Speaker 1 00:05 Hi. Welcome to HelixTalk, a podcast presented by the Rosalind Franklin University College of Pharmacy. Narrator - Dr. Abel 00:11 This podcast is produced by pharmacy faculty to supplement study material and provide relevant drug and professional topics. Speaker 1 00:19 We're hoping that our real life clinical pearls and discussions will help you stay up to date and improve your pharmacy knowledge. Narrator - Dr. Abel 00:27 This is an educational production copyright Rosalind Franklin University of Medicine and Science. Speaker 1 00:32 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 - Dr. Abel 00:47 And now on to the show, Dr. Sean Kane 00:51 hi HelixTalk listeners. This is Dr. Kane. After we released this episode, I received an email updating us about the packaging for Dabigatran brand name Pradaxa. So in this episode, we talk about after the bottle for Pradaxa is opened, it expires within four weeks. As it turns out, the labeling was updated, and now it is four months. So again, the bottle of Pradaxa, once opened, expires after four months, not four weeks, as was described in this episode. And now on to the show. Welcome to episode three of HelixTalk. I'm your co host, Dr. Kane, Speaker 2 01:28 and I'm Dr. Patel, and we're going to miss Dr. Schuman today. Dr. Sean Kane 01:31 Today we're talking about the no X or the novel oral anticoagulants. There's three new ones on the market, and because they're new, we thought that it'd be a good topic to talk about today. Speaker 2 01:40 I absolutely agree, especially people who are not familiar with those medications, are kind of confused as to which one is better, or how they compare to the older ones, especially our good old friend warfarin. Yeah. Dr. Sean Kane 01:52 So unlike warfarin, where Warfarin prevents the clotting cascade in a couple different places, the noacs work in one of two different places, either clotting factor 10 or the thing next to clotting factor 10, which is clotting factor two or thrombin Speaker 2 02:08 so we have our Pradaxa Generica zabigatran, and that is our direct factor two, or direct thrombin inhibitor. Dr. Sean Kane 02:15 And then we have two new direct 10 a inhibitors called Xarelto. The brand name is rivaraxaban, or the second one is Eliquis. Generic is apixaban. Speaker 2 02:26 So if you notice there is XA in both the generic name and that is how you separate that these two are directly inhibiting factor 10, exactly. Dr. Sean Kane 02:36 So when you hear Zaban X, A, B, A n at the ending of medication, it's probably a direct factor 10, a inhibitor. So what are these novel oral anticoagulants approved for? Speaker 2 02:49 I'll be honest, it's been hard to keep up with the indications, because as the studies are going on and as we get experience from other countries such as Canada and Europe, the FDA is slowly, by slowly, approving these indications. Dr. Sean Kane 03:01 Exactly and really, all three agents got their foothold in terms of being FDA approved for non Speaker 2 03:08 valvular atrial fibrillation. What do you mean by non valvular? Dr. Kane, so Dr. Sean Kane 03:12 non valvular means that you don't have a mechanical valve that you're trying to anticoagulate the patient with. Instead, you just have run of the mill atrial fibrillation, where you have normal heart valves, Speaker 2 03:22 I see, and then if you're talking about preventing DVT or PE, or even treatment of DVT or PE, including long term treatment, the two agents that are indicated is Dabigatran and riveraxaban. Dr. Sean Kane 03:37 Dabigatran actually just got this indication a number of weeks ago. So for a while, river axaban was the only agent approved for the treatment of DVT and PE but now Dabigatran also joins riveraxaban for that indication. Speaker 2 03:50 And if you're talking about getting DVT prophylaxis after hip or knee replacement surgery, we're looking at riveraxaban or apixaban. Dabigatran doesn't have that indication yet. Dr. Sean Kane 04:00 Then finally, for long term treatment of DVT and PE. So traditionally, when you have a DVT or a PE, you're treated for three to six months, depending on your risk factors. Then after that, if you're low risk, you can actually stop anticoagulation. So Dabigatran and rivaroxaban are actually approved for longer term use. So after you've undergone six months of anticoagulation after a DVT or a PE Dabigatran and rivaroxaban have approval where you continue anticoagulation therapy beyond that point. So you can probably appreciate that we have a lot of different indications, and different drugs are approved for different ones. Hopefully over time, different drugs will make their way to being the preferred agent or not preferred agent for different