Apixaban

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Farcus

Farcus

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I've been very fascinated by the available data on apixaban at least a year ago when I first read about it. Recently, as many of you might've noticed, it has been approved by the FDA for the prevention of stroke and embolism in non-valvular afib. Discuss your thoughts...

I feel bad for rivaroxaban too lol.
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Unless and until there is a reversal agent for any of the Xa inhibitors, I don't think warfarin has very much to worry about.
 
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TBH, I think its a great agent! I am actually normally the one that is very skeptical about new drugs, however, ever since I started reading about apixaban about a year ago I thought it was awesome. I mean the various study has shown that not only is it superior to a lot of current agents in terms of clinical efficacy but also in terms of safety (or noninfeior).

In the ADVANCE trails for DVT, it was superior vs lovenox 30mg but not 40mg, so potential for renal pts is seen here as the drug is approx 1/4 renal eliminated. These trials collectively over 11k pts. Safety was similiar to lovenox.

In ARISTOLE study for NVAF, superior vs warfarin in terms of efficacy and safety measure. The mortality difference between the two is significant favoring apixaban. This trial has over 18k pts.

In AVERROES trial, it was superior vs aspirin in pts unsuitable for warfarin if based preference or failure. Safety was no higher bleed than aspirin in terms of significance.

Interactions - similiar to existing ones --> CYP450, P-GP

I"m not trying to drink the Apixaban kool-aid or anything but I just think its a great drug compared to a lot of other drugs we have and I feel like it will transition into its role in therapy quicker than a lot of the other newer drugs like dabigatran or rivaroxaban.

As far as antidotes, well true but I don't think the lack of an antidote should be seen as the reason it wouldn't be used. Sure I wouldn't recommended to someone who has a history of dementia or Alzheimer but that is separate category on its own.
 
This is the agent I've been waiting for for the above reasons...obviously can't wait for more data to come out, but given Pfizer's strength in CV drugs, it's the better drug with the even better marketing/distribution plan.

But...we'll see.
 
In my opinion as an Emergency Physician - I would never prescribe pradaxa or anything without an antidote to my parents. The risk of having a closed head injury while being on it is staggeringly scary.

Imagine, you're on a drug, you bonk your head, you have a traumatic intracranial or extracranial bleed - game over. Nothing will save you, not ffp, not factor VII, not platelets. The only thing would be hemodialysis but that only helps elimination but it does NOTHING for the bleed itself.

I have looked at the Re-Ly studies and I'm not convinced that pradaxa is an improvement over coumadin... yes coumadin is a pain to be on and the fact that it is very variable with what you eat and what drugs you take, couple that with all the PT/INR tests you have to take and the long therapeutic onset... still, I would never want to be on pradaxa or similar drugs.

Just my 2 cents.

I had made this presentation to my Toxicology group of attendings and the consensus was that pradaxa is a much scarier drug than people realize.

My fear in the Er is getting that closed head bleed patient on pradaxa. Just game over in a matter of hours... either you herniate or you close off your intraventricular system with clots. Your GCS goes from 15 to 8 to less in a matter of minutes. Nothing I can do to save you... by the time neurosurg gets you to the OR, you're vegetable.
 
That said, I'm not too familiar with rivaroxaban... I know it is a Xa inhibitor which promotes prothrombin to thrombin (factor II).

I assume that based on the coagulation cascade, there is no reversible product/antidote out there, right?
 
pinipig523 said:
That said, I'm not too familiar with rivaroxaban... I know it is a Xa inhibitor which promotes prothrombin to thrombin (factor II).

I assume that based on the coagulation cascade, there is no reversible product/antidote out there, right?
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Yup, you're exactly right ...
 
pinipig523 said:
In my opinion as an Emergency Physician - I would never prescribe pradaxa or anything without an antidote to my parents. The risk of having a closed head injury while being on it is staggeringly scary.

Imagine, you're on a drug, you bonk your head, you have a traumatic intracranial or extracranial bleed - game over. Nothing will save you, not ffp, not factor VII, not platelets. The only thing would be hemodialysis but that only helps elimination but it does NOTHING for the bleed itself.

I have looked at the Re-Ly studies and I'm not convinced that pradaxa is an improvement over coumadin... yes coumadin is a pain to be on and the fact that it is very variable with what you eat and what drugs you take, couple that with all the PT/INR tests you have to take and the long therapeutic onset... still, I would never want to be on pradaxa or similar drugs.

Just my 2 cents.

I had made this presentation to my Toxicology group of attendings and the consensus was that pradaxa is a much scarier drug than people realize.

