February 1, 2023

This is a lecture that gives a background on DOAC usage in patients. Subjects covered include dosing, contraindications, indications, side effect, and landmark trials. Anticoagulation covered for non valvular atrial fibrillation (A fib), venous thromboembolism, and DVT prophylaxis. This review is intended for learning purposes and should not be used to guide patient care.

All right so today we’re going to talk about the direct oral anticoagulants abbreviated as doax um the ones we’re going to talk about are apixaban rivaroxaban edoxaban and debigatran the first three are direct factor 10a inhibitors the bigatran is a factor to an a or a direct thrombin inhibitor what we’re going to discuss is conjure indication judo accuse indications

Dosing pharmacology and clinical trials that look at doax so before we start we’re going to go over indications where we wouldn’t use a doab the first is we should exercise caution if the creatinine clearance is less than 15 and patients who are breastfeeding are pregnant dogs haven’t been studied if there’s drug interactions doax should be used with caution some

Common interactions would be chemotherapies and anti-epileptic medications for profound thrombocytopenia we would avoid anticoagulation in general um for anti-phospholipid antibody syndrome particularly the triple positive we would avoid delax um that technically we should not be using do accident phospholipid antibody syndrome for extremes of weight especially

Bmis greater than 120 or bmis greater than 40 with weights greater than 120 and for profoundly high clot burden generally we start with some sort of parental anticoagulation and then switch to dox over time all right so we’re going to make a table today going over the indications for the four dou x we are talking about the first indication would be non-valvular

Afib and for a pixel van the dose we use is five milligrams bid and of course po um the indications where we would use lower dose or 2.5 milligrams bid is if two of the three criteria are met the first one would be a weight less than 60 kilos age greater than 80 and a creatinine of greater than 1.5 so obviously that’s american units um for edoxaban non-valvular

Afib dosing we use 60 milligrams once daily if normal creatinine clearance if abnormal creatinine clearance so crown and clearance of less than 50 we can use 30 milligrams daily for river rock span we use a dose of 20 milligrams for non-valvular afib for lower crown and clearance you can also go to 15 milligrams if the crayon clearance is less than 50. um to

Pick a tran for crown and clearance of greater than 30 we use 150 milligrams vid if the crowning clearance is less than 30 then we would use 75 milligrams vid so that’s non-valvular afib for vte dosing is a bit different so for apixaban we use 10 milligrams eid for the first week and then after that you can use standard dosing five milligrams bid for a dox

And there’s no need for bridging with that for a doxaband there is need for parental anticoagulation and the first five to ten days of therapy should be overlapped with some sort of parental anticoagulation and bridging for a crowning clearance of greater than 50 we use the dose 60 milligrams once daily um otherwise you can use a dose of 30 milligrams once daily

Similar to the afib dose so that’s for a dox van for river oxbane um dosing is 15 milligrams bid for the first three weeks and then thereafter you can do 20 milligrams once daily and then finally for dabigatran uh dosing is the you do need to use parental anticoagulation for an overlap um there is a need for bridging here and we use the dose of 150 milligrams

B.i.d if the creatinine clearance greater than 30. otherwise you should exercise caution okay so let’s keep going so after you’ve treated your patient for the full course of anticoagulation that you’ve planned you might consider keeping them on anticoagulation lifelong because you might evaluate their risk as being high of developing recurrence so you can actually

Use doax for lifelong bte prevention as well so for apixaban the dose we would use is 2.5 milligrams bid and you’ll notice that that’s a lower dose for edoxaban secondary prevention is actually not approved for river oxyman um the secondary prevention dose can be 20 milligrams is approved and there is a trial that we will talk about shortly called the einstein

Choice trial which has looked at 10 milligrams as well so you can continue on with 10 milligrams and then for dabigatran you can extend prophylaxis with standard btu dosing for total hip replacement and total knee replacement both approved for apixaban um so we use 2.5 milligrams bid i should say bid and for the total hip replacement you actually do 35 days of

That for the total knee replacement you do 12 days of that for edoxaban not approved for total hip and total knee replacement for riveroxaban um the doses that we use for total hip replacement are 10 milligrams and total knee replacement but the duration is also the 35 and 12 days for total hip and total knee that down and then finally for um through bigatran

We used in total hip replacement not knee replacement because it’s not approved in knee replacement you can use 120 milligrams for the first day and then going forward you do 220 milligrams daily so the half-life for the doax are all fairly similar for a pigs fan we say 8 to 14 hours and the range will differ depending on the resource you find for edoxaban it’s

10 to 14 hours for rivarox van 5 to 13 hours and the bigatran is 12 to 17 hours um importantly rivaroxaban you need to take with food so i’ll put that as a specification here and it’s very important that you do not chew or break open the bigger tram as meta as bioavailability will increase by about 75 so take the taps um the max effect for a picks fan is three

To four hours for a doc’s van is one to two hours and for uh river rock span two to four hours and then for the bigatron is one to three hours apixaban’s least renally metabolized at 27 the rest is hepatic so 73 hepatic edoxaban is 50 50 um renal and hepatic metabolism as well as some biliary intestinal excretion um river oxaban is 50 renal the rest is hepatic

