NEW ORAL ANTICOAGULANTS: TREATING PE WITHOUT HEPARIN AND WARFARIN? FRANKLIN A. BONTEMPO, MD 1

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1 WARFARIN? FRANKLIN A. BONTEMPO, MD 1 All right, so let's go right to it. Here is the problem, in the last 4 years there's been a tremendous amount of information that's come out and it's very hard to know how to do this anymore because the indications for these drugs and the things that we find out about them keep on changing. It's you have to have a little cheat sheet all the time to be able to do this. So now we have 4 drugs, Dabigatran which is Pradaxa, Rivaroxaban which is Xarelto, Apixaban which is Eliquis and now there is a new one that came out a couple of weeks ago called Edoxaban which is also called Savaysa. Now there is a little trick to this, in case you are getting confused by this kind of thing the ones that they way they are spelled tells you how they work. The ones that have (atr)an those are direct antithrombin inhibitors, okay. And those that are (xa)ban are direct anti-xa inhibitors. And so the ones - you can get that by the names as they come out, so far they've held true to that kind of a situation which is somewhat beneficial. The first one that came down the pike about 15 years ago was called Ximelagatran, a direct thrombin inhibitors as the name suggests. And this was the greatest thing since sliced bread for a long time and in 2002 they had a big talk about this and I couldn't get into the meeting at the ASH meeting because of the fact that all the financial guys from Wall Street were waiting to hear what they said about the liver toxicity that was associated with this. And they said it was okay so they all ran out and said buy, but then the FDA put a big hold on it because people were dying from liver transplants a few months later in Europe and Canada so they stopped it. And this was the original direct thrombin inhibitor and there was about a 5 to 6% hepatotoxicity that was felt to be tolerable, but then it was later found that it caused serious problems and so they had to get rid of it.

2 WARFARIN? FRANKLIN A. BONTEMPO, MD 2 So the point is getting back to the original contention is though that the ones that act against Xa are like the direct Xa inhibitors are the ones we mentioned. Now the older ones like you know Enoxaparin, Lovenox, Dalteparin which is Fragmin were directed against Xa but they go through antithrombin III so those are indirect Xa inhibitors. And all the ones that are indirect that go through antithrombin III are the ones that are more prone to causing Heparin induced thrombocytopenia. The direct thrombin inhibitors we have now are - primarily it's Dabigatran but we used to have - we have Lepirudin and we used to have - now we have Argatroban, we used to have Lepirudin and those are direct thrombin inhibitors as well but those are not oral though. So the anti-xas that we are talking about today are the Rivaroxaban, Apixaban, and Edoxaban and Pradaxa and Dabigatran/Pradaxa is a direct thrombin inhibitor. Okay, now I have to go back because Dr. Smithers was going to be here today I had to put a little bit of atrial fibrillation in here I guess. But the first trial, the information that we know about these sort of comes from some of these other trials because atrial fibrillation - each one of these drugs has the hook that got them into the market and then they morphed from there and that's what makes it somewhat confusing to know what to do So the first trial for Dabigatran was called the RE-LY trial and it had a lot of patients and the bottom line was that it caused a 35% reduction in atrial fibrillation risk. And it's a large randomized trial, they used 2 doses of the direct thrombin inhibitor Dabigatran 150, 110 mg against Warfarin.

3 WARFARIN? FRANKLIN A. BONTEMPO, MD 3 Warfarin is always the bad guy here, because it's the standard and so everybody tests against Warfarin to show that they deserve to be in the market. Unfortunately they don't test against each other, I wouldn't hold my breath for that one okay. So but at 2 years the 110 mg dose was found to be not inferior but the 150 mg. dose was superior and as you can see here this is the 110, it's essentially the same but the Dabigatran dose at 150 was actually superior and I'm not going to do this for every one of these drugs but so you've got Dabigatran 110, Dabigatran 150, 150 against Warfarin over here was significantly improved for stroke and atrial fibrillation but when you did that though you gave up something in that it was - the Dabigatran dose against Warfarin was not inferior but the - the hemorrhagic risk for - for bleeding was higher and it was significant for Dabigatran versus Warfarin for GI bleeding. But if you take all the bleeding things together the bleeding risk with Pradaxa was actually for any bleeding was lower but for GI bleeding it was higher, which was part of the problem. And the other thing about this was that in the CHADS score for the people that had atrial fibrillation was a lot of the people which is shown on this slide here but it's kind of hard to see, the CHADS scores the majority of them, you know a plurality of them were 2 or less. And as a result that came into play when they did further studies and they said that if you looked at this trial and you kept, and you talked about the people who were in the therapeutic range 60, you know the people that were in the therapeutic range in the RE-LY study it was 64% and in patients with a TTR of greater than 65% it was not superior to Warfarin. And this was what happens when these studies come out they kind of analyze different facets of what happened in this and the reason this is an issue is because in later

