Narrator - Dr. Abel 00:00 Welcome to HelixTalk, an educational podcast for healthcare students and providers, covering real life clinical pearls, professional pharmacy topics and drug therapy discussions. This podcast Narrator - ? 00:11 is provided by pharmacists and faculty members at Rosalind Franklin University, College of Pharmacy. Narrator - Dr. Abel 00:17 This podcast contains general information for educational purposes only. This is not professional advice, and should not be used in lieu of obtaining advice from a qualified health care provider. Narrator - ? 00:27 And now on to the show. Dr. Sean Kane 00:31 Welcome to HelixTalk, Episode 121. I'm your co host, Dr. Kane, Speaker 1 00:35 and I'm Dr. Patel and in today's episode, but wait, there is more. We're going to talk about unusual Warfarin interactions. Dr. Sean Kane 00:44 The emphasis of today's episode is to talk about a handful of drug interactions that are relevant for warfarin, some of which are commonly known like the green leafy vegetables. But what about some of the other food items that are out there that do have a good amount of vitamin K in them that aren't green and leafy? So we're going to talk about a variety of drug interactors that are important for clinicians to know when it comes to warfarin or Coumadin. Speaker 1 01:08 And some of the audience may wonder, why are we still talking about warfarin? Right? Because we have doacs, and lot of patients who were on warfarin before have been transitioned to doacs. However, there are still some group of patients still remain on warfarin. These are your valvular atrial fibrillation patients, those who have mechanical heart valve, poor renal function, poor liver function. Maybe they have active liver disease. Their post transplant, they have certain thrombophilias, where, you know, doacs have not been studied yet. Or maybe they are taking those super CYP3A4-interacting drugs, where doacs are kind of borderline contraindicated, like phenytoin, for example. So that's where the use of Warfarin comes in. And so all these drug interactions we're going to talk about are still relevant in those who are still using warfarin. Dr. Sean Kane 01:56 And Dr. Patel, I can tell you, in my everyday clinical practice, absolutely we still see plenty of warfarin. It's not going away anytime soon, so absolutely, this is still clinically relevant. And as I mentioned at the beginning of the episode, there are so many interactors with warfarin. We could be here for many hours talking about all the potential drug interactions. It's a whole laundry list, and it's actually really hard for students and clinicians, to kind of keep straight, but to kind of summarize very briefly, some of the big players, these are going to be all antibiotics, CYP inducers and inhibitors that can change warfarin metabolism in the liver, food drug interaction. So this is foods that contain vitamin K, and then drugs that alter protein binding, so they can compete for binding site on albumin, and that can force Warfarin off of its binding site and change its kinetic profile. So, you know, those are four of the kind of core things that come up in clinical practice. But as I said, we've kind of picked out a handful of things that are other things that we want to emphasize when it comes to these Warfarin drug interactions. Speaker 1 03:00 And I'm actually very happy to talk about this, because I've personally seen and managed some of these interactions in my own practice. So I'm gonna throw in some examples of like, kind of like, my personal case reports that I've noticed in the clinic itself, and some of these niche type drug interactions. But one thing we need to make sure that the audience knows, as you just said, Dr. Kane, there's just so many interactions, right? So this is this list we are talking about today. Is not comprehensive. There's just some of the handfully selected a few that we are going to go over and. Dr. Sean Kane 03:32 Dr. Patel, I think it's also important that we talk about nomenclature here. So when we say an interaction, most patients, when they hear that term, they think, well, it's interacting, therefore I can't take it nine times out of 10. We can actually manage these interactions. And for each of these examples that we're going to go through, we will talk about what is the typical management but it's important, especially for students, to realize that just because a drug interacts with warfarin, that doesn't necessarily mean it's contraindicated. It doesn't mean that you can't do it. Usually it means that you have to monitor INR more frequently, and sometimes it means that you have to adjust your Warfarin dose empirically. You know when the interaction occurs, prior to getting, you know, future INRS. But generally speaking, these are manageable drug interactions, because we do titrate Warfarin as a dose, you know, a factor of 10, like a typical dose of Warfarin is between one and 10 milligrams per day. So we do have a lot of flexibility in terms of how much Warfarin we give a patient. Speaker 1 04:29 Yes, I 100% agree with you, although, as we will talk about some of those interaction I'll tell you this one item that I always tell my patients to stay away from. There is no no in my dictionary when it comes to Warfarin management, just like you said, we can always, you know, adjust the dose of the warfarin, but there is one that I said no to, and we'll go over that later. Dr. Sean Kane 04:51 Love it. Well, let's start with our first one. Dr. Patel, so what was, what was one of your first kind of underdog drug interactions that came to your mind? Speaker 1 04:58 This, this is an underdog. Interaction, but I'm kind of grouping it along with some some of the common things that we have heard right. Like N said, so we're going to talk about the group of substances that have anti platelet effect. And obviously, when they're used along with warfarin, they all may increase the risk of bleeding. So these are agents such as, you know, SSRI, selective serotonin reuptake inhibitors, our NSAIDs, non steroidal, anti inflammatory drugs, and then fish oils. And these Dr. Sean Kane 05:30 are a little bit tricky, Dr. Patel, because when you have these anti platelet interactions, and we haven't even talked about something like clopidogrel or Plavix, when you have these interactions that actually will not modify your INR. So unlike with SIP interactions or vitamin K related interactions, you won't have a laboratory value that tells you that the patient's blood