Professor Camm began by highlighting the decisions that need to be made when developing NOACs. Among the four available NOACs, two are taken once daily and two are taken twice daily. Since the half-life of each NOAC is around 12 h, the decision regarding whether to administer once or twice daily is a borderline one. Data from the EUropean Patient Survey in Atrial Fibrillation (EUPS-AF) regarding patient preferences for taking medication once daily or twice daily, show that, overall, 81 % stated a clear preference for once daily anticoagulation.16 However, the pharmacokinetics of these drugs is interesting. A drug given once daily has a much lower trough level after 24 h than a drug administered twice daily. If a once daily drug is missed, a very low trough level results, whereas the impact of missing a twice daily drug is of less concern since the patient remains presumably better anticoagulated. As a result, there is considerable debate about whether missing a single dose is more hazardous when a drug is given once or twice a day. However, in a phase II dose-finding study of edoxaban, the bleeding frequency was higher in the 30 mg twice daily group than in the 60 mg once daily group.17 Although studies with other NOACs did not show this effect, this intriguing finding has led physicians to question whether a once daily or twice daily regimen is preferable for NOACs.
Surveys have found that once daily regimens are associated with greater adherence than twice daily regimens: a database analysis of cardiovascular patients found that adherence to all agents was 16 % greater for once daily versus twice daily. (p<0.01).18 Another study found that nonvalvular AF patients treated with once daily dosing regimens for chronic medications were associated with approximately 26 % higher likelihood of adherence compared with subjects on twice daily regimens.19 Starting patients on rivaroxaban may decrease the number of total ischaemic strokes relative to warfarin treatment.20 It has been argued that if a patient is already taking medication on a twice daily basis, as many CV patients are, then giving another drug twice daily does not produce any issues, whereas others point out that once daily is more convenient, as most people can generally be in the same place once a day but not twice.
The panel reached no consensus on this controversial matter. In the experience of Professor Le Heuzey, patients who have previously taken once daily VKA have expressed reluctance to switch to a twice daily NOAC. Switching drugs from once daily to twice daily is more of an issue than initiation on a twice daily regimen. Other panellists considered that adherence to NOACs is essential and finding ways to improve adherence is a more important challenge than deciding whether once daily or twice daily dosing is better. Professor Kirchhof underlined the consistent signal from various phase III trials of less intracerebral haemorrhage with NOACs in comparison with VKA, irrespective of dosages, even the total dosages in some cases. In addition to pharmacokinetics, practical factors such as tablet size contribute to the totality of drug exposure. In terms of electrophysiology, missing a once-daily dose before a procedure could result in patients being suboptimally anticoagulated, e.g. for an ablation procedure, but whether once or twice a day, adherence in general remains a difficult matter. The panel agreed that it requires further study. Professor Camm concluded by stating that adherence is the key mediator between medical practice and patient outcomes.