Factor Xa Inhibitor Dosing in Medically Ill Patients

Deepak Bhatt, MD, MPH: Lots of great data that you guys have thrown out here at the audience, but I want to also keep things practical. Betrixaban, rivaroxaban, FDA-approved indications here for this extended duration in the medically ill. Let’s talk a little bit now about specifics. Let’s start with betrixaban. What sort of dosing are we talking about?

C. Michael Gibson, MS, MD: A loading dose of 160 mg and then after that, a maintenance dose of 80 mg a day for that extended duration period of 35 to 42 days.

Deepak Bhatt, MD, MPH: That’s practical, really helpful. What about rivaroxaban, what do we want to do with that one?

Gary Raskob, PhD: The approved dose is 10 mg once a day.

Deepak Bhatt, MD, MPH: OK, so really clear what the doses are. Any sorts of worries about renal dysfunction or anything else we have to adjust, or just start and go? Let’s start with betrixaban.

C. Michael Gibson, MS, MD: I think you have to be careful still, even though the drug is not cleared by the kidney or very little clearance, you still have to be very careful in the patient with renal insufficiency. So there in the label are guidances to avoid the drug in those situations.

Deepak Bhatt, MD, MPH: And what about rivaroxaban?

Alex C. Spyropoulos, MD, FACP, FCCP, FRCPC: The MARINER trial randomized patients to 2 doses of rivaroxaban based on renal function. This was at the time of randomization. If they had creatinine clearances between 30 and 50 mL/min, they had a reduced dose of rivaroxaban, a 25% reduced dose, or a 7.5 mg dose. And that was shown to be completely ineffective in the MARINER trial. I think the 10 mg dose, when we do further analysis looking at both the MAGELLAN and MARINER database, what’s more important than renal dosing, which turned out to be an ineffective strategy, is actually keep those key bleed risk criteria in mind when dosing the renally insufficient population. So 10 mg continues to be the optimal dose, even in the renal insufficient population.

Deepak Bhatt, MD, MPH: Really great points. It also points to something I think that’s really important for the audience. There are a lot of NOACs [new oral anticoagulants] out there. We’re talking about some here. There are lots of indications, AFib [atrial fibrillation], DVT [deep vein thrombosis], PE [pulmonary embolism]. We talked a lot about CAD [coronary artery disease] and PAD [peripheral arterial disease], which is specific to rivaroxaban, 2.5 [mg] bid [twice a day]. It can be confusing to throw in renal dysfunction, potential adjustments in doses. So there are a lot of doses. I wouldn’t recommend that anybody just try to keep it in their head. I know I have a hard time keeping it all in my head, and I think it’s important to check. It’s quite useful to have a pharmacist on the team to consult and hopefully an electronic health record that provides a back stop just to make sure we’re not accidentally prescribing the AFib dose for somebody who’s got PAD, for example.

Gregory Piazza, MD, MS: That’s where order templates make things easy because if it’s a VTE [venous thromboembolism] prophylaxis order template, you’ll have the right dose.

Deepak Bhatt, MD, MPH: I think it’s so important because it’s very hard to keep it, even for people like us who are immersed in this field. I get confused because there are so many trials and so many doses, and sometimes the approved dose isn’t exactly what was studied in the trials. It just gets messy, I think.

Alex C. Spyropoulos, MD, FACP, FCCP, FRCPC: Deepak, to your point, it’s an important point that the 2.5 mg dose of apixaban twice daily was completely ineffective. What I warn people is not to make that extension to say, well, rivaroxaban worked in the low dose environment, so therefore apixaban will work. Actually, the ADOPT trial was a trial specific to medically ill using almost an identical trial design to MAGELLAN, again randomization at hospital admission, 2 co-primary efficacy end points at day 10 and day about 35 or so, both driven by mostly asymptomatic lower extremity VTE using screening ultrasonography. In the ADOPT trial, number 1, they identified a fairly low VTE risk population, but the 2.5 mg dose of apixaban not only was not effective but also induced an almost 2- to 3-fold increased risk of major bleeding, so it was strike, strike.

Gregory Piazza, MD, MS: It’s not interchangeable.

Alex C. Spyropoulos, MD, FACP, FCCP, FRCPC: Not interchangeable.

Gregory Piazza, MD, MS: You can’t assume that that dose is going to be effective.

Deepak Bhatt, MD, MPH: Why is it that apixaban didn’t perform better in ADOPT? Why not?

Gregory Piazza, MD, MS: I think some of it was the population. At that point, we hadn’t quite grasped on to the concept of really identifying the highest risk population. The population enrolled in ADOPT was probably not as high risk for VTE and probably still robust in bleeding risk. I think the other thing, there were some methodological issues with picking up the asymptomatic VTE. A large number of patients didn’t complete their ultrasounds. I think that probably explains why we lost signal there.

Deepak Bhatt, MD, MPH: Perhaps if there were an ADOPT2, maybe in the right population it could look better?

Gregory Piazza, MD, MS: Clearly, what the trials have been doing, Alex in MARINER and Mike in APEX, made a substantial advancement in the way we think about medically ill and finally homing down to a higher risk population. No one ever thought that extended thromboprophylaxis was right for every medical patient being discharged. But there’s a subset where it is important.

Deepak Bhatt, MD, MPH: What about edoxaban and dabigatran, any role at all in this discussion for either of those agents?

Gregory Piazza, MD, MS: Neither have really been studied in this space. They’ve been studied in prophylaxis in orthopedic surgery but not for the medically ill.

Deepak Bhatt, MD, MPH: I think dabigatran is going to be going generic first, so that’s why I asked just in case somebody thought, well, can we slip that in. So really it wouldn’t be an evidence-based strategy or anything anyone would endorse.

Gary Raskob, PhD: Also important to know, dabigatran is cleared for predominantly renally, and it’s an issue with these medical patients.

Deepak Bhatt, MD, MPH: Sure, a lot of them have renal dysfunction and fluctuating renal function as well.

Transcript edited for clarity.