is thinner than it should be, or that you want it to be correct. Speaker 1 05:56 And so if you're interpreting this interaction, really it's increased risk of bleeding and bruising is the, basically the gist of interaction we are seeing with these agents Dr. Sean Kane 06:08 now in terms of what we'll pick on SSRIs, for example, traditionally, most clinicians do not associate SSRIs with bleeding, so this one might take people off guard a little bit. And I think clinically, most of the time that this comes up is because of an interaction alert that may come up in a computer physician order entry system or an electronic health record where a patient's on an SSRI and then Warfarin is prescribed, and it says that there's some interaction here. So Dr, given that we don't associate SSRIs as an anti platelet drug, necessarily? What's going on here? Speaker 1 06:43 Yeah, this is actually my favorite pimping up question for my happy students when they're at my rotation is to go back and learn about what effect does serotonin has on platelet aggregation, right? So there are serotonin receptors on platelets, and serotonin binds to these receptors and helps with the platelet aggregation. When we have SSRIs in the system, they selectively reuptake this inhibition. There is not enough serotonin available. Platelets don't make their own serotonin. There's not enough serotonin available to assist with platelet aggregation. Now, platelet aggregation doesn't solely rely on serotonin. However, serotonin is one of the factors that helps with plate aggregation. So there is this thought that not having enough serotonin, and therefore not having enough plate aggregation, can then further increase the risk of bleeding. Dr. Sean Kane 07:36 And you know, of course, this is the proposed mechanism of it. It's always nice to have some clinical data that shows whether this truly increases bleeding risk or not for patients. So I'm assuming Dr. Patel that we studied this at least once in terms of whether this is a true effect or something that is seen in a test tube, but not in real life, humans, right? Speaker 1 07:56 And you know, this is going to be a theme throughout the discussion today, in terms of, you know, what's the evidence behind this drug interaction? And so we're going to talk about small studies, small database cohorts, small case reports, a few isolated case reports. You know, we're not going to go into the detail of like, where the strength of evidence lies. Obviously, we know case reports are not very strong, but that's what we have in case of the SSRIs they looked at, there was a study done called atria cohort. They looked at about 13,000 patients in the Kaiser Permanente database, and they found that patients who were on SSRI or venlafaxine, there were higher bleeds. Reported those 2.32 bleeds per 100 person years of exposure versus 1.35 bleeds per 100 person years of exposure. And this, this, this finding was statistically significant. Dr. Sean Kane 08:52 You know, we do have other data. You know, some case controlled studies have really failed to show this as a thing. But then we also have some data that shows increased risk of hospitalization due to non GI bleeding. So the evidence is a little bit mixed. It's certainly a precaution, I would say, but maybe not something that is definitively proven as definitely causes an increased risk of bleed in all patients, but it's something that we should be aware of as clinicians correct. Speaker 1 09:19 And then the next agent that's an anti platelets is our NSAIDs. We commonly find patients being on aspirin for cardiovascular reasons while they're on warfarin. But this, this is not about aspirin. Using aspirin for cardiovascular reasons and needs while on Warfarin is okay. We know there is this drug interaction. This is going back to what you said, Dr. Kane. We Kane. We don't have to stop any of these agents. We just have to monitor closely. We're going to talk about the other NSAIDs, the NSAIDs that are non specific Cox one, Cox two inhibition and are used for pain management. And so this is the second piece of factor. It comes into play with platelet aggregation, right? We know how ancids work, Cox one enzyme converts prostaglandin into thromboxane a two. The you know, thromboxane a two is, again, one of the factors that activates the platelets and gets them ready for the aggregation. If we block the Cox one, again, this is non selective NSAIDs, therefore we then block the activation of the platelets and block the aggregation again, so that leads to increased risk of bleeding. Dr. Sean Kane 10:29 So Dr. Patel, we know for sure that NSAIDs do increase the risk of bleeding, especially GI bleeding, because it can cause gastric ulcers. What kind of data do we have specific for this particular interaction in terms of NSAIDs plus warfarin. Speaker 1 10:45 Yeah, so in looking at one of the drug interaction databases to find the evidence, you know, I was actually really surprised to see that there were quite a few, eight to nine studies that showed no interaction, no hyper proton, dynamic interaction when NSAIDs were used along with warfarin. But then subsequently, we also had some small case studies, some case reports that showed increase in minor bleeding episodes, so again, not major minor bleeding episodes, as well as increase in pro time. And we had one case report where in an older women fatal GI bleeding was reported. Dr. Sean Kane 11:24 So I would assume Dr. Patel, in your clinical practice, despite that handful of data, that generally speaking, you're going to try to avoid NSAIDs if possible in patients who take warfarin, right? Speaker 1 11:35 Oh, absolutely, yeah. I mean, you know, it not only in my practice. I think that's practice across the board where we tell patients not to go with NSAIDs as means of pain control, but use something else. Dr. Sean Kane 11:49 And then the last one that we mentioned in terms of this anti platelet effect is fish oil or omega three fatty acids. We do have kind of in vitro evidence that this can impair platelet aggregation and decreased concentrations of antithrombin three, fibrinogen and certain clotting factors, like clotting factors five and seven, usually, though, in human data, patients have to be exposed to a pretty good amount of that fish oil before we see any of this anti platelet like effect, or anticoagulant like effect, most patients take about a gram A day, which is what they'll get over the counter. Although therapeutically, to get a good cholesterol