One of the oldest medications in our pharmacopeia is digoxin. It may be used for atrial fibrillation and heart failure, although not as a first-line agent. Despite this, digoxin use is on the rise. Join host, Geoff Wall, as he evaluates why more prescribers are using digoxin.
The GameChanger
No new randomized controlled trials have been published to justify the increased use of digoxin. However, when used, providers should routinely monitor digoxin levels.
Host
Geoff Wall, PharmD, BCPS, FCCP, BCGP
Professor of Pharmacy Practice, Drake University
Internal Medicine/Critical Care, UnityPoint Health
Reference
Gazzaniga G, Menichelli D, Scaglione F, et al. Effect of digoxin on all-cause and cardiovascular mortality in patients with atrial fibrillation with and without heart failure: an umbrella review of systematic reviews and 12 meta-analyses. Eur J Clin Pharmacol. 2023 Apr;79(4):473-483. doi: 10.1007/s00228-023-03470-y. Epub 2023 Mar 6. PMID: 36872367; PMCID: PMC10039090.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10039090/
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CPE Information
Learning Objectives
Upon successful completion of this knowledge-based activity, participants should be able to:
1. Apply information on the potential uses and harms of digoxin
2. Apply a strategy for monitoring digoxin in heart failure patients
0.05 CEU/0.5 Hr
UAN: 0107-0000-23-400-H01-P
Initial release date: 12/18/2023
Expiration date: 12/18/2024
Additional CPE details can be found here.
One of the oldest medications in our pharmacopeia is digoxin. It may be used for atrial fibrillation and heart failure, although not as a first-line agent. Despite this, digoxin use is on the rise. Join host, Geoff Wall, as he evaluates why more prescribers are using digoxin.
The GameChanger
No new randomized controlled trials have been published to justify the increased use of digoxin. However, when used, providers should routinely monitor digoxin levels.
Host
Geoff Wall, PharmD, BCPS, FCCP, BCGP
Professor of Pharmacy Practice, Drake University
Internal Medicine/Critical Care, UnityPoint Health
Reference
Gazzaniga G, Menichelli D, Scaglione F, et al. Effect of digoxin on all-cause and cardiovascular mortality in patients with atrial fibrillation with and without heart failure: an umbrella review of systematic reviews and 12 meta-analyses. Eur J Clin Pharmacol. 2023 Apr;79(4):473-483. doi: 10.1007/s00228-023-03470-y. Epub 2023 Mar 6. PMID: 36872367; PMCID: PMC10039090.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10039090/
Pharmacist Members, REDEEM YOUR CPE HERE!
Not a member? Get a Pharmacist Membership & earn CE for GameChangers Podcast episodes! (30 mins/episode)
CPE Information
Learning Objectives
Upon successful completion of this knowledge-based activity, participants should be able to:
1. Apply information on the potential uses and harms of digoxin
2. Apply a strategy for monitoring digoxin in heart failure patients
0.05 CEU/0.5 Hr
UAN: 0107-0000-23-400-H01-P
Initial release date: 12/18/2023
Expiration date: 12/18/2024
Additional CPE details can be found here.
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. I'm a professor of pharmacy practice at Drake University and Turtle Medicine Clinical Pharmacist at Iowa Methodist Medical Center here in Des Moines.
Speaker 1:Iowa.
Speaker 2:So today we are going to talk about something new, but something old as well, and that is digoxin. And yes, digoxin has been around for a long, long, long long time. In fact it's one of the earliest drugs in the pharmacopoeia. But I personally and I've talked to colleagues of mine around the country have seen kind of a stupefying comeback or increase in the use of digoxin, and so that, coupled with the new meta-analysis that just came out looking at digoxin, I kind of thought maybe it'd be time to talk a little bit about why the comeback. I mean, we digoxin had been real popular in the 70s, 80s and maybe even early 90s and then its use really kind of fell off the map. And if you look at the latest guidelines for heart failure from the Marine College of cardiology, they don't even really hardly talk about digoxin. So, and it's certainly not a part of goal-directed therapy. So why have we seen such a comeback of it?
