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. Narrator - ? 00:11 This podcast 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 50. I'm your co host, Dr. Kane. I'm Dr. Schuman, and I'm Dr. Patel. And to celebrate episode 50, we've decided that from now on, every three weeks, when we introduce our HelixTalk episodes, we're going to have some provocative titles to help introduce the listeners to the topic a little bit better, and maybe draw them in a little bit more. Speaker 1 00:50 Well, that's very exciting. And I did not realize we were at episode 50, so I guess it calls for a celebration. Dr. Sean Kane 00:56 The title of this episode is three shocking recommendations from chest 2016 that will blow your mind. So essentially, we're talking today about the 2016 chest guidelines, which are guidelines dealing with basically, anticoagulants. And we picked out three of the recommendations from the chest guidelines that either were very surprising to us or that we just flat out don't necessarily agree with Speaker 1 01:20 so first and foremost, the controversy about what do we call these drugs, right? I've heard so many acronyms. I don't even know where to start. I've heard noacs, I've heard doacs. I've heard so AX, where t is kind of like a little silent. So what's the deal? Dr. Sean Kane 01:37 When they first came out, we called them no acts because they were novel or new. That's what the N stood for. And at some point, someone said, hey, at some point, these aren't going to be new or novel anymore. What are we going to call them at that point? So the name didn't really age well. So at this point, if you look at the chest guidelines, they continue to use the acronym NOAC. But instead of new or novel, The n now stands for non vitamin K, oral anticoagulant. So NOAC the N being non vitamin K, then OAC is oral anticoagulant, same acronym, but they've kind of redefined what the n means versus what it initially meant when the noacs first came out. Yeah. Speaker 1 02:17 And also, I was very surprised to read the concern from some of the clinicians that if you abbreviate the non vitamin K oral anticoagulants to noacs, you know, in the documentation or patient chart, it may be interpreted as no anticoagulation as well. Speaker 2 02:32 I could, I could foresee this point in a few years where Joint Commission comes in and on there do not use, you know, you got your morphine sulfate, magnesium sulfate, and then your noacs just right on there on that list. So I guess they headed it off at the pass. Yeah. Dr. Sean Kane 02:44 In all fairness, that's probably going to be the only thing in the future that would prevent the doac versus NOAC Civil War is to have someone like Joint Commission, or ISMP, the Institute of Safe Medication practice, basically say you can't, or shouldn't use NOAC as an abbreviation, but until something like that happens, we're always going to have a separation of NOAC versus doac Speaker 2 03:07 camps in our VA. We've gone through all the three we were we were in the nowac, then we're soac. And I think we're at doac right now, but it's hard to tell, because we get these little memos the police disregard all that previous stuff. Now it's this and just kidding. Now. Now change it here. Dr. Sean Kane 03:21 So Dr. Schuman, what does doac mean if we've kind of established NOAC? What is doac? Speaker 2 03:25 So I like this one, doac or direct oral anticoagulant, and it looks like this one's coming on strong as preferred abbreviation from some organizations. For example, isth, the international society and thrombosis and hemostasis. Dr. Sean Kane 03:39 And the isth actually made this recommendation after surveying about 150 clinicians who were hematologists and kind of in the know in terms of being involved in the anticoagulants. And what they found was, they asked the participants, you know, what do you like? Do you like? Soac, NOAC or doac? It was equally balanced between nowac and doac, and soac was really not preferred, and it wasn't until later on in the survey they asked about, do you foresee NOAC being a risk of being no anticoagulant, that they kind of made that recommendation. So the surveyors were equally likely to say NOAC versus doac, but the guideline from isth said, Hey, let's go with doac, simply because of this perceived risk of no act, meaning no anticoagulants. Yeah. Speaker 1 04:24 And that being said, you know, the rarely used, or not really preferred acronym is the silvac, and that basically elaborates as the target specific oral anticoagulants. Speaker 2 04:35 And anytime you got something with a letter that's silent on the end. I know we're not getting quite into etymology here, but I mean, get a little confusing, yeah. Dr. Sean Kane 04:42 So essentially, where we're at now is NOAC. If you do use it, you should know you're using it as a non vitamin K oral anticoagulant. If you use doac, you might snicker at the NOAC group saying that it could be no