effect, you're you're going to need more than that, something like four grams a day. And some of the data related to bleeding approaches six grams per day. So for the most part, this is not going to be an issue in most patients, because many patients can't tolerate the very high doses of fish oil. But if you had a patient on warfarin that was taking a higher dose of fish oil, just like the other interactions, this would be a precaution in terms of the increased risk of bruising and bleeding because of the fish oil potentially increasing that risk of bleeding. Yeah. Speaker 1 12:58 So you know, what do if we have these drugs, and you know, patients are on warfarin, they have to be used together. That's fine. We're going to educate the patient, obviously, about increased risk of bruising and bleeding. They're going to have to monitor for that. We don't necessarily have to monitor INR, as we said this, these drugs mostly do not increase or decrease INR. And so we're going to teach the patients some of the common terms of where they're going to have to monitor the bleeding and bruising. And when it comes to NSAID, you know, my rule of thumb is just avoid NSAIDs. You know, when we're using Warfarin at all possible? That being said, I had some patients in my practice where they they needed to be on NSAIDs for osteoarthritis control, for example. Could we do COX‑2 specific NSAIDs for them? Maybe knowing that COX‑1 inhibition is what impairs the platelet aggregation. Maybe COX‑2 specific ones, like celecoxib, might be the right one for them. But again, we have to individualize the approach for the patient. Dr. Sean Kane 14:04 And Dr. Patel, you know, a logical question that commonly comes up when I tell a patient No, NSAIDs like Aleve, Motrin, Advil. The next question is, what about Tylenol? So is there a concern about acetaminophen in patients who are also taking warfarin? Right? Speaker 1 14:21 Right? And so the golden approach for pain management is we can't take away the drug that treats the pain management without giving us, you know, alternative. And so for those who we say no to NSAIDs, you know, Tylenol, acetaminophen becomes the go to agent for pain management when they're on warfarin, right? There is data that acetaminophen interacts with the warfarin. However, despite this interaction, is deemed to be a safer choice to be used with warfarin, as opposed to the NSAIDs. Dr. Sean Kane 14:52 So is there kind of biochemical proposed mechanism of how acetaminophen could potentially interact with warfarin? Speaker 1 15:00 Yeah, there is a theory about CYP interaction, which competitively inhibits the warfarin metabolism. There is some information about the toxic metabolite of Tylenol called N-acetyl-p-benzoquinone imine that basically interrupts the vitamin K cycle, and it disrupts also the vitamin K-dependent carboxylase. And then there is possible formation of vascular peroxynitrite, which can then further disrupt the vitamin K cycle by, you know, inactivating the VKOR, which is the vitamin K epoxide reductase enzyme. Dr. Sean Kane 15:43 Suffice it to say, there are proposed mechanisms of how this could happen. Terms of the clinical data, we do have plenty of case reports that show in patients taking warfarin, who are given acetaminophen, that their INR went up, and we're looking at INRS of four all the way to 16. We also have similar case reports of bleeding occurring everything from kind of more benign gumbling to very serious retroperitoneal hematomas, GI bleeding, et cetera. Most of these are in patients that are taking pretty good doses, one to four grams per day of Tylenol. And they also do it for multiple days, you know, four to 10 days. Now, one of the challenges here, and Dr. Patel, you kind of mentioned it earlier, is that we have to go with the best available evidence, and at least for this particular interaction, most of the best available evidence is going to be these case reports. And I can tell you, Dr. Patel, if you and I wrote up a case report of a patient taking warfarin, we gave that patient Tylenol, and their INR was the same, we probably wouldn't be able to get that published right, because that's not interesting. So sometimes these case reports tend to be published at our these more outlandish things. And I can tell you that in patients that take warfarin, their INRS kind of go up and down, and sometimes we have no clue why it happens. So it's really hard unless you do more of a true trial of multiple patients over a longer period of time to really have a firm answer for this kind of interaction. But I would say, generally speaking, it potentially could impact your INR, but it's probably not as serious as the NSAIDs as an example in terms of the risk of bleeding. Speaker 1 17:18 That's That's correct, and that you know, following some of these case reports, some small prospective trials, as well as a meta analysis of these prospective trial was done, and they that showed about point six to point seven point elevation in INR, in those who were taking acetaminophen versus those who were not taking it. So we we know like it increases the INR we need to monitor it. Does it increase the risk of bleeding like the NSAIDs do? Probably not. Dr. Sean Kane 17:50 But again, this falls in that category of monitor a little bit more closely in patients that take it, probably if they took a dose here and there, not a big deal, but if they're going to take it every day at pretty good doses, we potentially would want to adjust their Warfarin dose appropriately and have them continue that same regimen. You know, consistency is the key with Warfarin drug interaction. So if they're going to do it, ideally, we want them to continue doing it consistently. And if they change the practice of how much Tylenol they need, potentially we would have to monitor INR closer and adjust the warfarin doses appropriate, right? Speaker 1 18:24 And just kind of giving a practical, practical clinical example, I always document and review patients concomitant conditions such as, maybe they have a pain syndrome, they have a, you know, degenerative joint disease. They're probably at a pain clinic. I keep an eye on what's going on in the pain you know, treatment. Because if that pain treatment is not enough, you know, their go to medication is Tylenol that's available over the counter, right? And so every time you speak with a patient, you kind of have to evaluate, what's their pain control? Are they using more Tylenol or not? You know, one Tylenol