indications. But for right now, it's kind of the wild wild west of what NOAC treats what. And is that accurate as of yesterday or not? Speaker 2 04:51 And also we have to look at the cost as well. So if your insurance have one agent on formulary versus the other, we might end up picking that agent. Dr. Sean Kane 05:00 Yeah, so to kind of put things into perspective, I think it's important to kind of compare and contrast. What's the difference between a NOAC really, in any of the three noacs and Coumadin or warfarin, Speaker 2 05:11 especially when we know that we are more comfortable with warfarin, because it's been in the market and been used for about 40 years Dr. Sean Kane 05:19 now, exactly. So I think probably the biggest thing that a patient will know about these no acts is that they don't require INR monitoring. And if you recall, INR is the blood test that we use to see how anticoagulated a patient on Coumadin or warfarin. Is the Speaker 2 05:34 problem on the other side is then we are wondering, okay, how do we know if the patients are properly anticoagulated with one of these noacs, exactly. Dr. Sean Kane 05:44 So it's kind of a double edged sword. So with the NOAC there's no blood test, at least currently, to know whether the patient is anticoagulated or not. So you don't have to monitor anything. But at the same time, there's really nothing that you can monitor to know that they're therapeutically anticoagulated. Speaker 2 06:01 We do know some tests like PTT or pro time are affected by one of these agents, however, particular test to monitor their anticoagulant effect is not been approved or officially set. Yeah. Dr. Sean Kane 06:16 So long story short is that you know these agents may affect some of your coagulation parameters, but we really don't have a very specific and sensitive test to really ascertain how anticoagulated you are on these NOAC agents. So one thing that's dramatically different with the noacs versus Coumadin is that the noacs are primarily eliminated through the kidney, so if your kidneys don't work very well, you're going to kind of hold on to these noacs. And I've seen a number of patients. Of patients in the ICU where I work, where they were given a NOAC, they had acute kidney injury, and now their PTT, or their pro time are really elevated because they've really accumulated a lot of these anticoagulants. Speaker 2 06:55 So hopefully for these patients, if needed for long term anticoagulation, Warfarin might be the better, better agent. Dr. Sean Kane 07:02 So another difference is the onset of action. So all of the noacs work extremely quickly, whereas, if you remember with Coumadin, I think of Coumadin as kind of a faucet in a sink. So when you give a patient Coumadin, the faucet is spitting out clotting factors. And the purpose of Coumadin is to turn off the faucet, but you still have clotting factors in the sink. The difference here is, with our no axes, we can remove the clotting factors from the sink almost immediately. There's no delay of three to five days waiting for that INR to go up. So that's actually a really nice thing, so that we're not having to bridge patients with Lovenox or Heparin, but as soon as they start taking the medication, they're anticoagulated. So Dr. Patel, I know that you lecture a lot on warfarin genomics. Is there a lot of genomic things or variability that we know about with the no X Speaker 2 07:48 actually no and that gives us a little peace of mind, knowing that these agents do not have any polymorphism identified yet, and so no particular dosing adjustments need to be done Dr. Sean Kane 08:01 with that said, that means that pretty much everyone, with a few exceptions, are going to get the same or a very similar dose, right? That is correct. So it's not a range of one to 10 milligrams of Warfarin per day. It's more, you know, a fixed dose, almost for everyone, for any of these noacs, Speaker 2 08:15 almost for everyone besides the patients who have low renal function, exactly. Dr. Sean Kane 08:20 Okay. Well, tell me about some interactions that we see with these no acts, because I know with Coumadin, it's a ton of interactions to remember even certain foods that you have to worry about. Speaker 2 08:29 Yes, and in practice, when I see patients being switched from Warfarin to any of these no acts, they're actually really happy, because now they can go ahead and eat anything, including green vegetables and grapefruit juice and cranberries and whatnot. So that's actually one of the benefit of this no accident. It does not require to avoid any food. However, rivaroxaban manufacturer recommends taking this particular medication with food only, and doesn't have to be what kind of food it