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 109 I'm your co host, Dr. Kane, and I'm Dr. Patel, and the title of today's episode is clinical controversy. Can obese patients take DOACs for acute VTE or venous thromboembolism. Dr. Khyati Patel 00:45 And so in this episode, we're going to cover the pros and the cons and what the latest and greatest literature that's out there regarding the use of these DOACs in patients who have VTE. Again, there's literature for patients using DOACs and obesity and atrial fibrillation. But we're not going to talk about the afib. We're keeping the anti-coagulation indication to venous thromboembolism (VTE) only. So we'll Dr. Sean Kane 01:11 kick it off by talking about a completely fictitious patient. We're going to call him George. George is a 55 year old guy who was admitted to the hospital. He had sudden onset shortness of breath, chest pain and hypoxemia. They do a CT chest with contrast and show that he has a big pulmonary embolism. So he's admitted to the hospital. They gave him full dose enoxaparin or a low molecular weight heparin. They don't really know why he had a vte, except they do note that he's 140 kilograms, or 308 pounds, and he has a BMI of 55 kilograms per meter squared, which puts him in an obese category. Really, the core clinical question for George is, you know, given his body weight, is it safe and effective to give him a doac, which would be Dabigatran, rivaraxaban, apixaban, edoxaban, something like that, or is the most optimal therapy for George warfarin? And there's kind of pros and cons to both, and we're going to go through those and also the evidence surrounding this clinical controversy. Dr. Khyati Patel 02:05 So just for the audience to set the stage, you know, why is this even a question? Why are we talking about it? Well, we know that body weight may influence the doac blood level. So if you think about the parenteral Lovenox, right? That's a factor Xa inhibitor. We know there are weight implications. Not all DOACs are direct Xa we have the Dabigatran. That's direct thrombin inhibitor, but it's, it's kind of in the same category. So the same dose you would give, for example, to a 70 kilogram patient may not be the same as giving it to 140 kilogram patient. Dr. Sean Kane 02:38 And if you look at the package insert for these products, it's never weight based. So if you're giving Dabigatran to a patient as an example, you would give the exact same dose to that 70 kilogram patient as you would to that 140 kilogram patient. And really the question is, Is that appropriate or not? Dr. Khyati Patel 02:54 And so we dive into what primary literature, right? We look at our phase three clinical trials for doacs and VT patients. Turns out that they actually did not include a whole lot of extremely obese patients. And our definition for this extremely obese patients is the weight is more than 120 kilograms, or their BMI is about 40. Dr. Sean Kane 03:14 And that's actually why the 2016 SSC is th, which is the scientific and standardization subcommittee of the International Society of thrombosis and hemostasis, which is why we call it the isth. They actually recommend against doac use and patients with a BMI above 40 or weight above 120 kilograms, simply because we have limited clinical outcomes data in that patient population, so it doesn't mean that we have evidence of harm. Is this that we don't have evidence that it's safe and effective, and we have concerns that perhaps their drug levels of these drugs would be too low to be efficacious. Dr. Khyati Patel 03:48 And when they came out and made this recommendation, just for clarification, they made it for both indication for anticoagulation for AFib and VTE again, for this episode, we're going to keep it to VTE only. Dr. Sean Kane 03:59 And of course, if you look at the chest guidelines, which are the guidelines we look at for VTE guidance in terms of preferred therapies. The chest guidelines do recommend doacs over warfarin. And I would actually, as a side note, say that's controversial, and maybe I personally don't agree with that 100% but we'll take it at face value that they recommend doacs over Warfarin for VTE treatment. So in that case, should we be using a doac in an obese patient because it's preferred by the guidelines, or should we avoid it because the isth guidelines say we don't have enough data in obese patients, and that's really the crux of this clinical controversy, right? Dr. Khyati Patel 04:34 And kind of separating this into smaller questions, let's talk about why would we want to use doac over warfarin, right? What are the advantages? Well, first and foremost is convenience, right? One dose doesn't need to be titrated. Don't need to do those INRS and frequent blood work, and we're dealing with less interactions, interactions with drugs, less interactions with food, and so patient is not as restricted. To eating the kind of food they want to eat. Dr. Sean Kane 05:02 And really, on the hospital side, there's huge advantages to using doacs over warfarin, specifically in someone like George, where, if he's on Lovenox, we don't have to worry about the bridging process of overlapping a heparin product with Warfarin for five days and achieving a specific INR and things like that. Basically, if we choose to give him a doac as long as it's appropriate timed, we can just give him the doac as soon as we want to. We don't have to have this overlap bridging process for multiple days. Dr. Khyati Patel 05:30 That definitely saves a lot of time and headache