My fear in the Er is getting that closed head bleed patient on pradaxa. Just game over in a matter of hours... either you herniate or you close off your intraventricular system with clots. Your GCS goes from 15 to 8 to less in a matter of minutes. Nothing I can do to save you... by the time neurosurg gets you to the OR, you're vegetable.
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I have a good friend who is a gastroenterologist who feels the same way. She's watched patients die from GI bleeds while on dabigatran and has been able to do nothing to save them. She's pretty much made it her mission to lower the number of patients on Xa inhibitors at her facility as a result ...
 
pinipig523 said:
That said, I'm not too familiar with rivaroxaban... I know it is a Xa inhibitor which promotes prothrombin to thrombin (factor II).

I assume that based on the coagulation cascade, there is no reversible product/antidote out there, right?
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Nothing specific, but activated prothrombin complex concentrates have been reported to work.
 
xiphoid2010 said:
Nothing specific, but activated prothrombin complex concentrates have been reported to work.
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Problem is, it's only FOUR-factor PCC that works. And that's not available in the USA, only three-factor PCC is available here.
 
pinipig523 said:
In my opinion as an Emergency Physician - I would never prescribe pradaxa or anything without an antidote to my parents. The risk of having a closed head injury while being on it is staggeringly scary.

Imagine, you're on a drug, you bonk your head, you have a traumatic intracranial or extracranial bleed - game over. Nothing will save you, not ffp, not factor VII, not platelets. The only thing would be hemodialysis but that only helps elimination but it does NOTHING for the bleed itself.

I have looked at the Re-Ly studies and I'm not convinced that pradaxa is an improvement over coumadin... yes coumadin is a pain to be on and the fact that it is very variable with what you eat and what drugs you take, couple that with all the PT/INR tests you have to take and the long therapeutic onset... still, I would never want to be on pradaxa or similar drugs.

Just my 2 cents.

I had made this presentation to my Toxicology group of attendings and the consensus was that pradaxa is a much scarier drug than people realize.

My fear in the Er is getting that closed head bleed patient on pradaxa. Just game over in a matter of hours... either you herniate or you close off your intraventricular system with clots. Your GCS goes from 15 to 8 to less in a matter of minutes. Nothing I can do to save you... by the time neurosurg gets you to the OR, you're vegetable.
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Completely agree with you on the pradaxa efficacy relative to warfarin :thumbup:
 
Silvermist said:
I have a good friend who is a gastroenterologist who feels the same way. She's watched patients die from GI bleeds while on dabigatran and has been able to do nothing to save them. She's pretty much made it her mission to lower the number of patients on Xa inhibitors at her facility as a result ...
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correct me if i am wrong but I was under the impression dabigatran was F2 inhibitor, and the only two X inhibitors are rivaroxban and now apixaban.

What was the dabigatran being used here for? I thought it was only for afib or hip so i'm just curious what a GI specialist is writing it for.
 
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Silvermist said:
Problem is, it's only FOUR-factor PCC that works. And that's not available in the USA, only three-factor PCC is available here.
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Cool find, i'm have to read up on this difference and the trials for the 4 factor PCC
 
Farcus said:
correct me if i am wrong but I was under the impression dabigatran was F2 inhibitor, and the only two X inhibitors are rivaroxban and now apixaban.

What was the dabigatran being used here for? I thought it was only for afib or hip so i'm just curious what a GI specialist is writing it for.
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Pradaxa is approved for a fib and strokes from nonvalvular causes. It is also being studied for VTE/PE.

Interesting thing is that dabigatran was approved for use on Valentines day 2011 by the AHA.
 
Silvermist said:
Yup, you're exactly right ...
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I was doing some more reading and there is an antidote to rivaroxaban... PCC with factor II. Not surprisingly, since dabigatran is so far down the coagulation cascade... PCC (even 4 factor) does not work period.

People should not be on dabigatran.
 
We've had some success with pcc for massive gi bleed on pradaxa. Will prob write a case report.

I'm not a fan of these new anticoagulants.
 
Farcus said:
correct me if i am wrong but I was under the impression dabigatran was F2 inhibitor, and the only two X inhibitors are rivaroxban and now apixaban.

What was the dabigatran being used here for? I thought it was only for afib or hip so i'm just curious what a GI specialist is writing it for.
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That's what I get for typing too fast about multiple drugs XD

Oh no, she didn't write for the dabigatran. The patients in question were admitted with major GI bleeds and their Rx's written by who-knows-what-MD. She's a gastroenterologist on staff so was brought in because of the location of the bleeds, I assume. I didn't ask details.
 
Farcus said:
In the ADVANCE trails for DVT, it was superior vs lovenox 30mg but not 40mg, so potential for renal pts is seen here as the drug is approx 1/4 renal eliminated. These trials collectively over 11k pts. Safety was similiar to lovenox.
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I thought it was the other way around between the 30 ming BID and 40 mg daily Lovenox doses when compared to apixaban?
 
pinipig523 said:
That said, I'm not too familiar with rivaroxaban... I know it is a Xa inhibitor which promotes prothrombin to thrombin (factor II).