just as long as patient takes it with meals. And as far as drug interaction goes, like you mentioned, warfarin, we got pages and pages of interactions and particular strategies to overcome these interactions. The only few drug interactions we see with this no access the three a, four inhibitor, or the P glycoprotein inhibitor type of interactions, yeah. Dr. Sean Kane 09:20 And so the three, a, four, cytochrome p4, 50 enzyme system, that's a pretty common enzyme system for drugs to utilize in order to be metabolized. So we do see drug interactions, but not to the same extent that we'll see with Coumadin. So there is a huge difference there, in terms of peace of mind, knowing that the patient's anticoagulation status is going to be more predictable than with Coumadin, knowing Speaker 2 09:42 the fact that these drugs have just entered the market, they're in the phase four study. So you know, like what happened with samostatin and figuring out all those drug interaction, it's quite possible that in future, we might be able to identify specific, three, a four drug interaction, and the management strategy will come about. Dr. Sean Kane 10:00 So we briefly talked about it, but cost is going to be a big difference. So there's a huge amount of controversy over the cost of the different agents. So with Coumadin, patients are going to have to pretty frequently go to a clinic of some type, get their INR tested, which costs money, and have their Coumadin dose adjusted. In contrast, though the no acts are going to cost a little bit more upfront in terms of the cost of the prescription, but part of that cost is offset by two things. One, many manufacturers are offering prescription discount programs. Two, many of these are now being covered by insurance. And three, there's no INR testing to be done on a weekly or every other week basis, whereas with Coumadin, we had that frequent testing. Speaker 2 10:41 Yeah, but I do recommend that if you are switching your patient from Warfarin to one of these agents, that you first figure out the coverage, whether they're going to be covered, the noacs, before you go ahead and tell the patient, okay, yeah, start taking it. Because, like I mentioned, there is that specific way you have to transition patient from Warfarin to the new agents exactly so unlike warfarin, so these agents would require twice a day dosing, especially apixaban is almost twice, almost always twice a day dosing. Roxaban could go either once a day or twice a day, depending on the indication. And it's the same thing with the bigger trend as well. And why we mentioned the frequency is because, again, you need to stress the compliance with the patient. Dr. Sean Kane 11:23 I think this is a really important point to kind of emphasize is that, you know, some patients can't take vid dosing, in the sense that they miss doses frequently. And unlike Coumadin, where we have this INR measure to know when they haven't taken their dose, there's no way as clinicians, for us to show or see that they're not taking their dose appropriately. So in certain patients, you know, phase three trials is one thing, but in real life, clinical practice, it's potentially a completely different thing, where if patients Miss doses frequently, they may not receive the same benefit that they would as when they were taking warfarin, where they had the convenience, if you will, of being able to miss a dose here and there in their INR not move as much as with a shorter Half Life drug, like any of our no Speaker 2 12:05 acts, right? So you're trying to say that you kind of have to pick and choose who qualify, which of your patient qualifies for one of these agents, exactly. Dr. Sean Kane 12:14 So I don't want to spend too much time on it, but I think reversal is a pretty important topic to talk about, especially in my neck of the woods in the ICU. So I know with warfarin or Coumadin, kind of the reversal strategy is primarily FFP or fresh frozen plasma, which is kind of your clotting factors in a frozen block of ice that you thawed and give to the patient, and then vitamin K, which is an antagonist to warfarin or Coumadin to reverse its anticoagulant effect. Speaker 2 12:41 What do we use with this no ax? Dr. Payne, Dr. Sean Kane 12:44 so we really don't know specifically what to use with the No x1 of the things that most people are recommending now are called PCCs, prothrombin complex concentrates, which is kind of a powder of clotting factors that is put in a vial, reconstituted and given to the patient. So it's kind of like FFP, but the volume is much smaller. The problem is that we have almost no data supporting the use of PCCs, so it's really relegated to the last line, life threatening bleed, type