Riley Bowers, PharmD, and Paul Ament, PharmD, discuss the dose adjustments necessary for DOACs in patients who are obese or overweight or those who have renal insufficiency.
Riley Bowers, PharmD, BCCP, BCPS: As far as the dose adjustments needed for patients who are overweight or obese, this is something that comes up all the time. While there are really no dose adjustments in the labeling with the exception of edoxaban, that’s for the underweight patients. The ISTH [International Society on Thrombosis and Haemostasis] in 2016 made its recommendation to avoid DOAC [direct oral anticoagulant] agents in patients who were greater than 120 kg or those who had a BMI [body mass index] over 40.
Since then you’ve had pharmacokinetic studies and clinical data, especially with Xarelto [rivaroxaban] with over 5000 patients just with VTE [venous thromboembolism] treatment who have shown that rivaroxaban is as effective as warfarin in patients who are obese, and they actually had less bleeding as well. In those same patients, when you look at the pharmacokinetic data, you had no decrease in the maximum concentration or the area under the curve [AUC]. At this point, it’s pretty safe to conclude that rivaroxaban is safe in the overweight and obese population. There are also some data out there on apixaban, but the pharmacokinetics did show decreased AUC and peaks in patients with apixaban that were severely obese.
Clinical data are still to be determined with apixaban. They are leaning toward the drug being safe in that population as well. Overall, in the severely overweight and obese population, I would consider rivaroxaban a viable option right now vs starting someone on warfarin.
Charles Kurt Mahan, PharmD, RPh, PhC: How about patients with severe renal insufficiency or those on dialysis? Are either of you using those in these populations? We [at Presbyterian Hospital] are using it in those patients given newer information coming out and some guidelines, so could you touch on that?
Riley Bowers, PharmD, BCCP, BCPS: Absolutely. We’re absolutely seeing more DOAC use in patients with severe renal insufficiency in dialysis. This is probably where I see the most dosing errors occur as well. You see patients start to get decreased renal function, and providers automatically default to those atrial fibrillation dose adjustments. That’s a heads-up. I always teach students and residents, even when I’m working with the medical teams, “Just make sure you’re keeping those dose adjustments separate.”
I hate to even call them dose adjustments when you’re talking about VTE treatment because they’re more or less cutoffs. Apixaban is the option without a real adjustment in the labeling for patients with severe renal insufficiency or dialysis, so that’s definitely the 1 we’re seeing the most in those patients. We don’t want to use edoxaban with creatinine clearance under 15 mL/min. We also don’t want to use it over 95 mL/min.
Rivaroxaban has had some recent changes to labeling. That now has the bottom-end cut-off at 15 mL/min instead of 30 mL/min, so we’re seeing a bit more use of rivaroxaban in patients with renal insufficiency. But that cutoff is still at 15 mL/min for creatinine clearance, and then we’re avoiding dabigatran for creatinine clearance less than 30 mL/min. Ultimately, in a patient on dialysis, your decision is still going to come down to apixaban or warfarin, but you are seeing more patients who are eligible for rivaroxaban as well.
Paul Ament, PharmD: If I could just add to that, it’s also important to separate the atrial fibrillation data from the VTE data. When you look at the clinical trial designs of both the AMPLIFY trial and the EINSTEIN Jr study, they excluded patients with creatinine clearance below 25 to 30 mL/min, so many clinicians are extrapolating some of the PK [pharmacokinetics] data from 6 or 8 dialysis patients whose data they looked at for atrial fibrillation. It’s important to appreciate that the treatment guidelines recommend that warfarin is still the drug of choice for VTE in patients with compromised renal function because we don’t have outcomes data at this point. With these doses that we’re using, 30 mg/day of rivaroxaban in VTE for 3 weeks or 20 mg/day apixaban, I am not convinced of their safety data because we don’t have them yet. There are times when we’re forced to do that because patients refuse Lovenox [enoxaparin] and warfarin, but they’ve extrapolated some of that atrial fibrillation data to VTE, and we just have to be careful about doing that.
Charles Kurt Mahan, PharmD, RPh, PhC: It’s great advice to use some caution in this arena. I thought the ACC [American College of Cardiology] guidelines suggesting apixaban over warfarin were a little preliminary given that they were based on retrospective data, and there was a subsequent presentation at ACC going over the renal atrial fibrillation data. I don’t believe those have been published, but the presentation suggests what you say: caution should be utilized. To me, if we’re dose adjusting for ABCs—age, body weight, creatinine—for that 5% of patients with atrial fibrillation, then it makes sense that we would adjust for the patient on dialysis as well. Clinically, that’s off-label, but that’s what we do at our facility. It’s important, though, that we need more data, as both of you suggest.