Speaker 2:So you know, a dig, of course, is an incredibly old drug. It's one that I think most pharmacists remember you know from if they ever took a pharmacognizia or weeds and seeds class. I certainly did back in the day that it came from the Fox Club, the Look Club plant. It's been used for about 450 years and in fact it's some of the earliest reported use of it, to come back from the 17th century. In particular, a guy named Nicholas Culpepper was probably the first person in writing to talk about the medical uses of the Fox Club plant. Now, my guess is it's been used for many years before that, but that was the first written publication with it. And then over the years, of course, more and more physicians, especially in Britain, had started to use it. In particular they used it for dropsy, which was the old term for pulmonary edema, again in most cases probably associated with heart failure, and other people had noticed that it slows the heart down as well.
Speaker 2:And in the late 19th and early 20th century when atrial fibrillation was basically described for the first time, there was a physician named Sir for James McKenzie who then said hey, you know, we know, digital digitalus decreases heart rate. Is our possibility that perhaps we could use it for for this indication? The actual drug, digioks and if you don't talk about, you know, using just basically scraping stuff off the Fox Leap plant was actually isolated by a guy named Dr Sidney Smith in 1930. And he used something called the calorie action to basically derive pure digioks and from the Fox Club plant and it, you know, then started to get used very commonly really from the 1950s to the 1990s for both heart failure and atrial fibrillation. And the reason for that, of course, is that it's unique among all the drugs really in the pharmacopeia that are cardiovascular nature and that is a positive ionotrope. It increases contractility of the heart. But it's a negative chronotrope. It decreases the heart rate and really that's the only positive chronotrope we've ever had that does that. They've over the years they've tried to come up with other positive ionotropes for the treatment of heart failure, making sense kind of increase the contractility, and every other time we've tried to do that it also increases heart rate and has led to bad outcomes, and so I think it's one of the reasons why digioks and is kind of stayed, you know, at least on the pharmacopeia someplace that hasn't completely vanished from the earth, in that it increases contractility but decreases heart rate, like all old old drugs. There was very little heart evidence, you know good randomized control trials that suggested its benefit. And then in the 1990s, probably the best study that was done or maybe ever will be done though I hope that's not true was called the unimaginably named dig study, and this was the largest study ever done with digioks and heart failure. I basically found that it did improve symptoms and it did decrease hospitalizations, but the original analysis didn't find it if I had a difference in mortality time, that it didn't improve or worse in mortality, but a sub, a post hoc analysis that was published a couple years later in fact did find that digioks and had an increased mortality in heart failure, especially if serum levels were high. And that's the other piece with serum levels is that in most hospitals the reference level for digoxin levels is one two, and the original post hoc analysis of the ditch study found that in fact levels above 1.2 are associated with increased mortality and levels from 0.8 to 1.2 actually were mortality neutral Atrial fibrillation we haven't seen an as big a study done as in heart failure, but several in-bed analyses and retrospective studies have found, as far as the mortality piece, pretty much the same thing that atrial fibrillation, as levels exceed 1, 2, 1, 3, also has an increase in mortality.
Speaker 2:Also, remembering that digoxin works as a negative chronotropic effects are actually mediated because it increases the parasympathetic nervous system. One of the things that it makes it not a great drug for rate control and atrial fib is the fact that you know it's parasympathetic mechanism. So you know, yes, if you're just laying there on the couch watching television, it'll keep your heart rate under control. But if you go to shovel snow or exercise or anything along those lines, you're activating the sympathetic nervous system and that is always gonna overwhelm the parasympathetic nervous system and people's heart rate goes right up. So it's very, very rare to see anybody on digoxin alone for rate control, because by itself it just doesn't do a very good job.
Speaker 2:You I have seen a big uptick, especially in my hospital where my cardiologists are using dig loading doses, so kind of the classic 0.5 milligrams times one and then 0.25 milligrams times two at six hour intervals afterwards to get acute control of heart rate in atrial, in acute atrial fibrillation in the hospital. Again, to my knowledge the evidence on that has never been very good and where I get kind of dismayed in its use, particularly as patients with septic shock on pressers. Again, these patients are getting this huge adrenergic surge and so it's probably unlikely that loading these patients with a parasympathetic drug is really gonna do anything.
Speaker 2:So, you know, that's kind of the background of atrial fib and heart failure at digoxin. Now, serum levels of Dejaxon have always been somewhat controversial If you've ever read the classic book the House of God, which is, I think, almost required reading for anybody entering medical school a book about, basically so, an intern basically surviving their residency at Massachusetts General Hospital in the 1970s.