I assume that based on the coagulation cascade, there is no reversible product/antidote out there, right?
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While there is no direct reversal agent approved*. There have been numerous papers published in the past year which talk about PCC, FFP, FVIIa, and Factor X concentrates which seem to reverse the anticoagulation. One of the annoyances associated with this is that it is only temporary because it is cleared from the system from what I've been told by other pharmacists. It needs to be redosed because the drug remains in the system longer than your supplementation. Does anyone know the dosing freq? Any thoughts?

***Gave a journal club almost a year ago on apixaban and remembered pulling this article at the time that did a cross-over study in healthy patients using pcc finding that it was able to reverse the effects with rivaroxaban but not pradaxa.

http://www.ncbi.nlm.nih.gov/pubmed/22000094
http://www.ncbi.nlm.nih.gov/pubmed/21900088
 
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PharMed2016 said:
While there is no direct reversal agent approved*. There have been numerous papers published in the past year which talk about PCC, FFP, FVIIa, and Factor X concentrates which seem to reverse the anticoagulation. One of the annoyances associated with this is that it is only temporary because it is cleared from the system from what I've been told by other pharmacists. It needs to be redosed because the drug remains in the system longer than your supplementation. Does anyone know the dosing freq? Any thoughts?

***Gave a journal club almost a year ago on apixaban and remembered pulling this article at the time that did a cross-over study in healthy patients using pcc finding that it was able to reverse the effects with rivaroxaban but not pradaxa.

http://www.ncbi.nlm.nih.gov/pubmed/22000094
http://www.ncbi.nlm.nih.gov/pubmed/21900088
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Yes I remember that study that looked at how PCC reversed rivaroxaban but not pradaxa... way too downstream on the coagulation cascade for factor replacements/pcc to work.
 
How quickly does vit k reverse warfarin?
 
rxlea said:
Get them to stop bleeding!

Hold warfarin, vitamin K, FFP and repeat vit K 12 hours or so if they think it's needed. Vitamin k can take 24~48 hours. Most likely a day.
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Remember try not to give more than 5mg because they will become warfarin resistant for awhile. I've seen 10-20mg which pretty much will make them warfarin resistant for a bit.
 
PharMed2016 said:
Remember try not to give more than 5mg because they will become warfarin resistant for awhile. I've seen 10-20mg which pretty much will make them warfarin resistant for a bit.
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But if your INR is high dont you want to be warfarin resistant to a certain extent?
 
I thought there was some type of anti-Pradaxa or anti-Xarelto immunoglobulin antidote similar to Digifab in the works?
 
rxlea said:
Get them to stop bleeding!

Hold warfarin, vitamin K, FFP and repeat vit K 12 hours or so if they think it's needed. Vitamin k can take 24~48 hours. Most likely a day.
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Right. So how long does it take to clear dabigatran or rivaroxaban?
 
spacecowgirl said:
Right. So how long does it take to clear dabigatran or rivaroxaban?
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Depends.... dabigatran has a half life of 15 ish hours but it's longer in renal impairment. Much better than warfarin with its 40 hour half life. AND you can get rid of ~50-60% of the drug in a few hours through dialysis if you're talking an OD (I looked this up and some say 35-60 so it seems pretty darn variable). BUT, without a reversal agent and really only supportive measures available in an OD, I'd take my chances with warfarin.

As for rivaroxaban, I will get back to you on that. I have to look up more about that drug.

EDIT: ok i found a couple sources and it says 5-9 hours for the half life and like dabigatran prolonged in renal impairment.
 
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rxlea said:
Depends.... dabigatran has a half life of 15 ish hours but it's longer in renal impairment. Much better than warfarin with its 40 hour half life. AND you can get rid of ~50-60% of the drug in a few hours through dialysis if you're talking an OD (I looked this up and some say 35-60 so it seems pretty darn variable). BUT, without a reversal agent and really only supportive measures available in an OD, I'd take my chances with warfarin.

As for rivaroxaban, I will get back to you on that. I have to look up more about that drug.

EDIT: ok i found a couple sources and it says 5-9 hours for the half life and like dabigatran prolonged in renal impairment.
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So yeah... in a few hours - you'll be dead with dabigatran and a closed head injury.

Like you, I prefer coumadin in me.
 
pinipig523 said:
So yeah... in a few hours - you'll be dead with dabigatran and a closed head injury.

