome to Game Changers Clinical Conversations. I'm your host, jeff Wall, professor of pharmacy practice at Drake University and internal medicine clinical pharmacist at Methodist Hospital. Today, I'm honored to have a special guest with me, our new cardiology clinical pharmacist at Methodist, dr Matt Boyd. So welcome.Speaker 3:
Matt Nice to be here.Speaker 2:
Dr Boyd is a welcome addition here at Methodist Hospital, but also, more importantly, he's a cardiology specialist who did his PGY2 at Northwestern I understand, so outstanding, so the guy will. Dr Boyd will definitely give more information than I possibly could when we're talking about cardiology subjects, so I hope he likes this enough that he's going to want to do it again.Speaker 1:
We'll see how it goes after this. He's going to go. I ain't going to do that again.Speaker 3:
So anyway. So again welcome, dr Boyd.Speaker 2:
So today we're going to talk about something that has definitely been at least in my circles, generated a lot of a hue and cry, and that's because I think it's it has the potential to really kind of turn what we've done in anticoagulation for atrial fibrillation in the last several years kind of on its head a little bit. So I can certainly see why a lot of experts are kind of talking about this paper. The paper is actually it's not been published yet. You can actually get it on the circulation website for free, but yeah, it's the actual final galley copy. The actual paper has not been fully published, but it was announced at the European Society of Cardiology meeting a couple of weeks ago and again has really set a lot of people talking, shall we say. And the title of the study is the Frail FAF study the use of anticoagulation for atrial fibrillation in elderly patients who are frail. So that's the key piece and of course that's where the name of the study came from. It is a chromatic randomized control trial that was done in the Netherlands. It is worth noting that whenever we talk about studies done in Europe or in Australia, that is a more integrated healthcare system in the United States and I actually think that that might be an issue with this paper. It was presented, as I said, at the ECS Congress just a couple of weeks ago, but again not fully published yet. But you can certainly download the draft for free on the circulation website and the paper itself notes that, and I'm sure everyone listening knows this atrial fib is associated with numerous bad things, including stroke, heart failure, acute increased mortality, et cetera, et cetera. It's stocks triangle related to age, as we all know, and they say that patients over age 80, about 10% of them are going to have atrial fibrillation. So again, as the population ages, we're just going to see more and more and more patients with atrial fib. We know that stroke prevention is the primary prevention tool of anticoagulation and if you're an old man like me, you remember when everybody was on war front and I have several friends who basically made their living doing anticoagulation clinics. They're not doing that much anymore. In fairness, there are some very good anticoagulation clinics still going out there because, again, despite everyone recommending do-axe, there's going to be a population. There's always going to be a role for war front. But the bottom line, as we all know, is that do-axe have largely replaced a war front, just because they're much easier to dose, you don't have to check INRs. But I think, most importantly, clinical studies have shown decreased bleeding, decreased major bleeding between the two big do-axes in the United States and war front. So at least in my world and I suspect those listening primarily in the United States you've seen a dramatic increase in do-axe use and a relative decline in war front use. I would say that my inpatient service is probably now a 10 to 1 ratio that people coming in or on you know, a picks a man or river ox man versus warfarin. So so you know, multiple guidelines, multiple studies have suggested that from at least from a safety perspective, these drugs are better and at least as effective at warfarin and for many, stroke and systemic embolism. So that's terrific. So why would anybody question that? The authors of the study note that one of the big exclusion criteria for for particularly the rocket and Aristotle studies was patients who are very frail and the definition of frail of course gets a little dicey, but but the bottom line is that they noted that that patients who who basically weren't fully healthy, ambulatory elderly patients, were often excluded from these trials, and so they noted that that it's maybe worth taking a look at whether the same benefits as as talking about bleeding with the dox is is really validated patients who are fragile. And so they say, because we don't have a lot of data suggesting that, because these patients have high comorbidities are usually on multiple, multiple medications, they're dependent on others for, for because of, due to reduced capacity, that you know that the outcomes may not be the same with with frail elderly patients, compared to the patients were studied in rocket for river ox man and Aristotle for a pixel band. So that's where the frail AF study goes, comes along. It was a pragmatic investigator, initiated multi center, open label, randomized superiority study trying to say that fast five times and it was done in the Netherlands, and so it was done primarily in seven large and a population clinics in the Netherlands and, of course, at all the criteria for getting it funded and having all the ethics associated with it being approved in the study to be included in the study needed to have over a 75. They were already enrolled in anti-quagulation treatment with warfarin. So that that's an important piece to keep in mind is that these