Speaker 2:One of the attending physicians' characters in that book says I don't give a damn what is Dejaxon level is. That was kind of the, I think, prevailing thought among cardiologists throughout the 80s and 70s, 80s and 90s is yeah, you can get levels if you want to, but they don't really mean anything, so I'm not going to do anything about them. I would argue that since the DIG study has been published and since other studies have suggested this increased mortality with high serum levels or higher serum levels that serum levels in fact really do matter. I think if you read people who are actually using Dejaxon in a thoughtful manner primarily several cardiology pharmacists that I either have talked to or have read some of their stuff on they note that they're actually very aggressive about monitoring serum Dejaxon levels and one of the problems that you run into, as I said, is that traditionally in most hospitals the serum levels referenced are one to two, and again, that's wrong. You really should not be targeting levels above 1.2, and then some people even say one. They should really be targeting levels kind of in the 0.5 to 1 or 0.5 to 1.2 range, and so it's going to take some education.
Speaker 2:When you know, when someone gets a DIG level and it isn't marked red in your electronic medical record that tells you there's something wrong, they're likely to just leave it. And I think that we need to do education on both sides of the fence. We need to talk to our lab colleagues and say, look, we need to change the reference range, though my attempt to do that in my hospital has largely failed, because even though I show them the studies, they say, well, that's that's, you know, that's not what our reference textbooks say. So we're just going to leave it the way it is, and I don't know if any listeners out there have had more success than I have done that. But even if you can't do that, talking to the prescribers who use this medication and say, yes, I know it's, it didn't show a red in the results, but we really need to adjust this.
Speaker 2:And again, that's because of this growing body of literature that suggests that higher cancer levels are associated with increased mortality. So again, I've seen, you know, a kind of a semi inexplicable rise of digoxin, primarily for atrial fibrillation, but also in some cases now for heart failure, and I know that some cardiology experts have advocated that. You know, if we're using other medications whose primary role it is is to decrease hospitalizations and improve symptoms, why don't we do that for for a digoxin? And I get that argument. You know that, that you know we use a lot of other medications, primarily things like the mero, corticoid receptor antagonists and really even in Tresto has most of its data in in in decreasing hospitalizations.
Speaker 2:Yes, it may have some role in decreasing mortality. The STL two drugs are kind of the same way. Their primary outcome, if you look at the big studies, has has, yes, there's some decrease in cardiovascular mortality, but it the prime mover with those studies has been largely improving symptoms and decreasing hospitalizations for heart failure. So I do get that, that, that line of theory. I think the only real big difference there is that we have large randomized control trials, that that, that show us that, and we just really don't have that with ditch, especially in the modern era. I mean, the ditch ditch study was done in the early 1990s where, yes, ace inhibitors were primarily used but even then beta blockers were just starting to be used for for heart failure. Mineral corticoid receptor antagonists weren't used at all. And of course you know the neprolysin drugs and the STL two drug weren't even invented yet. So now I think you know, because of the rapidly shifting landscape it's hard to say, well, hey, you know, we're just going to use a study from the 1990s to kind of figure that out. So the other reason this really kind of triggered me wanting you to do a pot on this was was the fact that, yeah, just recently there was a fairly nice meta analysis that was. That was done taking a look at this, and you know it was a systematic review. You know that again, I think you know people are and you see these meta analysis ever so often trying to say, okay, you know, can we really put these small older studies together and try and figure out you know what, what the overall benefit of digoxin and what the harm is. So in this meta analysis and we've got a link to the, to the study in our in our show notes they looked at patients with heart failure who did receive digoxin. It wasn't just randomized control studies, they also looked at retrospective studies and they wanted to focus on half ref, which makes sense. I don't think anyone ever thought that this drug would work for half, because decreased cardiac output is not the problem in those patients. So it's patients who really have primary pump failure that you would think positive ionotrope would help with.
Speaker 2:So they looked again at a number of studies. I think they went back to the early 70s. So again even some old or old studies that had looked at Joxson. They initially looked at 397 articles after initial search. Then, after removing duplicates and reaching consensus about what the screening was, they finally ended up with 11 studies that met eligibility for being in the meta-analysis and they used the standard Prisma design to make sure it's done and looking at that, so the study itself looked at. Again there was three randomized control studies. That rest was retrospective studies and again going way back to the 1980s. So again you have to keep that in mind.