4 WARFARIN? FRANKLIN A. BONTEMPO, MD 4 studies the CHADS scores were sometimes higher for other drugs and they were not inferior as opposed to superior for the decrease in the risk for stroke in people that had Dabigatran. Now the other things that we have to worry about in people that have these drugs are the monitoring situation. Now this is a big problem for us and there is like a counter thing about this that nobody picks up on and that is that the commercials all brag about how did I mention that you don't have to monitor like you do with Coumadin but the problem for me, and I have a different world view of this, is when people come to me and somebody is bleeding it's not only that you don't have to monitor, the other problem with this is you really can't monitor. As a result if something goes wrong you can't tell where you are and you can't know what to do, and you can't do that much for it anyway. So for Dabigatran no monitoring is required, it's unclear how to monitor it if you want It does prolong the PT, the INR and the PTT but the meaning with regard to bleeding is all over the place. We've had people at our COAG Conference come and talk about this and there is a big scatter gram and you really can't tell, there is no correlation between what the numbers mean except maybe if nothing is there you probably don't have much in there but it's really hard to know whether you are over-anticoagulated or not. And it also prolongs the thrombin time but not the reptilase time so it makes it look like you are on Heparin, which we expect, and may interfere with the activated protein C resistance assay screens for the Factor V Leiden mutation and the other thing that people don't really get is when you are trying to determine if a person is on - has a DVT or a PE and you want to stop anticoagulation if they have a lupus anticoagulant when they come in before you put them on anticoagulants these

5 WARFARIN? FRANKLIN A. BONTEMPO, MD 5 drugs oftentimes cause the lupus anticoagulant testing to be positive. And so if you are looking at the m at 6 months after when they had a lupus anticoagulant initially and hoping that it will go away so you can have reason to stop the anticoagulant that you are using if you are on Dabigatran for instance it makes it look like you are positive when you really aren't and they have go off of it to test for it before you do that. And most people don't really understand that and you have to keep that in mind. The other issue is that it's excreted by the kidneys and you have to - for all of these drugs you have to know what the renal and hepatic dosing situation is, which in compared to Coumadin is a downside. But if your creatinine clearance is over 150 and this holds for atrial fibrillation and for DVT and PE you have to - the standard recommendation is if you are creatinine clearance is above 30 you use the standard dose, if it's between 15 to 30 it's 75 and it's contraindicated if it's less than 15. There is a constant precaution not based on a lot of data but it says, they kind of just say that if you are treating somebody over the age of 70 maybe you just ought to decrease it to half the dose at 75 because they are worried about GI upset and overdosing, but that's not really supported by any kind of data that I can see. Now the reversal thing is also and issue, there is no real antidote for Dabigatran. It is about 60% dialyzable and treatment is supportive but that just means -it doesn't mean you should use NovoSeven and recombinant Factor VII, it doesn't mean you should use FFP, it doesn't mean you should use Protamine because none of those things work. You can do it but if you are treating it yourself you may be causing them to get thrombotic rather than anything else. And the PT and the

6 WARFARIN? FRANKLIN A. BONTEMPO, MD 6 PTT and the Thrombin time may provide some, yes there is some there, no, there is not. And it might guide your need for dialysis but it's really not a very good marker for telling you what to do. The GI side effects have been notoriously reported to be an issue. The bleeding is less severe than it is with /Warfarin but it's more frequent and in 2011 the number 1 and 2 drugs that were reported to the FDA for adverse drug - serious adverse drug reactions were Pradaxa was number 1 and Coumadin was number 2, but Coumadin with being used in a lot more people. But you know how it is for a new drug the side effect is unexpected and so they report it at a higher rate. For an old drug we know Coumadin causes hemorrhage, it doesn't surprise us, okay. Now the dosing schedule like I said is 75 mg bid for older patients and should be considered. The capsule has to be swallowed hole with or without food, dosing does not appear to need to be adjusted for up to moderate hepatic impairment. The shelf life is only 4 months, if you have it in the box you can't use it beyond 4 months. And the dosing for DVT treatment is the same as the atrial fibrillation treatment as I mentioned. And for the commercials you probably saw them come on at 11:00 o'clock at night all the time that would say that you know grandpa over here is really upset about having A- fib and he has that terrible Coumadin drug and if he looks a little deeper maybe he can find that something is better and Dabigatran is superior to people for stroke over all, for stroke for people that have atrial fibrillation and that's where it kind of got into the market. Now for DVT and PE it's not inferior, there is 3 randomized trials that looked at that and in 2014 Dabigatran came out in 2010 for atrial fibrillation and 2014 it got approval for non-inferiority for treating DVT and PE. And it's very difficult for me to pull all the differences in DVT so PE so I can't do that for you.