and monitoring as well. I agree. Efficacy wise, if you look at the vte, there is really no efficacy difference between Warfarin and one of the doacs for afib, it's either non inferior or slightly better than the warfarin, especially looking at either stroke or systemic embolism. Again, our patient that we talked about doesn't have afib. He's here for, you know, a PE A vte, so it's kind of nice to look into indications for other conditions such as AFib or stroke prevention Dr. Sean Kane 06:05 in terms of safety for the most part, the doac versus Warfarin data that we have, both for VTE and for afib, generally shows that total bleeding risk is typically fairly similar, maybe slightly better. Bleeding risk with doacs Depends on which doac you look at. However, within most of the literature, generally speaking, and there are exceptions to this, but generally speaking, doacs cause a little bit more gastric bleeding or GI bleeding, and Warfarin generally causes a little bit more intracranial hemorrhage. So you globally will bleed roughly about the same, maybe slightly better, with doacs. But there are different kinds of bleeds that are more or less common with different therapies between doacs and warfarin. Again, there are some exceptions, because we're kind of grouping all doacs into one category, but let's say general rule of thumb for this drug Dr. Khyati Patel 06:49 class, and it makes sense, and so playing the devil's advocate, why would we go with Warfarin over the doacs? Well, we have the INRS and the quote, unquote titurbility, meaning, you know, we can adjust the dose of the warfarin based on the INR, and sometimes INR also indicates the level of anticoagulation. Lower INR. Obviously, you're not completely anticoagulated. Higher INR you are, although we all agree, and this is what I do in clinic, day in, day out, is having patients to come and ask them to monitor their INR frequently. Dr. Sean Kane 07:22 And you know, for us pharmacists, sometimes we like to know the number. We like to know where the patient's at. And then an obese patient, we would know precisely what their level of anticoagulation is versus any of the doacs. Effectively, you can't do that. There are some tests out there that do measure anticoagulation status, but they're not very standardized, and we don't really have strong evidence for specific therapeutic levels. So for the most part, we don't monitor anticoagulation level with the doacs. But with warfarin, it's really easy with even a point of care INR test. And if you know the number, it doesn't matter if they're big or small, the number is how anticoagulated that patient Dr. Khyati Patel 07:57 is right? And Warfarin being a dinosaur drug, for lack of better word, we just have more data. We're going to say this for a few years down the line, doe x are still getting some more notoriety and being woven into the studies, and we're seeing the outcomes. We clearly have decades of data with warfarin. Dr. Sean Kane 08:17 So if you think about it, if we wanted to answer this question in terms of looking at obese patients based on that BMI above 40, body weight above 120 what would it actually take to answer that question? And if you start there, as opposed to looking at what data we do have, but just starting with what do you need, it's actually really difficult to answer that question. If you think about what kind of study you would actually have Dr. Khyati Patel 08:39 to have, we just have to do a randomized control trials, phase three randomized control trials with 1000s of patients who are in this extreme obesity category. Dr. Sean Kane 08:48 Yeah, and that sounds like the best possible scenario, but the problem with that is the end of that RCT. So if you consider the amplify study, we could pick any of the RCTs that are the phase three VTE studies for the doacs, but we'll just pick amplify it was for apixaban versus warfarin. That study had a little bit more than 5000 patients in the study, and the incidence rate was about two and a half percent. And in this case, the endpoint was recurrent vte, and the primary safety endpoint of major bleeding was about 1% so they needed 5000 people to detect an endpoint that was roughly one or two percentage points in either group. What that means is that if you wanted to redo an RCT only in obese patients, you're going to have to find 5000 very obese patients to have similar statistical power, assuming that the incidence rates are similar in the obese patient population versus the amplified patient population, that's a really hard asking a lot of money, Dr. Khyati Patel 09:47 yeah, certainly a lot of money, and it takes years of recruitment to get the kind of patient and that we need. Let's talk about some of the smaller studies that we have available. We have some retrospective analysis. Included less than 200 patients, but we have to worry about that these studies are Uber underpowered, and we have to worry about the type two error occurring in here too, to the point where should we even consider the impact of these studies at all? Dr. Sean Kane 10:16 Yeah, and I see this all of the time, where someone will say, well, there is this retrospective article of 200 people that looked at the study question and it didn't show any difference in terms of VTE recurrence. The problem is that you already know it's underpowered because they only had 200 people, you need 1000s of people to answer the question, and if you only have 200 people, you're guaranteed to be underpowered. That study is almost not worth doing unless