Speaker 2:But they wanted to look at all-cause cardiovascular mortality in heart failure and they basically found that actually Joxson was associated in these studies when they pulled everything together with an increase of mortality in the overall population with a hazard ratio of 1.19. And that was statistically significant. The heterogeneity was pretty high, as you might imagine, because you're talking about studies kind of both prospective and retrospective from the 1980s to the early 2000s, kind of all along the line there. So the I2 statistic was 75%. So kind of keep that in mind. But they rated it using the grade criteria as moderate certainty of evidence.
Speaker 2:And then they wanted to look at as a lot of patients with atrial fib also or heart failure also of atrial fibrillation. So they did a subgroup analysis in patients who have the combination of heart failure and atrial fibrillation. I think largely, because if there were to be a benefit with digoxin it would be you're kind of treating two birds with one stone If they have atrial fibrillation and heifereth, that might be a little bit to affect things there. So that made sense to me. Only eight studies out of the 11, they originally looked at had any data at all in patients with the combination of heart failure and atrial fibrillation and they found that again, digoxin was associated with an increase in mortality in the patients with combined atrial fibrillation and heart failure, with a hazard ratio of 1.23, and was statistically significant. Again very high heterogeneity 70%. But again this was a low certainty of evidence because the decreased number of people. So the bottom line was that cardiovascular mortality and all-cause mortality when they broke it down showed an increase in mortality.
Speaker 2:Now one of the arguments as I've said, is that none of these studies, or very few of these studies, actually looked at serum levels and correlated them with these outcomes, and other than the did studies, my knowledge none have done that, and so the authors of the meta-analysis note that may be the main player here, and it may be the main driver in whether digoxin actually has any positive benefit or is at least mortality neutral if it improves symptoms and decreases hospitalization.
Speaker 2:If we could get to a point where we could identify patients that digoxin is mortality neutral and you can keep serum levels at kind of 0.5 to one, that it might actually have a role. But the bottom line was they couldn't show that in this meta-analysis, and so their thoughts were that at this point digoxin probably should not be used in most patients with F, for F and A with or without atrial fibrillation, because of the outcomes that they found. So what does this all mean to the practitioner today? And what's kind of my cake on that? We're gonna talk about that after a message from our sponsor, ce Impact.
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Speaker 2:So we are talking about digoxin.
Speaker 2:The comeback whether it's a deserved comeback or not, I guess, is my question, because this meta-analysis that we just discussed and this isn't the only meta-analysis in the last ten years that's been done basically show the same thing that digoxin in general is associated with an increased risk of mortality and atrial fib and heart failure.
Speaker 2:Now it is worth noting that there's a lot of experts in the field who have largely, I would say, dismissed, but have have suggested that perhaps we shouldn't put a lot of faith in especially retrospective studies that have shown this, in particular John Mertola, who's a cardiologist and if you are on social media, the guy is a very prolific social media guy and he's a I don't know if you call him an influencer, but he's certainly well known in the world of cardiology. He's also what I would call a maverick. He's one of those contrarian clinicians who I think in many cases quite rightly wants to look at dogmas and make sure that what evidence supports the dogma. That being said, I think my personal opinion is he kind of went off the deep end during COVID because he's a noted anti-vaccine and anti-masking guy and he's been very clear about that, I think, in the social media. So I mean again, that kind of made any respect I had for the guy kind of go out the window. But he has largely advocated for the use of the joxen and who knows?
Speaker 2:maybe that's one of the reasons why a lot of cardiologists who listen to this guy think, yeah, hey, this is a good idea. He notes that observational studies, by their very definition, may have biases that we can't account for and that, you know, did joxen has a track record of 400 years of being safe, you know, or being used anyway for heart failure. He notes that a lot of the studies that were done, even though they were done before the modern era but again, we're observational studies and may have bias associated with them, and his personal opinion is that he feels that his personal practice has that it does improve symptoms and people feel better when they take it. I get that point, I get.
Speaker 2:We have drugs that have been in the pharmacopoeia for decades or centuries that have not really undergone rigorous randomized control studies. Other drugs, like colchicine, which until recently had no randomized control studies and now only has one small one to support its use, nitroglycerin has been used for hundreds of years for chest pain. There are, to my knowledge, no randomized control studies, you know, looking at mortality with nitroglycerin. So you know, I get that argument. But considering that the evidence that we have does show an increase in mortality, and given that we have no evidence at all in the modern era with gold directed therapy, with the neperolison inhibitors and with the SCL2 drugs. I would argue that we really need to do a large RCT with patients on modern gold directed therapy and then, if they need extra digoxin or they need digoxin for symptoms or for heart failure, that is what actually needs to be done Now.