dose, 500 milligram, you know, once in a while, twice a month, once a week. It's not going to be the end deal. It's more of the larger doses on a consistent basis, is what mounts to an interaction that then would lead to perhaps a dose change with warfarin. Dr. Sean Kane 19:18 You know, another common interaction that comes up. Dr. Patel is another readily available medication that is alcohol. So this is a common question in terms of, you know, can I take x medication with alcohol? What is the typical response when it comes to Warfarin with alcohol Speaker 1 19:37 and so, you know, Dr. Kane, just like any medications and alcohol. You know, as pharmacists and healthcare providers, we say don't use alcohols when you're taking medication, right? But it's interesting to see the effect of alcohol on warfarin interaction, and it really depends on is this new use? Is this chronic use? News. And so are we talking about, you know, those weekend binge drinking versus somebody who has, you know, alcoholism problem where they're drinking heavy amounts every day, the interaction is going to be a little different. So when it comes to acute binge drinking, this is more than two drinks per sitting alcohol decreases the warfarin metabolism, and so it results into an increased INR. However, flip side somebody who is using alcohol heavily on a chronic basis, so they have alcoholism, you know, diagnosis per se, these people are using, you know, more than 250 grams per day, longer than three months, alcohol is going to somewhat vary the effect of on warfarin, either it's going to increase or decrease the the effects of the warfarin. Most cases, we see decreased effect of the warfarin with chronic ingestion and Dr. Sean Kane 20:59 Dr. Patel, we haven't even talked about how in patients who abuse alcohol, that they're also more likely to have falls. And frequent Falls is a common reason that we wouldn't even consider Warfarin in certain patients, or anticoagulation in general, depending on the indication, like afib, for example. So someone with frequent falls probably a poor candidate for anticoagulation, and in this circumstance, in someone who abuses alcohol, they're going to have gait balance problems, higher risk of falls, probably that in itself, could also increase the risk of bleeds down the road, especially major hemorrhages, if they were to fall, hit their head and have an intracranial bleed, not necessarily because their Warfarin metabolism is altered, but just because they have a risky behavior associated with falls and bleeding, right? Speaker 1 21:45 And, you know, another common side effect of alcohol drinking, this is in general patient population too, is that it increases the risk of GI bleed, right? And so now we have alcohol that increases the risk of GI bleed, and then Warfarin that can also, you know, increase the risk of bleeding, combine the two together, the risk is further elevated. Dr. Sean Kane 22:08 So in terms of the mechanism, we're looking at inhibiting CYP2C9 metabolism of Warfarin and potentially also displacing Warfarin from its protein binding site. Now we've seen this in vitro, but we haven't really you know, observe this in vivo, human studies to actually prove this as a mechanism, right? Speaker 1 22:26 And then for chronic users, the theory of, you know, this interaction, again, is the induction of CYP2C9 that's where it decreases the concentration. But more so than the CYP induction. They're really focusing on perhaps underlying malnutrition issues, and those who are using alcohol chronically that can lead to the INR alterations. So it's more likely that they believe it's malnutrition causing the issues, rather than the SIP induction. Dr. Sean Kane 22:58 And you know, in terms of the actual human data that we have, these are small studies, a couple case reports, some retrospective database analyzes. So we do have some data supporting this as a true concern in patients that take warfarin, and compared to some of the other data that we have, this is a little bit more robust, but still not a slam dunk in terms of definitely going to see this interaction occur in all patients that ingest alcohol, right? Speaker 1 23:24 And so what do we do for patients who are using alcohol? You know, it's not uncommon where, you know, I'm talking with the patient on a Friday, and they're like, Yeah, I mean, my buddies are gonna go out and have a drink, and it's like, what do you say to that patient, right? Can I have one drink? As I said earlier, as healthcare providers, we say don't use alcohol at all while you're on warfarin, and if you're using it, you know this is what can happen to your INR. So really shared decision making comes in play. You explain to them, you know how exactly this is going to impact their INR. They're going to be in a roller coaster ride that you know, whenever their INR is up, you're going to have to ask them to come sooner for monitoring. It just kind of creates this unnecessary cycle of repeated monitoring, which altogether could be avoided if they are not using alcohol. Dr. Sean Kane 24:15 And of course, the reverse is true. Dr. Patel, if you have a patient who does ingest alcohol and then decides to quit while they're at warfarin. Now you're going to have to come up with a new Warfarin dose representative of the fact that they are no longer taking alcohol. So cessation is just as important as initiation, really, for any interaction, and alcohol is no exception here. Speaker 1 24:37 All right, so another interaction that comes upon frequently is all these herbal products, right again, over the counter, easily accessible. You know, we're talking about various different ones, but some of these are divided into major versus moderate versus minor interaction categories, and so dark. Turkane. What's the first drug that comes to mind when we're talking about medication and herbal interactions? Dr. Sean Kane 25:06 Every time it's St John's Wort, it comes up on every exam question, every board question, every time it's always St John's wort. Speaker 1 25:15 Yeah, and you're absolutely right. This is actually one of those major drug interaction where we know it can, you know, increase Warfarin metabolism and basically decrease the INR along with that major drug interaction, herbal categories, we have things like garlic and ginkgo and grapefruit and, you know, chamomile and cannabis. We're going to talk about some of the ones mentioned here later on, red clover, nicium. But then we have some moderate ones too, such as