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Author: Brent N. Reed, PharmD, BCPS-AQ Cardiology, FAHA
It’s probably a claim you’ve heard come up on rounds before, when the decision regarding oral anticoagulation in a patient with atrial fibrillation arises:
“This patient has had issues with adherence in the past; let’s go with rivaroxaban [Xarelto®] since it’s a once-daily medication.”
The rationale certainly makes sense. We routinely make the same case with other medications, like when selecting lisinopril over other angiotensin-converting enzyme (ACE) inhibitors because of its once-daily dosing. However, by the end of this entry I hope to convince you that the same isn’t true of rivaroxaban when compared to other target-specific oral anticoagulants (TSOACs), and why its use may even be worse in nonadherent patients.
First, the pharmacokinetic profile of rivaroxaban is unusual for a once-daily drug. Its half-life is 5-9 hours, which is actually shorter than those TSOACs that require twice-daily dosing in atrial fibrillation (approximately 12 and 14-17 hours for apixaban and dabigatran, respectively). The pharmacologic effects of rivaroxaban mirror its serum concentrations, meaning that its anti-Xa activity has mostly dissipated hours before the next dose is due (Figure 1) .
Figure 1. Serum concentrations of rivaroxaban after oral administration .
Although this once-daily dosing strategy may make rivaroxaban more ideal in patients at risk for drug accumulation (e.g., hepatic and/or renal impairment, heart failure), it is probably less ideal in those with normal metabolic function. This is especially true in patients likely to miss doses, as the quick offset of the drug means they will be unprotected from stroke and systemic embolism more quickly and for greater durations compared to both alternative TSOACs as well as warfarin.
But do these pharmacokinetic features make a difference clinically? I believe we have evidence that they do. In ROCKET-AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation), an increase in thromboembolic events was observed at the conclusion of the trial, when patients who were receiving rivaroxaban were being transitioned back to warfarin . We don’t have any evidence of pro-thrombotic effects when rivaroxaban is discontinued, so these differences were presumably due to patients being inadequately anticoagulated during this transition phase. Many of these events occurred within the first 2 weeks, suggesting that the short-term risk of thromboembolism may be higher than the annual risk predicted by the CHA2DS2-VASc score.
When comparing TSOACs to warfarin, the risk of nonadherence with warfarin has likely been over-estimated. Although missing doses may impact time-in-therapeutic range, there is a significant degree of residual anticoagulation provided even when the INR is sub-therapeutic. Warfarin has a mean half-life of 40 hours and it takes several days to regenerate the clotting factors whose synthesis has been inhibited by its use.
To summarize, I think the once-daily dosing of rivaroxaban is a matter of convenience. Rather than conferring a meaningful benefit in nonadherent patients, I think its rapid offset of action makes it an even less optimal choice. Even if you are unconvinced that it makes a difference clinically, why take the chance? There are alternative TSOACs that have performed equally well if not better compared to warfarin in patients with atrial fibrillation. I will concede that the population enrolled in ROCKET-AF was generally sicker (i.e., higher CHA2DS2-VASc scores, more comorbidities) than those enrolled in other TSOAC trials. However, I would contend that this is actually why once-daily rivaroxaban performed so well, as these patients probably had some degree of impaired metabolic function (i.e., it probably lasted as long as twice-daily dosing in patients with normal metabolic function). But even if the available TSOACs are equally safe and efficacious, why not favor an agent whose pharmacokinetic profile is more favorable?
For the above reasons, rivaroxaban remains my second-line TSOAC for patients with atrial fibrillation. I consider it in those patients whose formulary coverage requires it, or perhaps in those at risk for accumulation with alternatives (i.e., heart failure with evidence of metabolic derangements, hepatic impairment), but otherwise apixaban remains my first choice.
Brent N. Reed, PharmD, BCPS-AQ Cardiology, FAHA
Dr. Reed is an assistant professor in the Department of Pharmacy Practice and Science at the University of Maryland School of Pharmacy, and practices as a clinical pharmacy specialist in advanced heart failure at the University of Maryland Medical Center in Baltimore, MD. Follow him on Twitter @brentnreed
- Kreutz R. Pharmacodynamic and pharmacokinetic basics of rivaroxaban. Fundam Clin Pharmacol. 2012 Feb;26(1):27-32.
- Patel MR, Mahaffey KW, Garg J, et al; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011 Sep 8;365(10):883-91.
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