Speaker 2:The drug, of course, has long been generic. It would have to take something like the VA system and, as we've noted on this pod several times in the last couple years, the VA system, I think, is doing a good job of trying to answer a lot of these you know clinical conundrums using medications that are or are usually generic, so they'll never be sponsored by a drug company, and they're using this very pragmatic design to try and answer these questions where you know they don't force a placebo and a active control, and try to, you know, deploy that in VA centers. They basically utilize a pragmatic system where they have patients on standard of care and then they ask not tell physicians and appropriate patients to utilize whatever therapy they're using.
Speaker 2:So you know if anyone high up in the VA is listening. That would be nice, you know. Yeah, I think this really needs to be answered because I think if we're going to see the rise in digoxin use, I think we need to have some evidence looking whether it's beneficial or not. I've certainly seen my fair share of weirdo side effects with digoxin. Of course, you know bradycardia is the big one. Almost everybody who's on digoxin at a decent dose is going to develop a PR prolongation and at least first degree heart block. That, fortunately, is not usually harmful in patients, but you can't get significant bradycardia and more advanced heart block which can be life threatening.
Speaker 2:It also, of course, increases potassium and then some other common side effects. You know the I'm sure every pharmacy student in the universe has taught about the blue green halo effect when they, you know, in visual disturbances. So I've been a pharmacist for 30 years and never had anybody complain of that. Other common side effects anorexia and confusion of the elderly and Anna and many others as well. Plus, it's a very dirty drug from a drug interaction perspective. It has many interactions because it goes through primarily the G-like a protein pathway, but it also has some cyclone P450 actions as well, I think the drug that it probably most notably you need to watch out for is amiodarone Because, again, if you're using a natural fibrillation, a lot of these patients may have background amiodarone or you may be seeing amiodarone started on patients on digoxin and, as I understand it certainly this is what I've done for many years is, in someone who someone's on digoxin and you start amiodarone, you can pretty much expect a 50% or more increase in their serum level.
Speaker 2:And so you're gonna wanna back off by about 50% on the digoxin dose kind of empirically in these patients. Are there any other tips and tricks to monitoring these patients? I would say that if you're going to start digoxin for maintenance of atrial fib and heart failure and again I'm not suggesting that you do that, but if you do started, or you? Inherited a patient who's been on this. I think that at first you wanna go ahead and just get a serum level at first and kind of a baseline once they're at steady state.
Speaker 2:Remember, the ditch has a very long half-life, so getting a drug level the day after you start digoxin isn't gonna tell you anything. So you really want to get a baseline after about a week and that's in patients with normal renal function, because digoxin is at least partially cleared renal. You may have to go longer than patients with some degree of renal insufficiency. And then you wanna make sure again. Most experts are saying somewhere between kind of 0.5 and one or 0.5 and 1.2. Basically, if they develop worsening chronic kidney disease or certainly in the setting of a patient who's admitted with acute kidney injury, you're gonna wanna repeat another serum drug concentration or if they get started with medications that you know may interact or if they just
Speaker 2:start developing signs and symptoms. They may represent toxicity, such as bradycardia and hyperkalemia, both of which are related to serum drug levels. So if you have someone whose heart rates in the 40s and their serum level is 1.4, you very well may be able to continue the drug. Again, I'm not necessarily suggesting you should, but if you wanted to continue the drug, you could basically adjust the dose down and go from there. The other problem, of course, is that remember, the ditch only comes as two dosage forms, really when you're talking about the tablets, and that's 0.125 and 0.25 milligram tablets, and so doing fancy pharmacokinetics never made any sense to me in a drug that only comes in two dosage forms. So you're really just gonna have to kind of do your best and cut the dose in half If they're at steady state. If you're trying to do that, or in some cases I'll even recommend dosing the drug every two or three times a week instead of every day.
Speaker 2:If you've got a patient who you absolutely insist on using the joxin for and their renal function is not good, you may well have to dose it a couple of times or three times a week. So again, for the third or fourth time, I am certainly not advocating the use of this, but for better or worse. I'm seeing, in particular, some cardiologists who've decided to kind of pick up the joxin ball again and start using it in heart failure and, in some cases, atrial fib. If that is the way we're going to go with the use of this medication, I think we owe it to patients to really not ignore the house of God and really take a look at monitoring these patients closely, including a discerned drug levels. So that's it for this week of Game Changers. Again, 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. We'll see you next time.
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.