Xarelto was heavily marketed as a once-a-day medicine, which is better for marketing, but marketing doesn’t trump basic biology.
Two of the clinical trials of Xarelto, ODIXa-DVT and EINSTEIN DVT, showed that once-a-day dosing created higher maximum plasma concentrations and lower trough plasma concentration. It’s not hard to see how those kinds of fluctuations can both increase the risk of bleeding when concentrations are high and make the drug less effective for preventing clots when the concentrations are low.
Only one of the phase 3 trials for Xarelto (“ATLAS ACT 2 – TIMI 51”) compared once-a-day with twice-a-day, but the trial was poorly done. An article in the Journal of the American College of Cardiology pointed out a host of problems, including “an unanticipated high rate of missing data,” a “lack of an expected dose response,” a “divergent impact” between the cardiovascular risks of the low dose and the high dose, a “lack of supportive external evidence” for novel anticoagulants over standard dual antiplatelet therapy, and a “lack of a statistically persuasive efficacy benefit.”
In many ways, this is more of the same that we’re used to seeing from the pharmaceutical industry: the drug company sees signs of a problem early on then ignores it instead of looking deeper to see if it’s really a problem. The manufacturers of Xarelto didn’t do a single proper phase 3 clinical trial to compare once-a-day dosing to twice-a-day dosing, even though the differences in safety and efficacy were obvious from early trials and from basic biology. This point wasn’t lost on the FDA Advisory Committee, which raised questions about it during Xarelto’s approval. As one of the reviewers wrote,
[T]he sponsor’s rationale for evaluating only once daily dosing in Phase 3 is not strong. Most importantly, there is clinical information from Phase 2 trials in the sponsor’s ACS program and the VTE program and from clinical pharmacology studies suggesting that twice daily dosing, which would produce lower peak blood levels and higher trough blood levels of rivaroxaban, might have been associated with greater efficacy and/or a better safety profile. There is also information suggesting that a lower total daily dose might have been as effective as 20 mg.
Unfortunately, for now, Xarelto is still only approved for once daily dosing.