anticoagulant or the non vitamin K oral anticoagulant. It and then soac. You know, like you said, to have this silent word as part of your acronym probably isn't the best idea, either. So no one really agrees. At this point, chest is using NOAC. Doac is definitely the second preferred acronym as far as chest is concerned, but it's the primary version of the acronym as far as some other hematology organizations are concerned. So at this point, no one's going to say one is right and one is wrong. Speaker 2 05:25 All right. So now that we've established that, you know, there's obviously some some vagueness in some of these recommendations. And just starting out, just naming the dang things, all right, Dr. Kane, what's the next recommendation? There? Are they trying to argue about, like, the spacing of the font? Dr. Sean Kane 05:38 So the next interesting recommendation was recommendation number two, so they have, you know, a number of recommendations. The second one, I think, is the most provocative recommendation in the guidelines. And to quote them, it says in patients with DVT of the leg or pulmonary embolism and no cancer as long term anticoagulant therapy, we suggest dabigatran, rivaroxaban, apixaban, or edoxaban over vitamin K antagonist therapy. And this was a grade 2b recommendation in layman's terms. What they're saying is that you should pick a NOAC or a doac over warfarin in patients who have a DVT of the leg or a pulmonary embolism. Speaker 1 06:16 Yeah, and that recommendation is true for most individuals, but then they're always going to be patients who won't be candidate for these new agents, so or non vitamin K dependent anti coagulant, so they will still be getting the warfarin instead. Dr. Sean Kane 06:32 It's like a dialysis patient, for example. Great candidate for not knowac, right? Absolutely, that's a good example. So I think one thing to think about is the grade of recommendation. So this was a 2b recommendation grade so you either have a weak or a strong recommendation, one or a two. So this was a weak recommendation, and then the B stands for moderate evidence. So it's not high evidence, which would be a Grade A, and it's not low quality of evidence, Grade C. So it's weak, moderate evidence. Speaker 1 07:01 So talking about the level of recommendation, let's really look into where all these recommendations are coming from. Obviously, they are looking into the clinical trials and, you know, Head to Heart comparisons, but let's dive in a little bit deeper and see what we can find that is very shocking. Yeah. Dr. Sean Kane 07:16 And before we even get to the literature, just thinking about it, if you're going to recommend that you take a NOAC over warfarin, you should either see an efficacy benefit, a safety benefit or a cost benefit. That would be the only reason for most indications that you would consider one drug superior over another drug and recommend Speaker 2 07:34 it, especially when you're paradigm shifting completely, not just from a drug that's pretty similar, but you're talking just a shift in mechanisms as Dr. Sean Kane 07:40 well, right? So why don't we get started with the first group of studies which looked at dabigatran versus warfarin with the low molecular weight heparin bridge. There were two studies about 5,000 patients. These were called RE-COVER I and RE-COVER II studies. What they showed was that between dabigatran and warfarin, there was no difference in efficacy, which was VTE recurrence (venous thromboembolism recurrence), and there was no difference in major bleeding. So similar efficacy, similar safety. Speaker 1 08:11 And then the other agents that we have in that NOAC category is rivaroxaban. So rivaroxaban, again, was compared head to head with warfarin (or a combination of warfarin and low molecular weight heparin). The two different trials where the evidence is emerging from were acronymed as EINSTEIN-DVT and EINSTEIN-PE trials, just like the dabigatran trials we mentioned earlier. If you compare the efficacy, there was no difference in VTE recurrence. Speaker 2 08:42 What's interesting though, in looking at that, one is, and one of the things you start thinking about that sounds pretty good. Okay, major bleeding was lower or considered better, less of an issue with Roberto being and they had a relative risk of point five, five. So that sounds great. Only thing about that is it's really only shown in the pooled analysis of those two studies. Dr. Sean Kane 09:01 When you say pooled, you mean that they took two studies, glued them together, and then analyzed the results of the two trials combined versus any individual trial, right? Speaker 2 09:08 And again, it's a nice way to start pulling, you know, if you want to pick out little bits of data and kind of amplify them, it's kind of like, you know, cutting and pasting. So we don't have enough of a power maybe. But again, if we pull it together, get a big number things start coming out more