Off-Label Underdosing or Overdosing of Non-vitamin K Antagonist Oral Anticoagulants in Patients With Atrial Fibrillation: A Meta-Analysis

Background: Several studies have investigated the role of off-label non-vitamin K antagonist oral anticoagulants (NOACs) in patients with atrial fibrillation (AF). We aimed to compare the effectiveness and safety outcomes between off-label underdose or overdose vs. on-label dose of NOACs in AF patients. Methods: The PubMed database was systematically searched until August 2021. Observational cohorts were included if they compared the outcomes of off-label underdose or overdose with on-label dose of NOACs in AF patients. The risk ratios (RRs) and 95% confidence intervals (CIs) were pooled using a fixed-effects model (I-2 >= 50%) or a random-effects model (I-2 > 50%). Results: A total of 15 observational studies were included. Compared with on-label dose of NOACs, off-label underdose of NOACs was associated with increased risks of stroke or systemic embolism (RR = 1.09, 95% CI 1.02-1.16), and all-cause death (RR = 1.29, 95% CI 1.10-1.52) but not ischemic stroke (RR = 1.34, 95% CI 0.76-2.36), myocardial infarction (RR = 1.08, 95% CI 0.92-1.28), major bleeding (RR = 0.97, 95% CI 0.89-1.05), intracranial hemorrhage (RR = 1.12, 95% CI 0.90-1.40), and gastrointestinal bleeding (RR = 0.96, 95% CI 0.85-1.07), whereas off-label overdose of NOACs was associated with increased risks of SSE (RR = 1.20, 95% CI 1.05-1.36), all-cause death (RR = 1.22, 95% CI 1.06-1.39), and major bleeding (RR = 1.33, 95% CI 1.16-1.52) but not gastrointestinal bleeding (RR = 1.18, 95% CI 0.99-1.42) and myocardial infarction (RR = 0.98, 95% CI 0.75-1.30). Conclusion: Compared with on-label dose of NOACs, off-label underdose was associated with increased risks of stroke or systemic embolism and all-cause death, whereas off-label overdose of NOACs was associated with increased risks of stroke or systemic embolism, all-cause death, and major bleeding.