Like you, I prefer coumadin in me.
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There is a few post marketing studies showing increased bleeding risk in dabigatran and increase risk of death. i think direct xa inhibitors have much more potential, bleeding risk is somewhat lower and they can be used for everything like warfarin, all with predictable kinetics. problem with warfarin is that a lot of patient are just not therapeutic on it for some reason. whether they are missing their lab appointment, do not take the drug correctly, miss doses thinking it is not a big deal or the kinetics just get screwed up with any change (diet and OTC etc). I see a lot of pt coming subtherapeutic. For a fib risk of clots is not very high (i think is around 7-8% for people in their 80s, and lower for younger), but in dvt or pe it is a problem. so while you may not die from a ICH, you may die from a pe because you are not being anticoagulated properly.

in my opinion, which anticoagulant to use is not such a no brainer, just becuase there is no real reversal agent.

btw, does anyone know why ffp would not work on anti-xa and dTI?
 
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maldini99 said:
There is a few post marketing studies showing increased bleeding risk in dabigatran and increase risk of death. i think direct xa inhibitors have much more potential, bleeding risk is somewhat lower and they can be used for everything like warfarin, all with predictable kinetics. problem with warfarin is that a lot of patient are just not therapeutic on it for some reason. whether they are missing their lab appointment, do not take the drug correctly, miss doses thinking it is not a big deal or the kinetics just get screwed up with any change (diet and OTC etc). I see a lot of pt coming subtherapeutic. For a fib risk of clots is not very high (i think is around 7-8% for people in their 80s, and lower for younger), but in dvt or pe it is a problem. so while you may not die from a ICH, you may die from a pe because you are not being anticoagulated properly.

in my opinion, which anticoagulant to use is not such a no brainer, just becuase there is no real reversal agent.

btw, does anyone know why ffp would not work on anti-xa and dTI?
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Actually I saw an FDA announcement about the post marketing safety data. And they were saying that despite the initial concern about pradaxa's GI bleed risk, their data shows its actually lower than warfarin.

http://www.fda.gov/Drugs/DrugSafety/ucm326580.htm

"For the populations in the Mini-Sentinel data assessment, the combined incidence rate (ICH and GIH events per 100,000 days at risk) was 1.8 to 2.6 times higher for new users of warfarin than for new users of Pradaxa. The incidence rate of GIH events only per 100,000 days at risk was 1.6 to 2.2 times higher for warfarin new users than for Pradaxa new users, and the incidence rate of ICH events only per 100,000 days at risk was 2.1 to 3.0 times higher with warfarin than with Pradaxa. The results indicate that the observed bleeding rates associated with new use of Pradaxa do not appear to be higher than the bleeding rates associated with new use of warfarin."

Obviously this is no randomized controlled trial,but what struck me was the magnitude of the risk ratio FDA was stating.
 
Farcus said:
But if your INR is high dont you want to be warfarin resistant to a certain extent?
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If you give a really high dose of vitamin K, the patient will not respond to warfarin for quite a while which is not good. After you bring down the INR, you don't want it to be below therapeutic range for a long time because then you are at risk of a clot.
 
pharmgirl333 said:
If you give a really high dose of vitamin K, the patient will not respond to warfarin for quite a while which is not good. After you bring down the INR, you don't want it to be below therapeutic range for a long time because then you are at risk of a clot.
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:prof:
 
joetrisman said:
In aristotle, the warfarin arm was at INR goal 62% of the time. Haven't read any other trials about apixaban, but not entirely convinced of superiority.
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When I've done anticoag journal clubs, I've always been told this percentage is way above percentage of INRs at goal in real practice.
 
NICE just gave its nod of approval to Apixaban. The only drug that has some clear indications of superiority over warfarin. Pradexa and Dabigatran ...no way.
 
gmuskie said:
When I've done anticoag journal clubs, I've always been told this percentage is way above percentage of INRs at goal in real practice.
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That's not true. If you look at journal articles on time in therapeutic range for pharmacist run coumadin clinics, the percentage of time the INR is in goal is always above 63%.
 
pharmgirl333 said:
That's not true. If you look at journal articles on time in therapeutic range for pharmacist run coumadin clinics, the percentage of time the INR is in goal is always above 63%.
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That is maybe 5% of pts on warfarin. you are lucky if most show up to their PCPs office to get a bi-weekly INR checked. In the real world, most are managed by their cardiologist or PCP.

Tha trials are correct. Maybe 1/2 - 2/3 of the time warfarin pts are in the theraputic INR window. Warfarin is a horrible drug because of interactions, bleeds and dosing problems.

i wish i could say it will be a drug of the past but pradaxa failed in its attempt to get approval for valvular fib, only has non valvular and PE/DVT.
Xarelto now has PE/DVT.

both of those are non inferior. except in ICH, in which case all options are superior to warfarin.

Apixibans data is very promising. Cost will limit its use early on, same as pradaxa and xarelto, but if it can get a valvular fib indication, then warfarin may finally become an extinct drug.
 
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