if you do it that way. Dr. Sean Kane 09:23 So what they found in the DVT trial, Einstein, DVT major bleeding was point 8% versus 1.2% with a non significant P value. And they looked at major or clinically relevant bleeding, and both groups had the exact same percentage of 8.1% obviously no difference between the two groups. So in the DVT trial, no difference in major bleeding, no difference in major bleeding, or clinically relevant bleeding, if you combine the two together, Speaker 1 09:47 like we mentioned, there was a pool analysis. So take a look at what the major bleeding events were like in the EINSTEIN-PE trial. It was 1.1% in the rivaroxaban-treated group versus 2.2% in the warfarin group, and that P value was statistically significant. Again, it depends on how major bleeding versus major or clinically relevant bleeding was defined. Those incidences were 10.3% in the rivaroxaban group and 11.4% in the warfarin group, and this P value was not significant. Speaker 2 10:19 and that's an interesting thing, just in looking at study trial design and how they do the outcomes is depending upon you. If you're trying to classify a side effect or an adverse reaction, that kind of borders between a couple different things, it all depends on which group you put in. You can, especially if you're talking about things that are less common, you can really, really, really unbalance something, just depending upon if you're waving between classes, and you always see kind of the angst that maybe the person was going through and classifying just to see the end result of it, and boom, here Dr. Sean Kane 10:46 it is. So essentially, as far as rivaroxaban is concerned, it depends on how we decide to look at bleeding and which endpoint we choose. One analysis suggested rivaroxaban caused less bleeding, but looking at the data another way, it did not show a difference in bleeding versus warfarin. Speaker 2 11:01 All right, so then we kind of move on to the next agent here. So we've talked about our first so we get kind of to the new kid on the block of pixaban or eloquence. And so this one, they looked at Warfarin and low mole electrolyte, heparin. In one study with, again, similar to the other ones. We're looking at an n of about 5000 about or about 5400 the amplify study. And this one, they found no difference in terms of VTE recurrence, but they did find overall, the major bleed rate was lower again or better, depending on how you define it, with a pixel band, point 6% with the pixabane versus 1.8% with warfarin. Again, there's a p value less than, less than 0.001, looking, pretty nice Speaker 1 11:40 there, and then again, kind of defining that major bleeding further down to major or conically relevant bleeding. We also found that apixaban was better than the warfarin. So that effect difference was 4.3% with the pixabane versus 9.7% with the warfarin. And if we kind of listened to the Einstein trial, DBT and P trial results, we found that, you know, this effect was wasn't really seen with roxaban. It was pretty equal with Warfarin versus here, you can see that apixaban is a slightly better than warfarin, Dr. Sean Kane 12:15 and not to get too much into the AFib data, but we see similar signals in the AFib data of NOAC versus warfarin, and the apixaban appears to have a better bleeding profile versus warfarin, whereas some of the other agents either don't show that effect, or show that effect, depending on how you again, slice and dice the data a little bit. Speaker 1 12:33 And the very last agent in that category was the edoxaban that was also compared in the Hokusai VTE trial, gas Warfarin and low molecular weight heparin in the patient population, about 8000 and again, surprise, surprise. The result in terms of efficacy, was that there was no difference when it came to VTE recurrence. And what they also find looking at the safety analysis, that there was no difference in major bleeding. Dr. Sean Kane 12:57 So if we kind of take all of the data together, which presumably the chest 2016 guidelines did if we look at efficacy, which was one of the metrics that we said would be important to us to decide which way to go in terms of preferred therapy, no NOAC has better efficacy than warfarin. These were all non inferiority studies, meaning that Warfarin is just as good as a NOAC, and vice versa for the treatment of VTE to prevent that VTE from coming back right? Speaker 2 13:21 So what we're left with then is starting to make our decision more about the safety profile. And so we said, apixaban does seem to have a better bleeding profile versus Warfarin in VTE. Now ribaroxaban might, again, it all depends upon how you're looking at the data, whether or not you're talking about major bleed, minor bleed, or, you know, how you determine what's clinically relevant to you. So that's kind of up in the air. And then we know that dabigatran and edoxaban just flat out don't have any bleeding benefit over warfarin, so