7 WARFARIN? FRANKLIN A. BONTEMPO, MD 7 There are corollaries though in this situation. We know and people that take, that have cancer that Heparin products are superior to Coumadin for instance. The drug companies haven't given us very much information about this for cancer patients but I'm reluctant to use these kind of medications in people that have cancer because we don't have any data for it really. It may be better than Lovenox and things like that but they just don't have the data for us and it's not really a big concern of theirs but it's a concern for everybody that I talk to in hematology and oncology because this is an issue for them. So if it's a cancer patient I don't feel as comfortable using it in that situation as I would using Lovenox for instance. Now the other thing to be worried about with people that have Lovenox and Heparin is osteoporosis. When I ask this to the drug companies they really say you know we are not really sure, they don't seem to be focusing on that. Another thing is you know the most common reason hematologists get sued in the United States is Heparin induced thrombocytopenia and the thing is Dabigatran that we've not seen, I don't think we are really seeing it either in the HIT of any of these drugs, but HIT is always a concern for us. But the way it works by going not through Antithrombin III would suggest that there shouldn't be any expectation based on the concept of how it works, but it shouldn't cause any Heparin thrombocytopenia, we haven't seen it. Now the other thing is this, everybody knows that Coumadin is a pain, I don't like using Coumadin either, okay, but the problem is you have to get stuck and you have to worry about drug interactions and food, we all know that. The problem is that these other drugs aren't a free ride either because if

8 WARFARIN? FRANKLIN A. BONTEMPO, MD 8 you induce the p-glycoprotein systems, the inducers and the inhibitors, they actually have an impact. And especially if you are in pulmonary medicine and critical care in the ICUs you've got to be a little bit careful because certainly these drugs can actually modulate the level of the drugs and again you can't monitor very well so you have to be aware of the fact that if you are on Rifampin for instance you may reduce the level of Dabigatran and you may have more of a risk of getting a pulmonary embolism if you are not careful. And Ketoconazole, Verapamil, Amiodarone, Quinidine and Multaq can also cause problems, can increase the level of the drug because of competition for metabolism okay usually, so you may need the dose reduced to 75 mg twice a day. Now the other problems I'm not going to go through all of these but you have to have a little cheat sheet because if you have to do something to the person and stop anticoagulation or start it and it depends on which one you are on I can't memorize these and I have a pretty good memory, but I can't remember which one it is for what level of creatinine clearance and you've got to have a little sheet in your pocket to tell you what to do and this makes it a little bit harder, okay. I'm not going to say converting from Warfarin to Dabigatran, converting from IV Heparin to Dabigatran, converting from other parenteral anticoagulants to Dabigatran, that one is pretty easy, you start Dabigatran 0-2 hours before the next dose for that rapid onset of action, that's great, but you've got to think about it, it's not simple. Okay, put them on - and we have been known to get a few complicated patients around here and so oftentimes you don't often get a chance to say wow this is a very straightforward easy one. Okay. Perioperative management also, we hold Dabigatran for 1 or 2 days preop for creatinine clearance greater than 50, and 3 to 5 days for creatinine clearance less than 50, all right.