the effect difference is dramatic between doac versus Warfarin and obese patient population. Dr. Khyati Patel 10:46 And not to mention that these small studies that were done were like single center studies and not multi centers looking at, you know, different ethnicity and whatnot. So again, that limits the applicability of the results too. Dr. Sean Kane 11:00 Then the other problem with the literature that's out there is sometimes what will be done is that it will compare the efficacy of a doac and normal body weight patients versus efficacy of a doac and higher body weight patients. And that's actually not the clinical question that we have. So you have to be careful that you're not using that because we do know that in obese patients, the risk of having a VTE and a recurrent VTE is higher. So we already know the answer to the question, meaning we already know that if you gave an obese person versus a normal body weight Person A doac, the obese person is going to have a higher risk of the blood clot coming back. So we already know that the incidence rate is going to be worse. So isn't addressing the question of, is it better to give them a DOAC, or is it better to give them warfarin? You also have to be really careful when looking at the literature that you just don't assume. Well, DOACs don't work as well in obesity. Obesity itself is also a risk factor. Dr. Khyati Patel 11:51 So in a grand scheme, we'd like to do this study. We'd like to look at the clinical outcome, right? That's really what matters. But we do have some smaller studies that looked at just pkpd differences of how these doacs behave in a normal weight patient versus in these extremely obese patients. We have one article that we're going to put it on the site. It's Kido, 2020, article. And we do have some data. What's the data here? Dr. Sean Kane 12:16 So we have a little bit of PK data for rivaroxaban. And basically, if you compare patients that are obese, so more than 120 kilograms versus normal body weight, the C max, the AUC and the factor Xa inhibition, were fairly normal in rivaroxaban between the obese patients and the normal body weight patients, indicating that from a pkpd standpoint, probably there is no clear difference in terms of risk of efficacy failure with rivaroxaban, and Dr. Khyati Patel 12:46 it seems like with apixaban, we have shown that the Cmax was about 31% lower. The AUC was about 23% lower when comparing in these obese patients of greater than 120 kilogram of weight versus the normal body weight. So again, there are differences. But do we know whether this clinically means anything? Yeah. And the talk about, you know, the pkpd data, we have more for the rivaroxaban and apixaban. We really don't have any for the dabigatran or edoxaban. So in general, again, think about this small data just for rivaroxaban and apixaban, and we don't even know whether these little differences that we found in the pkpd parameters make any difference into the clinical endpoints of whether it be bleeding or causing another PE or a DVT. Dr. Sean Kane 13:39 And you also have to keep in mind too, that these are really, really, really small n studies, so there could be other factors, aside from obesity, that may be playing a role in these differences. And because we have such a small n we assume the difference in C max is because of obesity, but it could be because patient a absorbs one drug way better than another drug, for example. And also, these are typically single dose studies, so for that reason, we don't really know the pkpd differences as you accumulate more doses, maybe the distribution of the drug changes in adipose tissue versus not over chronic period of time. We don't know the answer to that either. Again, focusing on the fact that, sure, we can look at the PK data, but it isn't the end all to be all and it probably isn't enough to warrant using that for clinical decision making. Dr. Khyati Patel 14:25 And so, if not PK/PD data, what other higher quality data do we have? And so we turn to some meta analyzes. Dr. Sean Kane 14:32 So there was a meta analysis by Di Minno and colleagues published in 2015 and we have references on our website for this. This included six randomized controlled trials with about 27,000 patients, and it looked at doac versus Warfarin for VTE. And in this case, the DOACs were the four main ones, dabigatran, rivaroxaban, apixaban and edoxaban. Dr. Khyati Patel 14:53 And in this meta analysis, they define higher body weight as either greater than 100 or greater than 90. Kilogram depending on the trials that we're looking at. Again, this is not sufficient enough where we are answering the question for our patient, George, whose weight is 140 kilograms. So it's it's, again that answering the very high obese patients, but we'll take it for now. Dr. Sean Kane 15:17 So based on that definition of high body weight of 90 or 100 kilograms or more. Of the 27,000 patients that they started with, about 20% of that so about 5000 met the criteria for being high body weight in this meta analysis, Dr. Khyati Patel 15:34 and what we found, as far as the results, that there was no difference in VTE recurrence or VTE related death between the two groups. It was like 2.7% in the doac group versus a 2.8% in the warfarin group, with the non significant P value. Dr. Sean Kane 15:51 They also looked at safety outcomes so major or clinically relevant bleeding, and it was really, really similar, again, high P value, the incidence rate was 6.7% in the doacs and 7.1% in warfarin. So again, really