it's just kind of six of one, half a dozen of the other. Dr. Sean Kane 13:51 So then, in thinking about the recommendation, does this make sense now that we've gone through, you know, an overview of the data, it was a grade to be recommendation, which meant a weak recommendation, a suggestion versus a we recommend. Unfortunately, oftentimes it doesn't matter what the grade of recommendation is. If it's in a guideline, someone's going to say, well, the guidelines say you should do X, Y, Z, regardless of the strength of evidence. So once it's there, it's great to have the evidence recommendation grade or strength. But the problem is that frequently, clinicians ignore that, and then they just read it for what it is, black and white: 'You should do NOACs for VTE, and that's it.' Chest guidelines, they put their stamp of Speaker 2 14:29 approval on it. Yeah, it's the same thing we run into with approval studies. You know, if an approved you can tear an approval study apart all day. But as long as it's on the market and gotten its approval, people generally ignore it. Just say, well, it's there. I see it. I've got, you know, let's, let's use Speaker 1 14:41 it, yeah, and at the end of the day, you're gonna look at, you know, various patient specific factors. You know, what does patient prefer? I've, I manage a handful (not a whole lot) of anticoagulation patients in my clinic. And you know, most of those patients want to remain on warfarin, because they like to know what their number is. Whether they're going to bleed or clot, they're so worried, so it's satisfying to them to have that lab checked at least once a month, even though they're very stable on that warfarin; cost is another issue, although most of the insurance is both government as well as public players, I've noticed, you know, one of these agents always being as a preferred branded list medication. But then those patients who have renal insufficiencies, and we know we can't really use the noacs there is where the warfarin treatment would come in handy. So again, what has come out as a new recommendation is just a guideline. It's a guide we as a clinician need to direct the therapy according to the patient factors. And again, Speaker 2 15:38 Dr. tab, I'm glad you mentioned that about your patient population. I've noticed similar things with ours as well as I've been surprised that, given the options that so many of my individuals kind of choose the devil, you know, which is warfarin. It's not that they, they like that idea being on it, but the numbers, it's, it's so much of a lot of our conversations are flat on the foot. What's my number? What is, you know, that there's, there's kind of that a lot of the well being is, you know, can you give me, where is it at? And let's go from there. And and that unease of saying, Well, we think everything's okay, but not having that nice number to guide them, there's almost a sense of anxiety about that, that they just don't have that number to make to kind of give them relief. That says, Well, I'm worried, but the number says this, yeah, Speaker 1 16:16 I think it kind of gives them the sense of security, yes, yes. You know, they're good now, until the next INR is done. Dr. Sean Kane 16:23 So to kind of wrap up that, Recommendation Number two, I think that, at least from my point of view, I just don't agree with the fact that they're even weakly recommending a NOAC over Warfarin in VTE. I think that for me, there's no efficacy difference. If anything, they should be recommending apixaban for a better safety profile, knowing that you can't compare apples and oranges between trials. So either you put your stake on apixaban and say that's the one that you should do, or you say they're all equal, because basically, Warfarin is just as good for efficacy, and there's a safety potential benefit in one agent, and you can, you know, select based on patient preference or patient factors that would impact selection of agents. I don't think it's right. And I think that to me, it speaks more of undue influence of things like the drug companies, potentially influencing decision makers on the guideline committees to say, Hey, we should be recommending no acts over warfarin, because that's what we do in our practice, right? I just hate for Speaker 2 17:17 it just simply to be convenience, being the word, not even patient preference, but just convenience for all parties. Say, 'Well, I don't have to do the INR for them to come in.' So let's just, let's go to these Dr. Sean Kane 17:27 well, to move on to the third provocative thing. This is recommendation number 18, and it reads as in patients with acute DVT of the leg, we suggest not using compression stockings routinely to prevent post thrombotic syndrome, and we'll just call that PTS from that one. So it's also a grade 2b recommendation. Speaker 2 17:46 So I guess the big question comes up with, what is a compression stocking? Speaker 1 17:50 So there