Reduced doses of Xarelto were shown to lower the rate of bleeding in the PIONEER-AF trial. However, questions still remain as to how efficacious the smaller doses of Xarelto tested in the trial are at protecting against stroke. The uncertainty regarding the stroke protection of these doses may limit uptake.
Results from the PIONEER-AF trial of Xarelto (rivaroxaban; Bayer/Johnson & Johnson) in patients with atrial fibrillation who had recently undergone a percutaneous coronary intervention were presented at the 2016 American Heart Association Scientific Session in New Orleans, Louisiana (12–16 November 2016). Although Xarelto met the primary endpoint by reducing the rate of clinically significant bleeding, questions regarding the efficacy of the 15mg and 2.5mg doses in the trial still remain. This uncertainty regarding the stroke protection of the low doses of Xarelto tested in this trial may limit the uptake of the novel oral anticoagulant in this treatment setting.
The Phase III trial met its primary endpoint, as both Xarelto doses that were tested were found to lower the patient’s risk of clinically significant bleeding (hazard ratios: 0.59 – 15mg dose; 0.63 – 2.5mg dose). However, rates of stroke were numerically higher in both the Xarelto arms as compared to the standard of care (warfarin plus dual anti-platelet therapy [DAPT]; hazard ratios: 1.07 – 15mg dose; 1.36 – 2.5mg dose). Although the trial was underpowered to test this endpoint, the numerical difference calls into question whether the lower doses of the anticoagulant provide sufficient stroke protection in this patient group.
This study compared the rates of bleeding in patients receiving standard triple therapy with two Xarelto regimens. The two Xarelto regimens tested were 15mg Xarelto once daily and single anti-platelet therapy with a P2Y12 inhibitor; and 2.5mg Xarelto twice daily plus DAPT. It is important to note that both of these Xarelto doses are lower than the standard dose of Xarelto currently approved for stroke prevention in atrial fibrillation in the US (20mg). Evidence that these reduced doses of Xarelto provide adequate stroke protection is limited, and the numerical increase in stroke in the Xarelto arms of the trial raised further questions about the safety of these doses.
Physicians attending the conference questioned the reasoning behind not investigating a 20mg dose of Xarelto in the trial. The 20mg dose has been shown to be efficacious in preventing strokes in atrial fibrillation patients and would have provided physicians with confidence that their patients were adequately protected from an event. However, by testing lower doses of the anticoagulant in this trial, physicians are still unsure about the protection these regimens will provide for their patients. This uncertainty surrounding the stroke protection provided by the lower doses of Xarelto will likely limit the uptake of the drug in this patient population.