parsley, ginseng, green tea, ginger and soy. These are some of the common ones that we have patient taking. Dr. Sean Kane 25:56 And you know, again, this is clearly a laundry list of a variety of different herbals. Usually Dr. Patel, my answer when someone says, you know, can I take x herbal for whatever indication, as long as there's not a clear drug interaction and they have no problem affording the medication, generally speaking, I'm typically okay with it, as long as they recognize that it may not do anything. In this case, I'm actually not okay with it, because oftentimes we don't have good data on these herbal drug interactors, and when we do have that data, you know, it's concerning. So generally speaking, in patients who take warfarin, I'm not in favor of them picking and choosing their own DIY herbal regimen that they're going to take, just because it's so hard to figure out what effect that may have on their war. Speaker 1 26:41 Friend, you said it very perfectly. Um, safety is the first thing we look at when it comes to herbal use. And as we know, some of these agents have pretty bad safety report a lot when used along with warfarin. So that's the hard line we draw and say, No, you should not use these products when you are on warfarin. I actually had a pretty interesting case at the clinic. Had a patient had been managing for last nine years, now, eight, nine years, and she's very diligent. She's very compliant. Her TTR is probably close to 80% Dr. Sean Kane 27:16 Dr. Patel, just for the audience, what does TTR mean? Speaker 1 27:19 TTR is time and therapeutic range, basically, however long you have treated the patient, how many times had the patient's INR been in that therapeutic range, right? So whether your range be two to three or 2.5 to 3.5 and it produces a percentage and it gives you an idea how well controlled patients anticoagulation is so this patient had an INR of five. Obviously, she freaks out. She calls, we go through our checklist make sure she's not doing anything that could increase it. I'm perplexed too, because she's very careful. Otherwise, a few hours later, I get a call and say, Kathy, I've been using Ricola herbal cough drops. And so we pull up Ricola Herbert cough drops and find a list of 10 different herbs that are in there, and four of them. You say it, I go into the natural medicine database, Dr. Kane and find severe drug interaction with warfarin, so we found our culprit. Dr. Sean Kane 28:22 And that's so crazy to think about Dr. Patel, because what even healthcare provider would really associate a cough drop as causing anything relevant, especially a drug interaction. But I think it's hard to argue even with that one case report that you had, clearly it can happen, especially if you're combining multiple different herbals and what seems to be a fairly benign over the counter product that a patient chooses to take on their own that isn't a prescribed medication, Speaker 1 28:51 absolutely and that's why you know my first education session with patients on warfarin, it's like Anything and everything you pretty much eat when and consume when you're on warfarin. Could could interact with warfarin. So it's like a universal precautions for the warfarin use. Just assume that it's going to interact. Call your pharmacist, call your doctor, double check before you put it in your mouth. Dr. Sean Kane 29:17 In terms of how these are interacting, clearly, it's going to depend on which herbal you're talking about. St John's Wort comes up so often because we do have good data, that's it is a SIP inducer. So it induces metabolism and decreases Warfarin levels. Therefore decreases INR with all the other herbals. It just depends. So we're looking at some of the herbals are going to potentially impair the absorption of warfarin, so you won't absorb as much. We have some that interfere with metabolism, protein binding, platelet function, gut vitamin K synthesis from bacteria, the vitamin K cycle in terms of its oxidation and reduction, all the way to the impact on coagulation cascade. Unfortunately, because these are kind of unregulated herbal products, it's not. Like manufacturers of ginkgo have to come up with PK simulations, or PK data on how their drug actually causes interaction. So usually we don't have a lot of data in the way of does it interact, or especially less data on how it does the interaction. Usually we don't have specific mechanisms, but occasionally we do have clear evidence interaction does occur, like in your auricula cough trap example, right? Speaker 1 30:26 And think about these other products, right? We have an entire tree, and different parts of that shrub or tree that's used as an Albert product are used so depending on whether you consume the leaf versus the berries of that plant, the concentration of the active ingredient might be different. So again, it's really hard to pinpoint exactly to what degree the interaction is going to occur when people are consuming herbal products. Dr. Sean Kane 30:56 So Dr. Patel, what is your typical approach when a patient says, I want to take cinnamon or whatever herbal what is your approach in terms of identifying whether that's a clinically relevant drug interaction with Warfarin Speaker 1 31:09 or not, right? And so I kind of mentioned earlier that I love to go to natural medicine database. It's by therapeutic Research Center. It gives you a monograph of the drug. And then you scroll down and click on drug interactions, and it'll tell you, you know, how various drug interactions have been reported to some degree, some mainstream databases like Lexicomp and micromatics may have some drugs. However, some of the non conventional drugs are not part of these larger databases. You really have to dive into natural medicines database. Dr. Sean Kane 31:43 And at least from my perspective, Dr. Patel, as I said, my default answer is, no, you may not take that herbal if there's no data for it, and the patient is adamant that they really want to take it. At a minimum, we're going to look at more frequent INR monitoring. But generally speaking, my approach is going to be that they really shouldn't be taking it, because there are so many potential interactions that we wouldn't even know about. So if it has an anti platelet effect that is unknown, for example, the INR will not be impacted, but their bleeding and bruising risk will go up, and we'll never know. So the unknown really bothers me. As the pharmacist who's responsible for the safety of that