Or just eliminated and then the bigotry is the most renally dependent at eighty percent renally renal clearance the side effects that i want you to be familiar for for all dogs is bleeding and hypersensitivity um some special tidbits to know is that river oxidant can cause a granulocytosis and can also cause a stephen johnson syndrome to bigatran the bigatron

Commonly can cause gi effects um so you might get dyspepsia in your patient who you have onto bigatron um and a thrombocytopenia can also occur monitoring of the direct10a inhibitors you can actually do an anti-factor 10a level that’s just for the 10a inhibitors and then for debigatron you can actually do a debitron trough level some interaction that limits our use

Of drug interactions that’ll limit our use of doax for apixaban and river oxaban there’s a strong interaction between the sip 3a4 inhibitors and inducers as well as the peak like a protein inhibitors and inducers by contrast edoxaban and dabigatran only rely only attract with uh p glycoprotein inhibitors and inducers so some drugs that you might see listed for

As potentially interacting with um the doax common ones are going to be anti-epileptics especially phenytoin um other things would be kind of anti-fungals ketoconazole itraconazole those are both peak like protein and c343a4 inhibitors um some of the p glycoprotein inducers include rifampin um and p glycoprotein inhibitors include um and ketoconsul so essentially

All drugs should be screened for interaction with the doaxes there are many drugs that will interact with the doulax in terms of drug specific reversal agents in canada all we have available is i dare sisubab for the bigatron reversal for roxanna pickspan and a doxman we don’t have an agent available in canada so we actually just use a pcc prothrombin complex

Concentrate so for the next part of the talk i’m just going to talk about trials which provide evidence for the use of the douaks in certain indications so the first is use of non-valvular afib and then these studies the douakes were compared to warfarin and in the airster title trial which looked at a pixaband there was decrease in hemorrhagic stroke and decrease

In ic and fatal bleeding and decrease in vascular mortality the edoxaban study called the engage to me trial showed also a decrease in hemorrhagic stroke a non-inferiority in stroke or systemic embolism prevention and a superior cardiovascular mortality so i’m going to write less cv death here the rocket af trial was for rivaroxaban and it was non-inferior for

Stroke um major bleeding was fairly similar but there was an increase in gi bleeding and ich so intracranial hemorrhage was lower the rely trial was show looked at the bigatran um and uh depictron compared to warfarin had increased gi bleeding but a similar rate of major bleeding less vascular mortality and less ischemic stroke and hemorrhagic stroke so next we

Have our vte prophylaxis studies and we have total hip replacement versus total knee replacement both comparator groups looked at um an oxiparin and the apixaban trial which compared to nox to um apixaban was the advanced three trial and this was in total hip replacement and in total knee replacement we have the advance ii trial both trials showed superior vte

Prevention with no difference in bleeding so same result for both studies um the adoxaband trials i’m not going to talk about them because they’re not approved for the syndication but it just for reference you can look at stars jv here and you can look at stars e3 in your own time um rivaroxaban we have record one and two that looked at total hip replacement and

Record three and four which looked at total knee replacement um both were superior with no difference in bleeding and then the renovate one and two trial looked at the vegatron compared to inoxiparon and showed a non-inferior prevention of bte not approved for total knee replacement but i’ll say if you’d like to look this up they have some trials so you can look

Up the renovate trial there’s also the run of 82 trial and then the remodel and re-mobilize trial all right so vtes for um all the vte trials compared for treatment compared to the vitamin k antagonist a warfarin or a low molecular weight heparin so the v um the vti e trial looking at apixaban was called amplify and it showed non-inferiority in terms of recurrent

Vte and mortality but there was decreased major bleeding the edoxaban trial was non-inferior also for recurrence um and was superior for intracranial bleeding so less intracranial hemorrhage and for clinically relevant bleeding einstein was non-inferior for recurrent pte as well and mortality with lower just general bleeding and einstein was for rivaroxaban and

Then finally we have the recover trial which looked at bigatran again non-inferior for vte and mortality um with similar major bleeding and we have secondary prevention of vte so this is already in patients who have completed a course of anticoagulation and the decision has been made to continue on with lifelong anticoagulation so the amplify extend trial compared

To low-dose apixaban to placebo and showed decreased frequency of recurrence and similar major bleed um edoxaban is again not approved for the syndication and then the einstein extend and einstein choice looked at rivaroxaban and compared both placebo aspirin low-dose riveroxaban and high-dose rivaroxaban to each other and showed that rivaroxaban at both low

And high doses prevented vte recurrence to a greater extent than aspirin and then for depictran we have the remedy trial which compared to warfarin and the resonate trial which compared to placebo as you would expect non-inferior for bleeding and remedy in non-inferior in prevention and similar rates of bleeding in the warfarin trial um and for the resonate

Trial there was some increased bleeding but superior in prevention all right so that’s include concludes our talk on doax so in summary there are four dough acts that we use here in canada rivaroxaban apixaban edoxvan indepigatran today we went through dosing indications and contour indications and we went over a bit about the pharmacology of the drugs and we

Went through the trials which demonstrate the efficacy of the drugs thanks for listening and let me know if you have any feedback or comments in the comment box

Transcribed from video
Direct Oral Anticoagulants (DOAC): A review By Internal Medicine Board Exam PrepliveBroadcastDetails{isLiveNowfalsestartTimestamp2020-12-04T215610+0000endTimestamp2020-12-04T215658+0000}