patients were already stable patients who are getting their INR check regularly, I you know and again in in anti-quagulation clinics, already on warfarin. They then divided those patients and said, ok, we're going to take a cohort and continue them on warfarin and they're going to take a cohort and switch them over to a do back they to be in the. In the study itself, you had to score at least a three on the grownage in for fragility indicator. I actually had to pull the actual paper that it is interesting and I've just never heard of it and it's. It's a simple scoring system where they take a look at, you know, your overall mobility. Are you? Can you go grocery shopping? Can you, you know, go to the bathroom by yourself about help your vision? Ok, you know, have you lost weight because of unintentionally? And those all add up scores, basically. And so, when it all said and done, patients who have a score of three and that's what you needed to be in the study were capable only of limited self care. They were confined to bed or chair and at and at, and about less than 50% of waking hours where they up and around. So basically, these are patients that were largely housebound, that really can only go out out of their house with the help of some sort of supports that significant others or other sort of support and about 50% of their time they were combined to a better chair and I think worse than that was was a score of four which we had completely disabled patients that can't carry on any self care. So these were definitely frail patients. I might not, you know, I may not know everything about the definition of fragility. You know it comes to the elderly, but I absolutely think that these were not, you know, healthy ambulatory elderly patients by any stretch of the imagination, because that's what it had to be in the study. Then they were excluded if they had valvular atrial fib, which they defined as patients who had a mechanical heart valve or syrup mutual valve stenosis, which is basically what the indications for dox are. They couldn't have an e GFR below 30, and it couldn't be in any other study. Basically, so that that was how the study inclusion, exclusion criteria rolled. So, looking at the methods of the study, patient for randomized, the index group. So they, those are patients who are switched to a no act based treatment. And again, they did not necessarily say you had to be on on a. They didn't say which do I, can you to be on. They did suggest that when they were asked they would try to use either a pixel band or river oxaban, but you could pick any of them. So some patients actually were on a doxaban. I didn't see where patients run to have a gastronome, which is kind of what I see as well. And then the control group of patients who are just maintained on warfarin and they they use either one or three milligram tablets targeting and I and Rf two to three. These block randomization to stratified by which service? Because these were all Ionic regulation services in the Netherlands and as renal function as well. Taking a look at the outcomes, the primary outcome was the occurrence of major or clinically relevant non major bleeding, which is pretty much what you see. All the guys studies now look at know this was based on the ISTI, isth guidelines of what a major bleed is, which is defined as a fatal bleed or a bleed in a critical area or organs such as intercranial, intraspinal, interocular, retropare, neal, etc. Etc. Or bleeding leading to a fallot heme global and a more than two grams per deciliter, and or bleeding leading to a transfusion of two or more units, whereas clinically relevant non-major bleeding is defined as basically any bleeding that's not major bleeding but has either it prompts a face-to-face consultation with a healthcare provider, requires a medical intervention by a healthcare professional, or leads to hospitalization or increased level of care.Speaker 1:
So this was primarily a safety-based study.Speaker 2:
So I mean you know they designed and powered the study more for safety than for efficacy. However, the secondary end points included all cause mortality. They looked at different complications associated from bleeding, but they did again look at the occurrence of all cause thromboembolic events, including ischemic stroke, tias, peripheral artery thromboembolism, and then the composite of that and major or minor clinical bleeding as well. So again, the study was really designed as a safety study, but they did look at secondary outcomes as efficacy as well Study. The stats were pretty reasonable. I thought they assumed they were gonna get a relative reduction of 30% in bleeding complications when switched to a NOAC, which is about what you'd expect to see based on the studies that are currently published. Everything else about the stats kind of made sense. There was nothing really strange or unusual. They used the independent variability to a Cox model, which would make sense, and again, everything else kind of seemed to make sense as far as the stratification, the power and all that other stuff. So in the study themselves, they looked at patients from 2018 to 2022. They screened about 2,600 patients, but the majority of those not included were just basically non-frail patients, and so, when it was all said and done, they had about 1,400 patients that were then randomized to the two groups. What were these patients? What did they find, and what does our expert, dr Boyd, say about all this? We will find out about that as soon as we hear from our sponsor, cd M Pat.Speaker 1:
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So we are back talking about the Frey LAF study every time I say that I chuckle and looking at what the results were of this study that looked at Orphan versus Doax in patients who are fragile, looking at primarily bleeding outcomes. So when we take a look at the patients themselves, about 41% of the patients 41% of patients were female. The type of atrial fibrillation though, I'm not sure that really matters anymore. About half of them had permanent atrial fibrillation. And then there is the other two phenotypes that you saw. Their fragility score was four. The median fragility score was four. So again these were pretty fragile patients that were not ambulatory really, that really weren't able to live in the community by themselves. So these were, you know, pretty fragile patients. I guess is what you'd say, with actually 74% of patients having this groinage and fragility indicator of four or greater. Most of them were on multiple medications. Big surprise there Most of them had problems with their memory. About 20% of them had a difficult time just getting around the house, etc, etc. Meechad's vascular score was four. So again at high risk, a majority of that hypertension and then diabetes. All that other stuff was kind of along. Egfr was about 62 mils per minute between the two groups and concomitant anti-placelet drugs were actually fairly low to be honest with you. It sounds like in the Netherlands they do a better job of doing that than we do here. About 2% of patients in both arms, basically. So what? did they find in the study. Well, they basically had to stop the study and they actually had a data safety monitoring board and when they reviewed the data at a break point they decided to halt the study for futility, because they basically found that after complete follow-up, the hazard ratio for the primary outcome was actually 1.69 after switching to a NOAC, compared to continued INR-guided warfront treatment. So bottom line was that they found a 69% increase in major bleeding and clinically relevant non-major bleeding in patients who got switched to a NOAC. Yes, that's what you heard. I was surprised, as everybody else, when I read this that, yes, they found a relative increase of about 70% of major bleeding clinical or non-major bleeding in patients who were switched to warfront. Most of that was driven by clinical development, non-major bleeding, particularly your genital bleeding and, big surprise, gastrointestinal bleeding that was observed at the most difference, whereas differences in hemorrhagic stroke and intracranial bleeding was actually very similar between the two, so most of this was driven by non-critical site bleeding or depth from bleeding as well. Some group analysis really didn't show a whole lot of difference between those two. So when they looked at renal function, the numbers were very similar. When they looked at whether it was river oxymand versus a pixaband and I think this was probably surprising to a lot of people that the overall risk was very similar in bleed. I think there's at least some retrospective data to suggest that, for example, river oxymand may be associated with a higher incidence of GI bleed. So I think that would probably surprise some people. But they did find that all this did not apply to a DOCSAPAN. They found that the numbers were seemingly more in line with warfarin, with the DOCSAPAN. As I've said, I don't think I've ever seen anybody on a DOCSAPAN. I always joke to students that you know, I'm not really sure I want to use a drug where you can't use the drug if your GFR is too high. I mean that's got to be a first in the FDA, right? So basically, the authors suggest that. You know they were surprised. I think, as anybody else, that not only did they find a statistically significant increase in bleeding but it was, you know, I think, clinically relevant as well. I mean when you take a look at the overall numbers example for GI bleeding it's like 2% versus is 0.6% increase in patients who were on DOCSAPAN. They did find that there was no difference as far as the efficacy outcomes, that that thromboembolism was similar between the groups. I suspect the study wouldn't have been powered to show a difference in just efficacy, even if they had particularly looked at it. But they did not find that difference. They also note that there were some limits. They noted that their population was already tolerant to warfarin treatment and that you might not see the same results in patients who have never been on any anticoagulant and you decided to put that on warfarin versus a NOAC and I think, to my way of looking at things, that's probably one of the biggest strikes against this study. And, honestly, they know that other studies that you know were designed a little bit different. They were bigger, for example, they had probably more patients in them, so that may have played a role. They also note that you know how patients are treated with warfarin in the Netherlands may not reflect how patients are treated with warfarin in other parts of the world. They note that levels of time and therapeutic range which back when we used a lot of warfarin was kind of a marker for how efficient your anticoagulation clinic was were not measured. However, they know that historically in the Netherlands it's quite high and I suspect that the numbers would be lower, not so much in, I think, in standard anticoagulation clinics but, you know, in just Joe, primary Care, a clinician who's just using warfarin on patients. I think studies have suggested that in patients who aren't in anticoagulation clinics, time and therapeutic range is much different. So that may play a role as well. So they basically, you know, walk away from the study, suggesting that you know, not that we should not use DOACs in frail patients, but that in patients who are on warfarin or doing well on warfarin, who are very fragile, that the benefit of switching to a DOAC may be minimal. I think that was kind of a conservative way for them to look at it. So, Dr Boyd, what do you think about this study as an expert?Speaker 3:
I honestly I was a little taken aback by it. I kind of thought this was going to be like the last nail in the coffin that we needed for Warfarin and we were never going to have to dose Warfarin as pharmacist again. But unfortunately that's kind of not how it ended up and it even made me kind of reflect and like look back at the past literature. That even was done. I was like do I want to look at the aerosol? Do I want to look at the rocket? I even pulled up the Edoxaban trial Not that it even matters because we don't use it in the United.Speaker 2:
States very much at all. There's an Edoxaban study. Right, I know, I even pulled it up and I was like, oh, let's just see if the bleeding rates are different in the original study that came out.Speaker 3:
And nope, I was very surprised, I guess, by the result of this study. Looking at it, I was shocked that 50% of the time people chose Riveroxaban. I feel like that's maybe not the way that practice is trended. Maybe here in the United States Practice is definitely trended more towards picking a Picsaban over anything else, maybe just because of ease of people being able to dose it appropriately in the outpatient setting. So I think that maybe could have played a little bit of an aspect in this too, although it seems like these patients were followed probably much closer than what we have here in majority of our patients in the United States. So I would say that just based off of that alone, you can see that in their time to therapeutic range for their warfarin patients it was like 65 to 75%, which is like pretty remarkable. Honestly, in the United States I think we're close to maybe the 50, 55% time range. I think in good ones, Right in really good clinics, which is, I think, maybe the most concerning part about this, because you're kind of comparing apples to oranges at that point, because you're not really comparing what we in the United States are used to seeing for our warfarin patients. So I think it is a little more concerning. In addition, most of these patients I looked at the baseline characteristics for all these like initial studies that we did and I mean the study speaks for itself. We are truly including patients that are frail, which I think is a very nice thing as clinicians to have, because then we have the opportunity to kind of think about the patient, specific factors in our specific patients, instead of just kind of extrapolating what we know from our initial clinical studies. And then, if you kind of just look, it's kind of nice. In cardiology we always have these composite outcomes which can really sway people if they don't really look at the study really closely. And this one being a composite of like the major bleeds, then also like the non-major bleeds, and it really is pulled pretty heavily by like the non-major bleeds, which again in this study is included if it prompts a face-to-face consultation. And you know our frail patients in the United States, you know how if anything goes awry. My grandma, all the time she gets a little poke of her finger or anything, bleeds and she's on a blood thinner. She immediately calls her provider, which would spark a face-to-face or at least a call, and in this study that would count as a bleed. So I think that's something else to kind of keep in mind too, because I don't necessarily think if you go to the bathroom or poke your finger on your fork or you're you know, corn on the cob one day when you're having that, I don't really think that should mark as like a bleeding event in the study, which I think could be poorly extrapolated. But I do think this study kind of helps to reflect a little bit on how practices shifted so quickly to DOAX. And I even see it in practice in the hospital all the time where we have people who stable on warfarin, been on warfarin a really, really, really, really long time and then, almost like for convenience of providers, we switch to DOAX. So that way they don't have to worry about warfarin follow-up, they don't have to worry about INR monitoring and I think, and we don't have to worry about drug interactions as the pharmacist nearly as much. I mean, there's some that we have to worry about still, but not nearly as much with our DOAX. So I think that's kind of something that now, it's kind of making us reflect on whether we should switch patients to DOAX or whether we shouldn't, and I don't necessarily think it's a clear cut answer. This doesn't really give you yes, you should, no, you shouldn't. Are they frail? Yeah, maybe Most of the patients in the hospital are frail, regardless if they're over the age of 75 or not, and so I don't think this frailty score, which I also had never heard of before this I had to look it up and I was writing down all the different combinations that you can get to get to the frail score. I don't necessarily think this should be like a definitive yes, you're frail, keep you on warfarin. But I think it should almost be looking at again at the clinical picture. Patient to patient, every patient again, whether they can afford the medication is a huge, huge thing in today's society, especially with how expensive medications are. But I think, just again looking at, will this patient be able to have, I guess, a better quality of life, not having to move and not having to go back and forth for INR checks? Or when they're on warfarin, are they truly stable? Or is this somebody that comes into the ER with an INR of 10 all the time because they forgot what their dose was and they took 10 three times a day? Right, I think it's just kind of one of those. I think Doaks are great and I think they have a place in therapy, but I don't necessarily think they should kind of take the overarching place of everybody, especially patients. My grandma when I had to convince her to get off of the Pics-a-Ban, it took me probably a whole year and this was me as a pharmacy student, so not nearly as knowledgeable as I am now in the area, but it took me almost a whole year to even convince her that going to this and not having to go get her INR check was even a realistic or good option. So I do think it's just like, maybe case by case still, as we have with all of our patients.Speaker 2:
So and I completely agree with you, I think that's a good way to look at things, I guess. So you ran with our cardiologists very, very regularly. This paper will hit the, I suspect not just the medical literature, but I suspect you're gonna see a lot of CNN stuff about it and a lot of lay literature. So you've got a patient who comes in with a new stroke of atrial fibrillation and they say, well, I mean she's pretty much housebound. I just read this paper and says maybe we should put her on Warfarin. And yeah, you have to look at individual factors. Would this lean you at all towards going? Because I mean, up until this paper was published I'd be like, oh God, no Warfarin, I'm gonna put him on a dole. What are we talking about? What is this 1995? But now it's like, well gosh, maybe we should consider that. So I mean, how would you approach that?Speaker 3:
Yeah, I do think it kind of makes you pause and reflect should I actually initiate Warfarin on this patient based off of like these comorbidities that they come in with already in the hospital? But I do think one of the main points is that these patients had been stable on Warfarin for a long time. These weren't people that came into clinic one day and were like I'm having a hard time controlling my INR with my Warfarin. I needed a better solution. These were patients that were just randomly switched kind of out of the blue, I'm sure, for most of them, to a DOAC, which again can probably be a little life altering for these people too. They've kind of gotten to the ebb and flow of I get my INR checked on Tuesday, I get my dose adjustments, yada, yada, yada. I know how to monitor what I'm eating, and now they have this whole new med that they now have to take twice a day, not once a day. Well, 50% of them have to still take it once a day, right right. And then you kind of have those patients who I know they're bedbound but this is still part of their daily routine, whether their INR checker comes and gets it at their house or whether they have to go in. So I think kind of this abrupt change they did in the study doesn't necessarily always reflect kind of how we dose meds in the United States, or at least in clinical practice. If it was a new athead, new stroke, I still think I'm trending more towards keeping a DOAC for these patients, regardless of how frail they are, especially if you're someone that you know they're bedbound or housebound.Speaker 2:
How are they gonna get to get their INR?Speaker 3:
Exactly going to get your INR is not a simple thing. And then the United States. They make it very clear in the study that they have a lot of people that go out. They're like basically house calls to get INR checked and we do not have that.Speaker 2:
We don't do house calls In the least here in the United States.Speaker 3:
So I don't think it's necessarily reproducible from Europe or the Netherlands to here, but I do think it does show a good trend that if we have these services for these patients maybe war friend, where we can more tightly monitor it, we don't have the variable pharmacokinetics with these drugs that we don't have to necessarily get levels on, but we have these patients who could be 50 pounds, soaking wet and 95 years old, who are super frail. So I think, just kind of thinking about the perfect atmosphere for success, was this study for war friend, and I don't necessarily think, unless you have this perfect storm, whether war friend should be preferred over DOAC.Speaker 2:
And I think that was kind of the take I drew away from this is that you and I, and I suspect some of our colleagues, are gonna get kind of bombarded when this paper hits and I think that's gonna be my standard. Response is gonna be okay. Well, this study is not really generalizable, I think, to the United States. I think if I take anything from this is just as you said, that if somebody comes in already on war friend and some eager beaver clinicians as well, why are we doing this? And it's like, well, hold it a second, They've been on war from from years. They seem to be doing well on it. Maybe we should just let well enough alone, because in this real frail patient we have at least some evidence to suggest that we may be doing harm and not good to them. So I agree with you. I think that would largely be my approach. Again, I was an aside. I've had enough friends who are Anticoic pharmacists. They will tell you that they've caught all sources of stuff when people come in for their visit, right, oh? yeah, by the way my blood sugars have been 500. Have you told anybody about that? No, I'm telling you about it and while I'm getting my INR drawn. So a lot of my friends who are organic coagulators have said you'd be surprised some of the stuff they catch. So I mean it is more contact with the healthcare system in our hand, especially in the frail elderly, necessarily a bad thing so yeah, any other things you'd like to talk about? No, I think that's it All right. Cool, dr Boyd. Thank you so much. This was cool. This was actually really cool. We'd love to have you back on. Like I said, I'd say at least 30 to 40% of the stuff we talk about here in game changers is cardiology based. So when you've got the time, I'd love to have you on, so all right well thanks very much everyone for joining us for this week's game changers. Again, time flies. I don't know where it's going, but the most important day is today. Take care.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.