actually, as the name says, it provides proper pressure in the legs to move basically the fluids up back into the circulation. There is the graduated compression stockings and the elastic compression stocking. And the basically, the idea is that they are a little bit tighter towards your ankle and little bit looser when it comes towards the thigh. So it basically brings all that fluid back from lower legs to upper legs and back into the circulation. Dr. Sean Kane 18:18 And in theory, even if you don't have a DVT in your leg, this could potentially help if you have edema in your lower extremities after an eight hour day on your feet. If you have kind of pain and swelling in your ankles from being on your feet too long, in theory, it helps with that. But prior to the chest 2016 guidelines, they recommended it for prevention of this thing called post thrombotic syndrome, and that's basically pain, swelling, discoloration, or even ulcerations in your skin caused by venous insufficiency, caused by a big blood clot that's blocking blood return on the venous side of your lower extremity. Speaker 1 18:53 How often do we see those PTs in patients who've had VTE? Dr. Sean Kane 18:58 So if you have a proximal DVT, which means blood clot above your knee, anywhere from about 20 to 50% of patients will have PTS where they have the pain, edema, swelling, things like that, in the lower extremity. That's a little higher number. And really, you know, because this is so common, to have something that even has a little efficacy would be a really big deal. And again, prior to chest 2016 we had two smaller, single center RCTs, randomized, controlled trials that appeared to show good benefit. The problem was a, they were small, B, single center and then C, they didn't use what are called placebo stockings. And you're like, Well, what is the placebo stocking? It's basically a graduated compression stocking that isn't as tight, so it's a pantyhose, if you will, that is just not as tight as these compression stockings that are quite a bit tighter, Speaker 2 19:48 all right. So what we know, though, is, again, as you mentioned, Dr. Kane, that there's some smaller studies that came out with a bigger study since since those guidelines, or since chest nine. And that one was large and multi centered study, and this one was called. Called, wait for it, the socks trial, and this one had placebo blinding this time, and they had no benefit of using the stockings to prevent PTS, prevent being the operative Speaker 1 20:09 word there. I think the word sock just blew my mind. Yes, there you go. There you go. You always got to Unknown Speaker 20:13 come up with good, catchy names, too. Dr. Sean Kane 20:15 So really, what this trial focused on was people who did not yet have PTS, so they had an acute DVT, they put these compression stockings on, and then they followed them for two years to see, did they develop pts? So that's a very specific question where it's a prevention trial, not a treatment trial. So once you have PTS, we don't have good data that these are efficacious or not. Anecdotally, patients will say, Hey, I feel better because they have less swelling in my legs and things like that. So once you have PTS symptoms, the guidelines are pretty clear in the discussion section that it's okay to use these graduated compression stockings, either once you have PTS, or even if you don't have PTS, but you just have acute pain from your DVT, you're good to go to put a compression stocking on the leg that has a DVT. You're not going to break it off and cause of pulmonary embolism or anything like that. It's okay to do that for symptomatic management when you have symptoms of PTS, Speaker 1 21:06 but this really is for should be used for prevention of PTS, and that's what the trial was aimed to study. Yep. So it Dr. Sean Kane 21:13 appears that it doesn't prevent it. So if you don't have symptoms, don't do it. If you do have symptoms and you like using them great. If you have symptoms and you don't like them, then don't wear them. It's not going to change anything if you don't perceive a benefit from them, right? Speaker 2 21:28 So again, it's one of those where it's silent in those other areas. But here we have a big recommendation, and that's what most people are going to follow. I believe there's, you know, a quote that can be pulled out of the right, out of the study. It's, or excuse me, right out of the guidelines themselves for patients with acute or chronic symptoms. A trial graduated compression stockings is often justified. So you have a somewhat positive statement there, but again, maybe buried in the text. And as Dr. Kane, as you mentioned so many times, you view these guidelines as these kind of these bullet points of I'm going to do A and B and C and D, and there's a lot of subtext and nuance in there that just kind of gets fallen by the wayside. Dr. Sean Kane 22:02 So guarantee you, what's going to happen is now, when