medication, Speaker 1 32:21 I 100% agree. And so when it comes to Warfarin safety, we take herbals pretty seriously, Dr. Sean Kane 32:27 kind of going along the lines of herbals, but a little different is food. So, you know, herbal products and foods are very correlated with each other in terms of, typically, these are plants that are eaten and things like that. And when I think of food interactions. I would hope that everyone who's familiar with Warfarin thinks of green leafy vegetables. That's like the go to thing in terms of vitamin K containing foods. We always think about that to put a number to it like a typical green leafy vegetable. We're thinking like greens, Brussels sprouts, kale, spinach, broccoli. These are going to contain hundreds of micrograms of vitamin K per serving, anywhere from 100 to 500 all the way to 1000 depending on what green leafy vegetable you're looking at and what resource you're looking at. And just for reference, if you look at like a typical multivitamin, a given multivitamin may have 2550, maybe a little bit more micrograms per tablet of vitamin K. So to have a food item that has 500 like, literally, 10 times more than a multivitamin, these definitely contain a lot of vitamin K to them. But Dr. Patel, you know, I think everyone's familiar with that. What about some of the non green leafy things that are out there that do have potentially food drug interaction that may go off the radar when it comes to warfarin. Speaker 1 33:44 Yeah, and I there was a good preface Dr. Kane about, you know, those conventional ones, but these non conventional ones, again, don't have a whole lot of vitamin K in them, so in order to mount a drug interaction, they have to be consuming a lot of it. But it's worth noticing, because sometimes you call the patient and you go through some of your common interactors in the food, and they say, nope, nope, nope, nope, nope, nope, nope. But then they say, oh, wait a second. You know, I bought a bunch of fresh blueberries from farmers market, and I just like, ate the whole pint in one sitting? Well, that could be problematic. So going with blueberries, yeah, certain berries, prunes, avocados, are fruits that that have not a high or moderate amount, but like mild amount of vitamin K and M. But if they're going to sit and consume a lot of it that could, that could make a difference in their INR Dr. Sean Kane 34:45 and doctor tell just to touch on that. You know, you might say avocado to a patient and they may say, No, I don't eat avocados. But if you say guacamole to a patient that might have a completely different perspective to them, where they say, like you, like you mentioned, oh yeah, I went out and I got. Got a delicious thing of avocado, and I ate half of it. And maybe that's why my INR is now lower than it should be, because I inadvertently didn't realize that I was consuming more vitamin K than I normally do, right? Speaker 1 35:12 And some of these hidden other foods that have vitamin K, like again, in a larger amount, can make a difference. Are beans, like your kidney beans, fava beans, peas, Black Eyed Peas. So kind of legume families oils, right? Canola oil, soybean oil, again, depending on what oil you go with, there is high, moderate and low amount. So olive oil is somewhere in the middle, but then corn and peanut oil is at the low. Margarine has about somewhere in the moderate amount. And then mayonnaise tends to have quote, unquote high vitamin K category. So I've even asked some, some of my patients, did you eat whole lot of mayonnaise, or did you have tuna fish, you know, that was marinated in mayonnaise as a tuna salad. That could make a difference. If I'm not reaching to any of the high vitamin K vegetables, I'll go for some of these underdog foods. Dr. Sean Kane 36:07 Yeah, and you know, protein shakes, meal replacement shakes, especially the ones that are meal replacement, these are going to contain vitamins in them. So it depends on which one you're looking at, fruit juices, blends, things like that, whether the patient makes it or they buy it, you know, in the store in terms of, like a pre packaged item, potentially, these can definitely have it in their opinion, on how they're formulated and what, what all goes in it. Generally speaking, you know, the safer foods are going to be things like mini dairy, cereals, breads, meats, eggs, nuts and seeds. Typically, these are low enough that this isn't on the radar in terms of big deal items. But again, as Dr. Patel you mentioned, you know, someone eats a ton of it. It can add up depending on how much they're consuming, right? Speaker 1 36:50 And then green tea is another one that I normally would say contains vitamin K. However, depending on you know, how the green tea is brewed, there's there's my there might be some other interactions coming through that could impact the INR, mostly lowers the INR. And so there you have it. These are some of the weird foods that you wouldn't think have vitamin K, just because they're not green, but do have some amount of vitamin K. Dr. Sean Kane 37:19 Dr, tell you already mentioned berries, like blackberries, blueberries, raspberries. I know that grapefruit juice comes up a lot, and I know that we had talked offline about cranberries as well. What can you tell us about cranberries and grapefruit? Right? Speaker 1 37:33 It's very interesting to talk about grapefruit because I found conflicting evidence on whether grapefruit does anything to the warfarin when it comes to grapefruit and and medications in general, we tell patients to avoid it if they're really taking any medication that are metabolized via the SIP pathway. One thing to note is that you know your grapefruit SIP inhibition is the gut SIP inhibition and not the liver SIP inhibition. So there is some difference. And and medications that are affected by the gut SIP enzymes will be more affected. And so, you know, and one, one database I was looking at, it's that, you know, if your patient's drinking up to three glasses of, you know, eight ounce grapefruit juice per day, they should be fine, but anything more than that would cause trouble. Another database was saying, Well, no, they should be avoiding grapefruit altogether. So with the grapefruit, you know, if I see patients on warfarin and they're on other medications that are sick, I would say, technically, you should avoid it. But once in a while, if you had a, you know, a slice or two of the grapefruit. It's not going to be the end of the deal. Cranberries, on the other