Polypharmacy and effects of apixaban versus warfarin in patients with atrial fibrillation: post hoc analysis of the ARISTOTLE trial

Polypharmacy plays a large role in patients with atrial fibrillation, as many patients usually have other medical conditions for which they also have to take medications. (1 2) Consequently, the study by Jaspers Focks et al. (3) adds relevant evidence in terms of efficacy and safety after comparing the factor Xa inhibitor apixaban with the vitamin k antagonist warfarin. I have two comments to this interesting and nice study:

1. As a clinician, I frequently see patients in the Emergency Department who cannot tell me what medications they take. I have even seen patients who were prescribed medications with relevant cytochrome P450 (CYP) 3A4 interactions by physicians who had carefully asked for other medications. The physicians did not get the right information from the patients, however, because the patients were not able to report that they took apixaban or other oral anticoagulants. In this carefully designed trial, such as scenario is unlikely, because there was a protocol to register all concomitant drugs. In day to day clinical routine, however, I not only see patients who bring a list with all their current medications, but I also see patients who go to different specialists or different generalists and who eventually end up with medications that have relevant interactions. It is my impression, however, that patients are more likely to remember the booklet and the regular international normalised ratio (INR) measurements. In such as case it is often easier for the involved physicians to infer that the respective patient is treated with a vitamin k antagonist, and to check for potential interactions. Such a scenario might play a role in day to day clinical practice when considering polypharmacy and potential interactions.

2. Although more often out of range in patients with a larger number of concomitant medications, the INR in this trial was out of range to a similar extent for all subgroups with warfarin treatment. In all warfarin-subgroups, roughly half of the patients (ranging from 44.9 percent to 53.2 percent) had an INR that was in therapeutic range in less than 66 percent of the follow up period. I wonder to what extent the differences between apixaban and warfarin in terms of efficacy and safety can be explained by the INR being out of range in the warfarin-subgroups. This hypothesis is derived from the fact that apixaban not only had a better outcome than warfarin in patients with a high number of concomitant medications, but in all three subgroups (0-5, 6-8 and > 9 concomitant medications).

1. Proietti M, Raparelli V, Olshansky B, Lip GYH. Polypharmacy and major adverse events in atrial fibrillation: observations from the AFFIRM trial. Clin Res Cardiol 2016;105:412-20.
2. Piccini JP, Hellkamp AS, Washam JB, et al. Polypharmacy and the efficacy and safety of rivaroxaban versus warfarin in the prevention of stroke in patients with nonvalvular atrial fibrillation. Circulation 2016;133:352-60.
3. Jaspers Focks J, Brower MA, Wojdyla DM, et al. Polypharmacy and effects of apixaban versus warfarin in patients with atrial fibrillation: post hoc analysis of the ARISTOTLE trial. BMJ 2016;353:i2868