of patient, where they will probably die if we don't try to do something for them. But absolutely, in the next couple years, I think the entire medical community is waiting for better data of how to reverse these noacs. Speaker 2 13:23 So can we do anything else, like gi removal of these agents? Dr. Sean Kane 13:28 So activated charcoal, if it's caught early, is great for all three agents. With apixaban, it actually has a really delayed absorption profile, so we can give it a number of hours after the dose is taken, and then dabigatran is the only one that is dialyzable. So in certain patients, but probably in pretty rare circumstances, dialysis may be indicated with dabigatran but not the other two. Speaker 2 13:51 That's interesting facts to know. So we covered the basic, you know, know, how's dosing, indications, reversals, importance of adherence and INR lab monitoring. When it comes to the meat of treating the patient, we always worry about the efficacy and safety. So can you give us some insight, Dr. Kane, about what an efficacy and safety of one of these new agents? Dr. Sean Kane 14:15 Sure. So I think the easiest way to think about efficacy and safety is to go back to that core indication that all of these agents were initially approved for, which was non the ovular atrial fibrillation. So in patients who add who have afib, we want to prevent stroke in them. And strokes can happen because of a clot that forms in the heart and goes up to the brain. So we want to prevent that, but we also don't want to cause bleeding by making them too anticoagulated. So that's really our two end points. And as it turns out, in all of the studies, compared to warfarin, the no acts did reduce the risk of stroke by about 20% with a number needed to treat of about 140 what that means is that we have to give 140 patients a NOAC instead of giving them Coumadin for them to not have a new. Stroke or systemic embolism, which would be a clot somewhere else in their body. With that said, though, as I mentioned, we also are worried about bleeding. So the big thing with these noacs Is that intracranial hemorrhage, which is a bleed in the brain, was reduced by about 50% in patients who took a NOAC compared to someone who took Warfarin with about the same number needed to treat. So again, for every 140 patients we give a no act to, they won't have a stroke and they won't have a bleed in their brain, compared to someone who got warfarin. Speaker 2 15:31 And when it comes to bleeding, you know, in the studies, we look at data such as major bleeding, and it's kind of also broken down into, you know, GI bleeding and sub what are the data available there? Dr. Sean Kane 15:43 Yeah, so that's a great question. So obviously, like a bleed in the brain is a pretty big deal, but bleeds other places in your body are also important. So the first two agents that were approved, Dabigatran and rivaroxaban, both of those agents had no difference in major bleeding, but actually had a higher incidence of GI bleeding. So apixaban had similar amounts of GI bleeding, but had less major bleeding, which is bleeding anywhere in the body, compared to Coumadin. So we don't really know for sure yet, but based on the data alone, it would look like apixaban may have a little bit of an edge in terms of equivalent efficacy but better safety profile than the other two no acts, but it's really hard to compare different studies, because they're going to have different types of patients, different geographies of patients that were included in Speaker 2 16:28 the trials. So we hope that these agents are then head to head compared in near future. Dr. Sean Kane 16:32 That would be awesome if it happened, but it's unlikely to, because the drug companies are going to have to fund it, and no one wants to sit at a board meeting and say we funded a study for millions of dollars, and now no one wants to use our drug because our drug lost in the fight between the two. That makes sense. So Dr. Patel, we really focused a lot on the data as it relates to the atrial fibrillation setting. Can you give me an idea of how these agents compare to some of the other indications that we talked about, like DVT and PE for example? Sure. Speaker 2 16:59 So there are some comparative studies when we look at these agents in non atrial fibrillation settings. So we have apixaban, and when it was studied for VTE prevention, along with enoxaparin, we found that it was as effective as enoxaparin, and when we looked at the bleeding again, looking at the tolerability of the medication too. The bleeding rates were similar between the two agents. Now, when we look at Dabigatran again for the VT prevention in hip and knee replacement setting, it