no efficacy and no safety difference that was able to be detected in this population of about 5000 above body weight patient population. Dr. Khyati Patel 16:12 And I believe they kind of looked at group up patients and labeled them at obesity of BMI more than 30 and the results were still efficacy wise, similar between the two groups. Dr. Sean Kane 16:23 And again, the core problem with this meta analysis, which is commonly cited to look at, is their criteria for being obese is a little bit low. It would be nice if they would have used 40 as a BMI cut off, or 120 kilograms as a body weight cut off. The problem is that the RCTs that they looked at didn't provide that data. So they have to work with what is published, and that's the nature of a meta analysis. So kudos to them to doing the analysis, but it still doesn't fully address the question that we're interested in. Dr. Khyati Patel 16:50 Agree, we have actually the newest retrospective analysis in acute VTE that's also cited on our site. It's coons 2020, it's freshly off the presses we talked about how earlier the issue with retrospective analysis of that includes patients less than 200 we're getting into that, you know, issue with type two errors and stuff. But this one, on the other hand, was notably a little bit more, about 1800 patients who were hospitalized within acute VTE, and about 600 patients. 630 patients were on doac versus the rest, 1200 were on warfarin. Dr. Sean Kane 17:26 So they included patients whose criteria for obesity was between 100 and 300 kilograms who did not have a history of afib. And they basically matched these 600 plus doac patients to that 1200 Warfarin patients, and they use something called propensity score matching, which tries to correct for differences in baseline characteristics, aside from body weight. So it could be a history of VTE, how many clots they've had in the past, if they're on an anti platelet therapy, stuff like that, where they try to find obese patient a and find the person who's closest to obese patient a within the warfarin data set. And that's how they came up with roughly about 600 doac patients and roughly about 1200 Warfarin patients. Dr. Khyati Patel 18:05 And so looking at the baseline characteristic, we found that 92% of the patients were put on Xarelto (rivaroxaban), and medium weight was about 115 kilogram, greater than 40% had weight that we were looking at the 100, 120 kilogram or above, or that BMI we were looking at of greater than 40. Dr. Sean Kane 18:26 So what they found was the risk of VTE recurrence was six and a half percent with do X versus 6.4% with warfarin, really high P value, indicating definitely no clear evidence of any efficacy difference. And really numerically, these are statistical noise, so efficacy wise, no difference observed between doac and Warfarin for VTE recurrence, Dr. Khyati Patel 18:45 and I think the results for safety were also not significantly different between the two groups. Though, bleeding that was related to the ER visits or hospital admits were about the same, 1.7% and those who took doacs versus 1.2% and those who took Warfarin again, this was not statistically significant. And you know, this is Dr. Sean Kane 19:05 different than that meta analysis, because the meta analysis included only randomized control trials. That randomization process is really important to have this balance in baseline characteristics. This was a retrospective analysis, so there's always a potential that we have residual confounding, where even though they did this propensity score matching to try to correct for baseline differences, they still could be there. We just don't know about them. Dr. Khyati Patel 19:27 And also, another weak point was that their efficacy and safety end points were evaluated based on their admit diagnosis, like ICD nine or ICD 10 codes in the ER or the hospital. And so if a patient had an outpatient episode of a VTE recurrence, then that event wasn't counted in here. Dr. Sean Kane 19:47 Then finally, 1800 patients is nice, but it's still probably underpowered, for the same reason we talked about earlier, that we probably need several 1000 patients to really fully address this question and not be a. Risk for type two error. However, this article vastly represents the largest data set that we have, specifically looking at weight above 120 BMI above 40 with doac versus warfarin. It's a very specific question that we're trying to answer, and this is definitely the best data that we currently have. Dr. Khyati Patel 20:16 Interestingly enough, this trial ran from 2011 to 2015 if they continued it, perhaps we would have looked at a bigger end, or perhaps we will in future. Dr. Sean Kane 20:25 So in terms of like, very broad conclusions, clearly, we don't have the evidence that we need to definitively answer the question. But what broad conclusions can we draw? Dr. Khyati Patel 20:34 Well, the first and foremost is we just don't have enough data specifically answering the question, again, looking at the differences between doac and Warfarin in patients who are more than 120 kilogram or greater than 40 of the BMI Dr. Sean Kane 20:48 and of our PK/PD data that we have either there is no clear difference in terms of PK parameters in obese patients versus non obese patients, or there are very small differences that are observed that may or may not be clinically relevant, that we just don't know the answer to, right? Dr. Khyati Patel 21:03 And we did not go and talk about the AFib indication. I mean, we were looking at