side, it's completely different. And so this is one of my hard line when it comes to warfarin, I'd say, avoid cranberries and any cranberry juices when you are on warfarin. So much so evidence was mounted after you know, phase four reports that the Bristol Myers Squibb, the manufacturer of Coumadin, actually included cranberries as a drug interaction warning in the package insert of the drug too, Dr. Sean Kane 39:16 and that cranberry is going to increase your INR. Then, is that correct? Correct. Speaker 1 39:21 So we know there are quite a few different natural compounds in the cranberries. There's some focus on the SIB two, c9 inhibition because of cranberries. But then there is also salicylic acid found in the cranberries, which doesn't really increase the INR, but it could increase the risk of bleeding. So it's a mixed bag interaction, but yes, in general, it would elevate the INR, Dr. Kane, and Dr. Sean Kane 39:45 you know, in terms of the mechanism of vitamin K, Dr. Patel, I think it's worth noting that just strictly in terms of vitamin K intake from dietary sources, the mechanism here is that Warfarin makes it so that your body can't activate. Vitamin K. So the way it works is that Vitamin K is used to make clotting factors. It goes from its reduced form to its oxidized form, or its inactive form, and then there's an enzyme that will basically reduce it back to its active form. It's called vitamin K reductase. So when you intake vitamin K, you're in taking the active form of vitamin K, the reduced form. So essentially you're bypassing what Warfarin is blocking at that point. So you're, you're giving the body the vitamin K that it normally wouldn't have because of the warfarin. And that's the nature of this interaction here. Is dietary Vitamin K is the active form, and then your body can then use it to make clotting factors, and your INR will go down. Speaker 1 40:36 And that, that is really the way I kind of talk to patient about, you know, explaining why some of these foods interact. And I will tell you, after so many times of educating, they will still ask, Does this make my inner go up or down? Usually, it's done because you're taking more vitamin K. So in general, what do I tell patients? There is, again, no no besides cranberries, when it comes to all these foods that we talked about, however, consistency and small intake and one sitting is the approach I go with. So you know, you don't want to have patients sit down and eat an entire plate full of, you know, salad, or some of these even underdog vitamin K foods, like I said, pint of blueberries, for example. But if they're doing small amounts, you know, and then kind of dividing throughout the week, that shouldn't be that bad. Dr. Sean Kane 41:30 And I think again, a very common misconception is that these are off limit foods, like you can't have salad on warfarin. But like you said, actor Patel, it's not that you can't do it, it's just that you have to be consistent in how you do it, and your healthcare provider, your pharmacist, or whoever is going to pick the warfarin dose that corresponds to the amount of vitamin K intake that you normally take in. And if that changes, then obviously your Warfarin dose also has to change. So consistency is the key, right? Speaker 1 41:56 And then always, I always tell patients to notify, you know me, if they're making any drastic changes in their diet, for example, you know they have wound care established, and they're asked to drink protein shakes. Well, depending on what protein shakes they're getting, some have vitamin K in it. So we have to kind of keep an eye on those two. Dr. Sean Kane 42:15 So Dr. Patel, transitioning to our last kind of underdog drug interaction, this probably is coming up a little bit more, at least in the state of Illinois, because of, you know, state law changes with respect to recreational marijuana, but CBD and THC are two drug interactors that we're probably going to get more questions on as this becomes more legal throughout different states, and potentially even nationally. Are these drug interactors? So maybe we start with what is CBD and THC, and then we'll talk about whether they interact with Warfarin or not, right? Speaker 1 42:46 And so CBD is basically short form for cannabidiol. This is the non psychoactive component of hemp or marijuana. It's used for the non high, the non euphoric type of, you know, health benefits. There is variety of that, you know, we've seen commercially, CBD oils become available for, I don't know, aromatherapy, topical applications, putting in the, you know, few drops in the tea and drink it, and things like that. And then there is THC, which is the tetrahydro cannabidiol. This is the psychoactive component of marijuana. This is the one that gives you that high effect for those who are using it for potential drug abuse. Dr. Sean Kane 43:31 So depending on you know what formulation you're looking at, you can get different ratios of CBD to teach see where it could be. All CBD could be mostly THC, with very small amounts of CBD, or kind of a mix of both. And this kind of clouds the picture a little bit, because now you're dealing with two different drugs that are in different ratios in different products, and also how you take it is different in terms of whether you ingest it, smoke it, or how you ingest it, whether it's more the oils under the tongue or something that is prepared in a food product. Speaker 1 44:02 And then, you know, let's be honest, right? We know that these two products are derived from the plants, right? And depending on the quality of the plant, how it's grown, the concentrations are going to be different. So not only that, the you know, the amount of each agent is different, but the really the active CBD and THC that's coming from the plant where this product is coming from varies depending on where the raw material, for example, came from, Dr. Sean Kane 44:32 and piggybacking on quality we've also seen in Illinois, several years ago, we had an issue where marijuana was actually laced with synthetic anticoagulant that massively increased INR to the point where we had to give tons, I mean, tons of vitamin K, to reverse the coagulopathy caused by the synthetic warfarin, like adulterants that were in the product. Again, you never really know what you're getting, especially when the. When you're buying it in an uncontrolled fashion, right? Speaker 1 45:03 I actually had a very interesting clinic case where had a patient referred to me for a consistently