9 WARFARIN? FRANKLIN A. BONTEMPO, MD 9 Other considerations, for all of these drugs it's the same kind of thing. You avoid concomitant antiplatelet agents and anticoagulants and Dabigatran decreases implantation and increases intrauterine fetal death and vaginal uterine bleeding in rats. So guess what, don't use it in pregnancy. Nursing mothers they say avoid it, avoid it in patients with indwelling epidural catheters or spinal anesthesia and we don't know what it does in kids. And the other ting for all of these drugs there is a concern about rebound hypercoagulability. Now I don't know where it comes from but people have always been concerned about rebound, hypercoagulability when you stop Warfarin as well. I don't personally usually take - I mean I figure that Coumadin kind of gets tapered over 3 to 5 days by itself naturally when you stop it but I don't put people on Lovenox or something like that if they've come off Coumadin most of the time. And but there is a concern and there is some more concern has been raised about this in the oral anticoagulant, in the new anticoagulant era but there is more of a concern that's been reported about rebound hypercoagulability but there is no recommendation about what to do about it. So the bottom line with some reservations because of complexity Dabigatran offers non-inferiority for treatment of acute PE after treatment with parenteral - now that's the other issue, the recommendation for Dabigatran was only done with people that had 5 to 10 days of parenteral therapy initially, but after that treatment with Dabigatran was approved for patients previously treated with DVT and PE. So you had to be treated with something else. Now it didn't have to be inpatient or outpatient necessarily but it couldn't be with Dabigatran initially. That was the idea. Second is Rivaroxaban, Xarelto. Now this got initially approved in Now the hook for Xarelto was and it was initially approved for DVT prophylaxis in total hips and total knee replacements, two of the most provoking things that we have, and it's actually very good for that it seems to me. I

10 WARFARIN? FRANKLIN A. BONTEMPO, MD 10 know because they've been using it at Magee and I haven't heard- and the Magee people don't talk to me because they are always in the OR. They have people that will talk to me but not the actual surgeons, and I know that if they were having a problem I'd be hearing about it and they haven't been doing it - and for 2 years I haven't heard a peep so it must be working pretty well. Now there were two, there was a ROCKET trial and an Einstein trial and the ROCKET trial showed non-inferiority to Warfarin for non-valvular atrial fibrillation and with similar bleeding with FDA approval in later 2011 and began with higher CHADSS scores though than with Dabigatran and there are people who are only too happy to remind you of the fact that maybe if they would have used the lower CHADSS scores they would have been superior to Warfarin as well. All right so the Einstein trial showed non-inferiority for treatment with people who have acute DVT and PE in reducing recurrent DTE risk versus Warfarin with similar bleeding with FDA approval in Now the graphs say, this shows that the bleeding risk was - that the efficacy was equivalent and clinically significant bleeding was equivalent but major bleeding was actually lower. Okay, the pharmacokinetics again rapid onset of action 2 to 4 hours, protein binding 95%, There were some issues. Rivaroxaban was the one that Arnold Palmer advertising online and grandpa I think is the one that can go to the Grand Canyon on this one because he doesn't have to have the evil Coumadin checked for while he's on vacation. And the Rivaroxaban is also the food one. The bioavailability of a 10 mg dose is 80 to 100% after oral administration and not affected by food, but the 20 mg dose is only 66% after oral administration but improves with food. And so there is some concern about decreased bioavailability if it's administered by a feeding tube and if the tube is in the proximal small

11 WARFARIN? FRANKLIN A. BONTEMPO, MD 11 intestine and it's distal to the stomach it could be an issue. And they say question avoiding it in that situation. It's not affected by drugs altering gastric ph however. They can screen it renally but there is no antidote and it's not dialyzable so that's a problem, they start to bleed. The monitoring, once again no monitoring required and people say that's great. But for me I go the person is bleeding what should I do? He said I don't know, I can't tell where they are in this kind of thing you know, but nobody seems to care about that except at 12:00 o'clock at night when somebody is bleeding in their head. Okay, so it prolongs the PT, the INR and the PTT but the meaning with regard to bleeding is again unclear. It may increase the measure level of anti-xa activity but we are not really sure about that yet, it may interfere wit the activated protein C and the factor V Leiden and it definitely, definitely cause false positive lupus anticoagulants. So if you have a person with a LAC coming into a DVT at the beginning before they are on anticoagulation if they still have it 6 months later on Rivaroxaban you've got to take them off and put them on something else or put them on aspirin for a few days and test it and then to see if you can - if you are using that criterion for whether you can stop anticoagulation or not. Now the thing that's kind of nice about it is that it seems, the dosing schedule is amazingly good for people that have - for DVT prophylaxis in total knees. You only have to use it for 12 days to get equivalence to Enoxaparin but we are not talking about that, we are talking about DVT and PE. And but for DVT and PE that's acute it's different than it is for long term. For acute DVT and PE you have to use 15 po BID for 21 days with food in the beginning, but after 21 days you would use 20 mg po once a day, so you'd have to use it once a day for the long term. And the recommendation is

