Minimal Adherence Threshold to Non-Vitamin K Antagonist Oral Anticoagulants in Patients with Atrial Fibrillation to Reduce the Risk of Thromboembolism and Death: A Nationwide Cohort Study

Purpose: Poor adherence to non-vitamin K antagonist oral anticoagulants (NOACs) may raise thromboembolic risks in patients with atrial fibrillation (AF). However, the minimal adherence to maintain the protective effect of NOACs is currently unknown. Therefore, we investigated thresholds of NOAC adherence in association with thromboembolic and mortality risks. Methods: Patients with AF initiating NOACs between 2013 and 2019 were identified in Belgian nationwide data. Adherence was measured using the proportion of days covered (PDC) after one year of treatment. Inverse probability of treatment weighted Cox regression was used to investigate outcomes. Results: 92,111 persons were included (250,750 person-years). Compared to NOAC users with a one-year PDC of 100%, significantly higher risks of stroke or systemic embolism were observed among NOAC users with PDCs of 85–89% (adjusted hazard ratio (aHR) 1.35, 95% confidence interval (CI) (1.19–1.54)), 80–84% (aHR 1.31, 95%CI (1.08–1.58)) and < 80% (aHR 1.64, 95%CI (1.34–2.01)), while no significant differences were observed among NOAC users with one-year PDCs of 95–99% (aHR 1.02, 95%CI (0.94–1.12)) or 90–94% (aHR 1.06, 95%CI (0.95–1.18)). Significantly higher risks of all-cause mortality were observed with decreasing levels of NOAC adherence, which were already higher among NOAC users with a one-year PDC of 90–94% versus 100% (aHR 1.09, 95%CI (1.01–1.17)). Findings were similar with once-daily and twice-daily dosed NOACs. Conclusion: Poor adherence to NOACs is associated with increased risks of thromboembolism and all-cause mortality. The minimal adherence threshold should be ≥ 90%, preferably even ≥ 95%.