elevated INR, despite stopping the warfarin, it's usually when you have elevated INR, you hold one or two Warfarin doses, the INR should drop. This patient INR was not going anywhere. It was staying elevated. We even consider liver disease. Patient was fairly healthy. We we did a thorough medication reconciliation and evaluation of potential drug interactions and stuff. Nothing came about. Two days later, we get a call from the patient saying, Oh, I have started to use CBD oil for my knee joints, and I put a few drops in my warm cup of water in the morning and drink it. Guess what? That's that was it? So that's my personal case report of a CBD oil and how it elevated patients INR. Dr. Sean Kane 45:58 So in terms of mechanism, again, some of these are going to be adulterants put in the CBD oil or the marijuana that has a Warfarin like quality to it. CBD itself is a two c9 inhibitor and a substrate, so it's going to compete with Warfarin and potentially inhibit Warfarin metabolism through two c9 so we certainly see this, and we also have case reports about exposure with CBD oil causing an increase in INR, another case reported bleeding. Dr. Patel, your personal case report. It comes down to, basically, we can't guarantee the safety of this drug interaction, so it's something that is definitely on our radar in terms of, probably not a great idea for patients to be using this when they're on warfarin, right? Speaker 1 46:41 And then, so what do I say to my patients, you know, if they're really trying to use it for recreational purposes, or just, I want to try the CBD oil, you know, while there are other pharmacotherapeutics, safer alternatives available for, let's say, pain therapy, I would say, probably don't do it. But if they're using it for medical purposes where there is no other pharmacotherapeutic alternatives that are safer, we may have to continue the use of these cannabinoids and perhaps just apply additional INR monitoring and Warfarin dose adjustments. Dr. Sean Kane 47:14 As we mentioned in the intro for this episode, there are so many laundry lists of drug interactions. Some of these are going to impact the INR. Some are not so, like we talked about with SIP interactions that will show the INR and you can adjust, whereas with anti platelet interactions, you're not going to know that they're at increased risk of bruising and bleeding, because the INR isn't telling you that, right? Speaker 1 47:34 And there, this is where it calls the demand for pharmacists, right? We need to be educators for our patients about these drug interactions. We need to be educators to our fellow healthcare professionals about these drug interactions, and really dive more into understanding what these interactions are and how to manage them, you know, for the team and as well as for the patient, this may mean, you know, asking patients to come back for monitoring, for INR, or advising that they may they be on a different drug altogether, such as maybe antibiotic selection. Dr. Sean Kane 48:10 And you know, suffice it to say. And hopefully, every Warfarin patient knows this, but every encounter that they have with a healthcare provider, from dentist to chiropractor to, you know, nurse practitioner, whoever, they should always be mentioning the fact that they're on warfarin and that potentially could change how they're treated, whether it's a dental extraction to administration of an antibiotic to whatever, this should always be one of the first things that they indicate to another healthcare provider to keep them safe, because if providers don't know that they're anticoagulated with warfarin, you know bad things could happen with respect to bleeding and drug interactions and things like that. So Dr. Joe, what are some of the key elements from today's episode that you'd love the listeners to take away? Speaker 1 48:56 I think you know that the essence of this entire discussion is about being informed, right? So patient needs to be informed by their healthcare providers about such interactions, and then they need to inform us in the care about starting some of these medications, lifestyle substances, so we can assure that they can safely use them with warfarin. Or if you need to make any adjustments in the warfarin, those can be done. Dr. Sean Kane 49:24 I think for me, one key take home point is that, for the most part, most interactions can be managed by more frequent monitoring of the INR and then adjusting the dose is appropriate. With that said, though, as clinicians, we need to be aware of when drug interactions will not modify the INR and then basically consider risk versus benefit for those medications. The classic example there is going to be any of the anti platelet drugs where they increase the risk of bruising and bleeding on top of being on warfarin and that INR is not going to be modified in order for you to really assess how anticoagulated a patient is. So again, usually we can mod. Editor INR, but sometimes we can't. We need to know when we have a case of one versus the other. Speaker 1 50:06 And I think the third important point I want to make is what you said earlier, Dr. Kane, is that interaction doesn't mean contraindication. We can always adjust, in most instances, Warfarin dose to bring the INR where we need it to be if, again, going back to point one, we were informed about these changes. In some instances, like cranberry, it's better to avoid it all together when using warfarin, but in most cases, yeah, there is some room for flexibility, again, if we were informed ahead of time. Dr. Sean Kane 50:39 That wraps up today's episode nicely for the listeners. We have some show notes at HelixTalk.com this is episode 121, we're also on Twitter at HelixTalk, if you want to see clinical pearls from this and previous episodes. And then finally, in iTunes or the Apple Podcast Directory, we love the five star reviews and the comments. So keep those coming. That keeps us motivated to keep producing these episodes. So with that, I'm Dr. Kane Speaker 1 51:03 and I'm Dr. Patel, and as always, study hard. Narrator - Dr. Abel 51:07 If you enjoyed the show, please help us climb the iTunes rankings for medical podcasts by giving us a five star review in the iTunes Store. Search for HelixTalk and place your review Narrator - ? 51:17 there to suggest an episode or contact us or online at HelixTalk.com thank you for listening to this episode of HelixTalk. This is an educational production copyright Rosalind Franklin University of Medicine and Science.