doac use and obesity, but we have a couple articles, as well as meta analysis and systematic review that's posted again, but we're not talking about AFib for this episode scope. However, there is some data, and that's essentially the same. Dr. Sean Kane 21:24 So of the data we do have, we have a meta analysis, including about 5000 obese patients, and then we have a retrospective match cohort study of about 1800 patients. Neither of these have shown a signal of concern for efficacy or safety. So taking into account, we have no signal of harm associated with the PK/PD data, no signal of harm associated with a big meta analysis in a in a larger retrospective study. For the most part, it seems unreasonable to fully exclude this obese patient population, because we don't even have like a signal of potential harm with this drug therapy, right? Dr. Khyati Patel 22:00 And if you look at the Kido 2020 article, the conclusion was made saying that we need to continue the caution when considering the DOAC use in morbidly obese patients, particularly for those requiring anticoagulation for VTE treatment, until additional higher quality data become available. So that goes back to their point number one that we just don't have enough data. Dr. Sean Kane 22:23 So if we go back to George, back to our patient case, you know, he's 140 kilograms. BMI is 55 he has an acute vte, acute pulmonary embolism. You can die of a pulmonary embolism. So clearly, we want to treat that aggressively, and we want to make sure that that PE gets better and doesn't come back. Really, the question is going to be, do we follow the 2016 SSC is th guidelines that say we should avoid doac use in George, because his BMI is above 40, his body weight is above 120 or should we ask George what he wants and see, you know, what values he has in terms of one versus the other in terms of his therapy, right? Dr. Khyati Patel 22:57 And there's a lot of different facets to put, you know, next to each other, we want to look at the risk factors, right? So is his risk of getting a VTE recurrence or even the bleeding is high or not, right? Dr. Sean Kane 23:10 Maybe he is not excited to change his diet or be consistent with his vitamin K intake, or he's not excited to see Dr. Patel in her anticoagulation clinic frequently, and that sounds like the worst thing in the world for him. And if that is the case, maybe it makes sense to give him a doc, because a DOAC and an obese patient is always going to be better than warfarin and an obese patient who's non-compliant with their warfarin. That makes no sense to give them a therapy that they're not going to follow. And it makes way more sense to give them a therapy that they have a realistic shot about being Dr. Khyati Patel 23:41 compliant with. Right? So again, going back to what we concluded, we don't really have enough evidence to conclude what we want to do for our patient, George over here, it's a little extreme to bring out the 2016 is th guidelines and say no, we don't want to use it however certain other patient specific factor, as we discussed, you know, maybe asking George would be better, right? In this case, could be helpful. Just as we discussed the data, including the pkpd data, most of the data lies with rivaroxaban, a little bit less with apixaban, and almost none with the other DOACs. So if you do decide to do it with a DOAC your best bet is using either rivaroxaban or apixaban (Eliquis). Dr. Sean Kane 24:25 And I would say that you know, in terms of prescribing patterns in the US, among non obese patients, that's kind of those are the two most commonly prescribed doacs Anyway. So if you're gonna do it, pick the two most common ones that also happen have the most data in obese patients. Granted, the data isn't great. It's better than having zero data with the other doacs in the market. I think at the end of the day, this is a George decision, probably in terms of what makes sense for George based on his patient specific factors. And that is going to be, in my opinion, a very individualized decision for each patient who's obese, it has a VTE and is deciding between the two therapies, Dr. Khyati Patel 24:58 and certainly it garners the. You know, a discussion, sitting down with him and showing this, you know, newest data that we have, and say, hey, the data is not great, but here are your options and that make like that shared decision, that'll be the best choice for George. Dr. Sean Kane 25:13 So for the audience, if you don't want to take our word for it, you can go to our website, HelixTalk.com episode 109 you can go through the evidence. We have the references for the articles discussed in this episode, and you can make your own decision based on what the guidelines say, what the current evidence has, the meta analysis, including the RCTs and that retrospective study, all are referenced on the website, and you can make your own decision as well. With that, if you would like some clinical pearls in your Twitter inbox, you can follow us at HelixTalk to get clinical pearls in previous episodes. We love the five star reviews in iTunes, so keep those coming. If you have episode suggestions, please feel free to email us. Our email address is available at our website, at HelixTalk.com so with that, I'm Dr. Kane and Dr. Khyati Patel 25:55 I'm Dr. Patel, and as always, study hard. Narrator - Dr. Abel 25:59 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 there to Narrator - ? 26:10 suggest an episode or contact us. We're 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.