was as effective as enoxaparin. We also looked at Dabigatran compared to Warfarin in the VTE treatment, and we found it to be as effective. However, in both the settings, we found that Dabigatran was associated with the similar rates of major bleeding as both enoxaparin as well as warfarin. And then now we have our rivaroxaban, and it's been studied again in VTE prevention for patients who undergo knee and hip replacement, and we found that medication to be as effective as enoxaparin. And same thing when we looked at enoxaparin and Warfarin in VTE prevention and treatment, we found that the efficacy of rivaroxaban was similar. Dr. Sean Kane 18:17 So in short, pretty much everything outside of the AFib setting, we're seeing comparable data in terms of safety and efficacy between our noacs and whatever the standard of care is, either Warfarin or low molecular weight heparin. That is correct. And I do want to point out one thing in terms of the indications that I think is really interesting. So aside from atrial fibrillation, which again, was kind of the standard bearer indication for all of these no acts DVT and PE was the next really nice indication for any of the drug manufacturers to get with that said, though rivaroxaban was first and they got the DVT and PE indication, no problem with Dabigatran, and because of how they designed their DVT and PE study, it's actually approved in patients who Have a DVT and PE who are then treated with a parenteral or an IV anticoagulant for five to 10 days and then started on Dabigatran. And the reason that that is significant is that it really changes the course of therapy. So if you're a new PE or DVT patient, you can start rivaroxaban immediately, but if you want to start Dabigatran, in theory, based on the trial, you really have to have five to 10 days of an anticoagulant, IV anticoagulant, Speaker 2 19:27 so meaning, like bridge them either with the unfractionated Heparin, or use the molecular weight heparin, and then start Dabigatran. Apixaban is already approved in Europe for the indication of DVT and PE prevention and treatment. All we are waiting for is the new trial data so the FDA can go ahead and approve that indication for apixaban as well. Dr. Sean Kane 19:48 So to kind of wrap our discussion up about noacs, I think that there's two kind of clinical pearls or things to think about with dabigatran and apixaban that are worthy of mentioning. So with dabigatran. An interesting thing is that the bottle itself has a desiccant in it. So Dr. Patel, what does that mean? And why does Speaker 2 20:05 so this desiccant and the dabigatran bottle is a little bit high tech than what you see in the other pre packaged bottles, and the manufacturer recommends that do not remove the medication from the original container, because the desiccant is actually there to remove any moisture that would alter the response of the medication. Dr. Sean Kane 20:26 So what are we supposed to do in patients that use pill boxes where they need to take the medication out and put it in a pill box, like the bigger train. Speaker 2 20:33 So actually, we have to advise patients not to do so, which sounds a little bit counter innovative to our increased compliance with these noacs too, because we know that pill boxes can help to increase the compliance. But however, for perdoxa, we want to tell the patients not to use the pill boxes. However, another effective way of increasing compliance is the blister packs. So these blister packs are also available from manufacturer that are used for unit dosing that can be packed into the pill boxes, Dr. Sean Kane 21:07 and again, going along, the idea of the dabigatran bottle is special. With this desiccant, once you actually open up the bottle, it's only good for four weeks. So in a patient who's compliant with the medication, this isn't a big deal, but for someone who misses doses, or maybe they're hospitalized for a few weeks, and then they start taking their home Dabigatran, again, it's important to counsel them. It's only good for one month, and after that it expires. Speaker 2 21:30 So good idea for our patient to do is, when they open the bottle, write down their four week expiration date on the bottle, so what they will know that okay, beyond this, they cannot use this medication from this bottle. Dr. Sean Kane 21:43 Great point, Dr. Patel, and if I recall correctly, there's one adverse effect that we see with Dabigatran that we don't see with the other noacs. Speaker 2 21:51 So on top of bleeding, I think you're suggesting the GI side effects that comes with Dabigatran. And I think mainly that's dyspepsia that occurs significantly with Dabigatran, exactly. Dr. Sean Kane 22:03 So if you're a provider