12 WARFARIN? FRANKLIN A. BONTEMPO, MD 12 if you have a creatinine clearance of less than 30 you shouldn't use it. And you are supposed to for renal dosing you are supposed to avoid Rivaroxaban if the creatinine is less than 30 and even so for people that have total knees or total hips the same kind of thing, you should observe them closely for 30 to - between 30 and 50. So what does that mean? You watch them until they bleed and then you stop? I mean I guess that's what it is. All right they also recommend avoid Rivaroxaban in CHADS B and C hepatic impairment patients. No approved antidote, not dialyzable. Now when they came out there was a big interest about this because there was some suggestion and some data that the new prothrombin complex concentrates with 3 or 4 factors in them might be better but the reality is it's not really been shown to be that beneficial and I don t feel comfortable recommending it, no one really does. Treatment is supportive again - but there is no recommendation to use anything except just make sure you know you keep their other things in as good a shape as you can. But PT and PTT and Rivaroxaban assays may give some evidence for lack of presence of the drug if negative. We have a Rivaroxaban assay in our lab, I'm not ecstatic about it but it's a start and it will probably get better in the future. Side effects are similar. The bleeding risks are similar to Warfarin in DVT and PE patients except there is less major bleeding. Overall bleeding is about the same however. In cancer patients we have a similar situation, I'm reluctant to make a recommendation on osteoporosis, little data available. Similar situations for Rivaroxaban for inducers and PG, glycoprotein CYP3A4 pathways these drugs are now in St. John's Wart and HIV protease inhibitors

13 WARFARIN? FRANKLIN A. BONTEMPO, MD 13 are also an issue for Rivaroxaban. And you kind of have to know these because a lot of the people you have around here have these things and you might get burned if you don t pay attention to it. I'm not going to go through them all but I have a little cheat sheet for this that I can use for all the different conversions. You've got to know what to do for each one. I can't do them all today, I can never remember them anyway, okay, so the preoperative management, you hold Rivaroxaban for at least 24 hours preoperatively weighing the bleeding risk against urgency. Question longer if there is renal impairment, okay. All right other considerations. No known antiplatelet agents and other anticoagulants, pregnancy and nursing mothers, no good. Indwelling epidural catheters, the recommendation is the last dose should be before removal, no sooner than 18 hours prior, or spinal anesthesia. Safety and efficacy is not known in kids and rebound hypercoagulability is similar to Dabigatran, they mention it but they don't make a strong, that strong of a recommendation. Bottom line with some reservations for complexity. Rivaroxaban offers non-inferiority for treatment of acute PE after treatment, and this is without initial parenteral anticoagulants in this situation. They were approved for not giving them parenteral things before and for reduction of recurrence of DVT and PE for the first 6 or 12 months afterwards. It's good to use for DVT prophylaxis for hips and knees. Rivaroxaban offers convenience and lack of need for monitoring. It could be attractive for - I use it, I like it for DVT prophylaxis for plane trips and antidotes may be available for this in the near future. We are waiting to see what happens and this could be - make it better.

14 WARFARIN? FRANKLIN A. BONTEMPO, MD 14 The third is Apixaban which is Eliquis. Indications, it was approved in 2012 for superiority to Warfarin for non-valvular atrial fibrillation with less major bleeding but similar CHADS scores to the RE-LY trial with Dabigatran. For non-inferiority for DVT prophylaxis but was approved in 2014 for non-inferiority for treatment of acute DVT and PE in reducing recurrent BTE risk versus Warfarin with less major bleeding. The people though had a mixture of Enoxaparin and I think they had a mixed bag of the initial people that had the treatment and it's questionable whether you can use it without parenteral treatment or not. The pharmacokinetics 3 or 5 hours with onset of action, half life 12 hours, protein binding 87%. Bioavailability of a 10 mg dose is 50% after oral administration and not affected by food, so this is not the food one. Apixaban is the hot wife with the car with the guy in northern California just hoping this doctor if he digs a little deeper and searches a little harder he might find something better for him personally than the evil drug Warfarin, okay. And there is no antidote and it's not dialyzable, okay. Monitoring is not required, we don't have anything for it and it may affect the PTT, probably causes lupus anticoagulants but I haven't seen it as much, they don't tell you that so far. Activated charcoal may be beneficial in lowering the plasma level of the drug, there is some reports of that. Dosing for DVT let's look at 2, 3 and 4 here. And PE treatments, 10 mg twice a day for 7 days initially followed by 5 mg bid. Now the Apixaban is the bid drug, okay, for most of its indications here. For DVT prophylaxis it's 2.5 bid and with first dose 12 to 24 hours postoperatively and once

