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LLSA Prep 2020: Reversal of Dabigatran

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LLSA Prep 2020 is here! Get high-yield synopses of each paper in 5-10 minutes, plus a real-time test walkthrough, delivered by Drs. Rob Orman, Mizuho Morrison, and Matthieu DeClerck. It’s the most productive and entertaining way to stay on top of your clinical game–and also just happens to help you breeze through your ABEM MOC.

Kind cowboy sir i need your assistance i have uh coming from europe and i’m on this medication uh dabigatran and i have unfortunately been kicked in the head by a horse and i’m bleeding as you can see there’s a lot of blood coming from this laceration on my my forehead sir can can you help me i can help you i mean since we’re out here on the prairie not a lot i

Can do i don’t have a cat scan i don’t have any medicine old cookie’s got some raw hide stitches maybe a little cowhide poultice i could push on it with my hand but if you’re looking for anything fancy dance or even a cat scan i’m afraid you’re sol my friend but uh according to the four volumes of glenn that i have it says that there’s some sort of medication

That’s maybe you can use to stop this bleeding i i do say i rawhide and stitches they will not look good with my my my wig yeah that medication that is shrouded in skepticism controversy conflict of interest small studies without any true clinical outcome maybe a little bit of bleeding i’m skeptical maybe it works pretty safe but i’ll tell you this i don’t have

Any but if you want some pork and beans we got some in the cupboard wagon well what says the good dr morrison then all right well we let’s talk about it you’re talking about the drug debigatran and more importantly what do we do to reverse it uh in addition to pork and beans let’s dive right in so dabigatran right this is one of the noaks or doax that has come

Onto the scene in the last decade or so and we like it because it’s easy to prescribe for patients but it has had its issues this was first approved in 2010 for the prevention of ischemic stroke and systemic embolization but it’s not completely benign it has a bleeding risk of 16 it’s not that’s not tiny and one and a half percent of life-threatening bleeds

So this can be a problem and sometimes we need to reverse it now historically we didn’t have much while we still don’t have much but that’s controversial we’ll get into that in a moment but the lack of a direct antidote left minimal treatment options so we would initially give some hemostatic agents like ffp or pcc or factor seven and ultimately sometimes we

Would even need to hemodialyze these patients until this drug came on the market ida ruximab and this was the first quote reversal agent specifically designed for dabigatran now what is it it’s a humanized monoclonal antibody fragment it actually binds to the thrombin site 350 times more affinity than thrombin it does have a short half-life and the good news

Is we don’t think it actually increases your risk for hypercoagulability right which is the main concern about reversing someone so yes they’re bleeding but you also don’t want to overshoot and make them hypercoagulable this paper reviews five original research articles we’re going to talk about these because there’s a little bit of controversy with them but

Let’s just go with it so we’re going to go through each paper starting with the first one now i want you to look at the author’s last name glund at all you’re going to see this over and over and over again this first paper was published in 2015. it was a phase one double blind randomized control trial and it included 110 patients and they looked at basically

The effect of various coagulation parameters they’re trying to ask the question does this medication idioreximab changed the coagulation parameters on patients and their conclusion was idioreximab has no significant effect on coagulation parameters or endogenous thrombin generation potential the rate of adverse effects were similar between both study groups

Moving on to the next paper look at the author again glenn it all again this time in lancet 2015 and again another phase one double blind randomized control trial this was smaller only 50 patients and they looked at whether the incidence of drug related adverse events and reversal of multiple coagulation parameters occurred and they concluded that idioreximab

Demonstrated immediate reversal of dabigatran related elevations of multiple coagulation parameters okay we’re going to take this with a grain of salt we’re gonna talk about this at the end number three third paper same author glund dr glund loves his de bigatran and idiorexmab this one was in 2017. randomized double-blind crossover study this time very small

28 patients 18 of them had mild to moderate renal impairment and the reason that’s important is because they wanted to know the safety of idarexymab for the reversal of dabigatran in elderly patients or those with renal impairment and what they found was dabigatran related coagulation parameters were all reversed back to baseline regardless of renal function

Or age all right number four look at the author again glund this guy’s a machine 2016. this is a tiny study 12 patients pre-treated with debigatron for four days and they wanted to know if idaroxymab reduced dabigatran levels and normalized coagulation parameters and what they found was they gave the placebo or idioreximab after their last debytron dose and

Then they compared and hydroxymab provides an option for rapid reversal of dabigatran induced anticoagulation and allows for re-initiation of debigatron 24 hours later that was a pretty big conclusion that they came to and controversial for a few reasons and for the fifth paper this is the first time you see that gland isn’t the primary author this one was

Published by pollock in 2016 and this was a prospective cohort study assessing the safety and efficacy of ida rex mab in adults presenting with serious bleeding or need for an urgent procedure it’s a decent-sized study they used 90 patients 51 of them had serious head bleeding like head bleeds gi bleeds trauma 39 of them actually required an urgent procedure

They were given five grams of vitarexumab to try and reverse them and the results were interesting the median maximum percentage reversal was a hundred percent and their conclusion was that idioreximab rapidly and completely reversed the anticoagulation caused by digabigotron and no safety concerns among the 90 patients uh studied uh occurred now here is

My question to both of you is that there is a lot of biases with these five papers because unfortunately both glund and pollock would you know worked for the company that produced both dabigatran and hydroxymab not only that that’s a major problem right but both drugs both to bigatran and this anecdote iderexymab are both created by the same drug company

As well so not only is the same company creating both medications but the authors of these studies and the researchers worked for these industry funded companies so there’s some significant biases there’s some controversy as well that only one article actually assessed a clinically relevant outcome of hemostasis all the studies were pretty small and there’s a

Question about whether idaroximab actually works to reverse the bigatran or is it just due to the fact that debigatran actually has a pretty short half-life so in summary idioreximab so far does seem to have a pretty safe you know side effect profile and so sure in the clerk’s case of having an internal head bleed or a massive trauma should you give it you

Should because it looks like when you’re weighing risks versus benefits of dabigatran giving itereximab is fairly safe so if you have a life-threatening bleed sure you should give it but understand that the existing data is limited it seems safe but we definitely need larger studies with unbiased investigators preferably now here’s a question for both of you

Let’s say you have a large laceration to your arm or leg and we know that the patient’s on dabigatran before you reach for iteraximab what else can you do for that laceration you got on the armor leg just push on that puppy push on that puppy right there yeah and what would you do after direct pressure let’s say you’re still oozing couldn’t you throw some

Stitches in if you can topically treat a bleed an external bleed then yes i would still say start with those basic things first before you reach for these reversal agents because if you don’t have to reverse them you don’t want to there’s always risks and benefit involved

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LLSA Prep 2020: Reversal of Dabigatran By Hippo Education