trying to decide between, let's say, Dabigatran and rivaroxaban, if you have a patient that already has, you know, heartburn, dyspepsia, a history of peptic ulcer disease, maybe it's a good idea to avoid Dabigatran because it may make those symptoms worse. Correct? Speaker 2 22:18 And if patient doesn't have any of these history, and you want to start Dabigatran and I think it becomes a very important education point that they might develop dyspepsia because of Dabigatran, and we have to tell them not to just discontinue this medication without notifying their providers. And another thing that we need to think about before prescribing Dabigatran is that, you know, if the patient is 75 years or over older, or patients with poor renal function, as we already mentioned, or patients who are underweight, we have found higher incidences of bleeding. And so we have to kind of pick and choose and make sure that we are picking the right agent for the as an anti thrombotic. Dr. Sean Kane 22:59 And potentially one of the reasons that we see that favorable bleeding adverse effect with apixaban compared to the other two noacs Is that the dosing of it actually accounts for older age, greater than 80 years old, underweight patients less than 60 kilos, or patients who have a higher serum creatinine, greater than one and a half. We actually give them half the dose than we would a normal patient. So potentially, that's one of the reasons that we see a better adverse effect profile with respect to bleeding, is that we're intentionally giving these higher risk patients a lower dose. Speaker 2 23:31 And so you were saying is that what Dabigatran manufacturer did not catch during the trials is what an apixaban manufacturer did, and that's what they employed in the trials. Exactly. Dr. Sean Kane 23:40 Maybe in this case, it's better to be kind of late to the game, because you can see the mistakes of the two drugs ahead of time and design your trial appropriately so that you take advantage of the mistakes of other manufacturers, Speaker 2 23:52 smart people who made a big Savannah. In order to conclude our discussion today, we're just going to snapshot some of the important things about the NOAC. So we have our davigatran. The brand name is prodoxa, and it is a direct factor to inhibitor. And the novel thing about perdoxa, or something to remember, is that make sure you tell your patients to keep it in the original container. Do not put it in the pill box, because there's that four week expiration time once they open the bottle. And a unique side effect that you also need to educate the patient about, which is dyspepsia, tell them not to discontinue it, or the patient had a history of certain conditions like GERD or PUD. Then go ahead and choose a different agent, definitely. Dr. Sean Kane 24:36 So then the next agent that was approved in the United States was Xarelto, or the generic was rivaraxaban. This is a direct factor 10, a inhibitor. The thing that's kind of cool about rivaraxaban is that it's basically approved for all of the indications, everywhere, from non valvular atrial fibrillation to DVT and PE treatment to prevention of DVT and PE in post hip and knee replacement patients. And even an extension of treatment of DVT and PE in patients who have already been anticoagulated for more than six months. So it's kind of run the gambit in terms of the FDA approval for a lot of these indications. So you're probably more likely to see rivaraxaban clinically because it's approved for so many different indications. The one thing that, from a patient counseling standpoint, is important to remember is that it should be taken Speaker 2 25:22 with food and late, but not the least in the same class of direct factor 10 inhibitor is our apixaban or brand name aliquis. And as we know, currently, we have indications for non valvular atrial fibrillation as well as DVT prophylaxis after hip or knee replacement surgery, the indication approval process for the other conditions are underway through FDA. One other thing that sticks out for apixaban is compared to the other noacs and warfarin, we know that the bleeding rate is a little bit better Absolutely. Dr. Sean Kane 26:00 So this concludes our discussion of the noacs. If you haven't done so already, we'd love a favorable review in iTunes. Again. If you want to check out some of our other episodes, we're in iTunes, or you can go to HelixTalk.com so I'm going to go ahead and wrap it up. I'm Dr. Kane, Speaker 2 26:14 and I'm Dr. Patel, and as always, my standard statement, please study hard. Narrator - Dr. Abel 26:18 Thank you for listening to this episode of HelixTalk. For more information about the show, please visit us at HelixTalk.com you.