15 WARFARIN? FRANKLIN A. BONTEMPO, MD 15 hemostasis is established but the thing about Apixaban which is its bigger hook is that for DVT and PE treatment after 6 months they actually have data, now you have to be careful what they say though, the data is that if it's 2.5 mg po bid for people who compared to placebo it was superior to placebo for long term treatment after 6 months, but it doesn t have good data for compared to Warfarin or Lovenox so far I don t think. And but this is the first time this has ever really been documented. There was always this issue about after you've been treated with any anticoagulant you want to talk about for 6 months for a DVT or a PE and you want to reduce it after that period of time for the longer term is that okay to do? There is some evidence that might be beneficial but it's never really been proven very definitively but they are working toward this with Apixaban, and this is an area of investigation that they may rule over for a while. Okay, no renal dosing changes are also needed in - or are needed in DVT prophylaxis patients or those being treated for DVT or PE but for dialysis hey don't go that far to say that for dialysis you don't have to worry about it. For dialysis we have a problem but for the other things there is no renal dosing changes that are recommended. It is not recommended to change the dose in severe hepatic impairment and no recommendation can be made for moderate hepatic impairment. In non-valvular atrial fibrillation there is an issue but - there is an issue for non-valvular atrial fibrillation but for DVT and PE it's not an issue. All right in cancer patients the same situation, obtains osteoporosis is the same, HIT it doesn't cause it. The same kind of situations for the drug interactions. Now again these things aren't severe but you can't measure the drugs that well to tell how bad it is in the first place but it's just a recommendation

16 WARFARIN? FRANKLIN A. BONTEMPO, MD 16 to consider what's going on. If you have a patient in the ICU, if they are on these drugs you might want to be more careful about what you are doing and keeping in mind what could be happening and they haven't gotten great recommendations about what you know l-when you should stop the drug or whatever but you should just be cognizant of the fact that some of these things may have an impact on the level in the blood stream. Conversion, it's easier. There is not as many things as it is for the other two but I'll just leave it at that. Okay, perioperative - preoperative management hold Apixaban for 48 hours for moderate to high risk elective surgeries and at least 24 hours for elective low risk surgeries. You restart postop when adequate hemostasis has been achieved. Other considerations are the same. The only difference about this one is that the rebound situation is felt to be a little bit more potentially a problem, there is no strict recommendation for this yet but they seem to be more worried about rebound hyperplasia building in Apixaban than the other ones. Bottom line, twice a day dosing may be a bit of a negative for some people, but for long term DVT and PE treatment that may offset the lack of reversal but cause a lower peak effect and maybe the bleeding risk was higher than placebo but they don't have actually - they don't have data really for - there actually is some for the 5 mg dose but I don't think they have any for Coumadin yet okay. It's less complicated renal impairment and less complicated perioperative dosing schedule. So that's the better thing for Apixaban.

17 WARFARIN? FRANKLIN A. BONTEMPO, MD 17 The last one that came out a couple of weeks ago, January, 2015, Edoxaban, which is going to be called Savaysa. It was approved in January of 2015 for stroke prevention and non-valvular atrial fibrillation with less major bleeding, but it's also been approved for DVT and PE. But once again after 5 to 10 days of treatment with parenterals. The dosing schedule is 60 once a day for nonvalvular atrial fibrillation, with dose reductions for creatine clearance of 15 to 50 and 60 mg po qd after initial treatment of DVT and PE. Rapid onset of action 1 to 2 hours, excreted renally, no antidote and not dialyzable. Not recommended - now this is the thing that gets me, I've never seen this in my entire career, it's not recommended in patients with a creatinine clearance of greater than 95. Now I don't know about this but it's also got an association with - for Edoxaban there is a concern because it causes - there is a question of interstitial lung disease. But the thing I don't know about is are we going to have to check people to see if their creatinine clearance is greater than 95 to see if you can use it? They say if you put them on - if you have a creatinine clearance of greater than 95 the implication is that the dose of the drug may get excreted too rapidly and may not give you efficacious effect. So we have to - I've never thought about doing that before but that's what they - that's what is in the package insert. Okay?