someone reads this guideline, they don't read the text or the body. They just read the recommendation. They're going to assume, okay, compression stackings don't work. Period. We should never recommend them. But that's not what it's saying. It's saying it's not good for prevention, but for treatment. It's okay to go with that. And this is actually true with many guidelines statements. Either we have insufficient quality of data, but we make a weak recommendation that gets interpreted as black and white gospel of what we should do, or we just assume that the guidelines are up to date. You know, some of our guidelines are decades old, and we still use them and say, Well, this is what the guidelines say. So critical thought is always important. Looking at newer data is all important. The guidelines alone are not the end all to be all in terms of what you should do in clinical practice. I want Speaker 2 22:49 to talk about students that a lot of things we end up doing end up in more of a gray area that, again, clinical trials based our clinical over the recommendations based on clinical trials. Again, in a perfect population, you're going to see more of a nuanced population in practice. And so again, we have guidelines for a reason in general, but you also have to be aware of some of those grayer areas on the fringes there, and then you that's where the clinical judgment comes in as well. Yeah. Speaker 1 23:12 And I've seen that, you know, we being in Chicago land area and thinking that, you know, we're all on the same board, we're practicing the same way, doesn't mean necessarily, out there in California, the practice is the same, because I go to national meetings and attend all these CES and stuff, and sometimes, you know, at the end of the sessions, when there are questions and discussions coming up, that you realize that people are sometimes in those very particular recommendation, not just pertaining to anticoagulation, is that the interpretation is completely different. So this, right here, is a good example to not just read the bolded, you know, two sentence kind of main recommendation, but to kind of focus also on, okay, where is that recommendation coming from? What is the supporting evidence? Dr. Sean Kane 23:55 So to kind of wrap up, hopefully we've blown your mind with our three shocking recommendations from chest 2016 or at least knock your socks off. At least knock the socks off. I love it. So for me, the one thing is the age old question of, is it a NOAC or doac? And we don't have a good answer. But if you do choose to use the terminology of NOAC, you should know that you should be using it as a non vitamin K oral anticoagulant, and NOAC is your direct oral anticoagulant. No one agrees, but just be aware that NOAC may be a patient safety issue if it's interpreted as no anticoagulant. Speaker 1 24:31 To sum up, our second crazy recommendation from the new guidelines is where they compared the NOACs to warfarin when it came to the treatment of DVT and PE in those patients who didn't have cancer for long-term use. And basically what we found was the efficacy across the board was similar. So again, these were non-inferiority trials, and these agents were not superior to warfarin when it came to VTE recurrence. But what was different was the bleeding side effect. Dabigatran and edoxaban were similar to warfarin with respect to bleeding; apixaban showed a better bleeding profile versus warfarin, and rivaroxaban might have less bleeding depending on how you look at the data. Speaker 2 25:25 warfarin, all right? And so for my recommendation, the third one we find is that they've recommended that in patients with an acute DVT of the leg, they're suggesting not using compression stockings routinely to prevent post-thrombotic syndrome. And so what that doesn't mean is that no patient. It doesn't mean that there's nobody that's going to benefit from going to benefit from especially if somebody has acute symptoms. So if they have developed a clot, for example, then it's perfectly justified. Or if a patient prefers to have something like that on board, it's fine to use it. They were kind of silent on these other areas. And so just to be aware of that more nuanced practice. Dr. Sean Kane 26:00 So with that, if you would like to look at the chest 2016 guidelines, if you'd like to look at the i, s, t, h guideline or recommendation statement about NOAC versus doac versus soac, or if you want to look at the Sox trial, take a look at our references on HelixTalk.com where, if you click on episode 50, you'll be able to see the references that we used and also some of the key points from this episode. So with that, we'll be back in three weeks. As always, I'm Dr. Kane, I'm Dr Speaker 1 26:29 Schuman, and I'm Dr. Patel, and as always, study hard. Narrator - Dr. Abel 26:33 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 Narrator - ? 26:44 to 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.