Effect of non‐recommended doses versus recommended doses of direct oral anticoagulants in atrial fibrillation patients: A meta‐analysis

Abstract

Background Several observational studies have shown that the inappropriate dosing use of direct oral anticoagulants (DOACs) in atrial fibrillation (AF) that does not conform to recommendations is becoming a widespread phenomenon. Therefore, we performed a meta‐analysis and systematic review to assess the effect of non‐recommended doses versus recommended doses of DOACs on the effectiveness and safety outcomes among AF patients. Methods The PubMed and Ovid databases were systematically searched to identify the relevant studies until December 2020. The effect estimates were hazard ratios (HRs) and 95% confidence intervals (CIs), which were pooled using a fixed‐effects model (I2 ≤ 50%) or a random‐effects model (I2 > 50%). Results A total of 11 studies were included in this meta‐analysis. Compared with recommended dosing of DOACs, non‐recommended low dosing of DOACs was associated with increased risks of stroke or systemic embolism (SSE, HR = 1.29, 95% CI 1.12–1.49) and all‐cause death (HR = 1.37, 95% CI 1.15–1.62), but not the ischemic stroke, myocardial infarction, gastrointestinal bleeding, intracranial bleeding, and major bleeding. Compared with recommended dosing of DOACs, non‐recommended high dosing of DOACs was associated with increased risks of SSE (HR = 1.44, 95% CI 1.01–2.04), major bleeding (HR = 1.99, 95% CI 1.48–2.68), and all‐cause death(HR = 1.38, 95% CI 1.02–1.87). Conclusion Compared with recommended dosing of DOACs, non‐recommended low dosing of DOACs was associated with increased risks of SSE and all‐cause death. Further study should confirm the findings of non‐recommended high dosing versus recommended dosing of DOACs.

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

“…In the present study, our results suggested that compared with the on-label dose of NOACs, the use of off-label underdose of NOACs was associated with increased risks of SSE and all-cause death but not IS, MI, and bleeding outcomes, whereas the use of off-label overdose of NOACs was associated with increased risks of SSE, all-cause death, and major bleeding but not MI and GI bleeding. Our current evidence further support the findings of previous meta-analyses ( 41 , 42 ) by adding the latest studies, suggesting the importance of appropriate NOAC dosing according to the NOAC-dose adjustment criteria.…”

Underdosed Direct Oral Anticoagulants in Atrial Fibrillation Patients Reduce Stroke Severity and Improve Outcome

“…The primary outcome was the initial stroke severity on admission, which was categorized based on the NIHSS score: mild (NI-HSS score ≤7), moderate (8)(9)(10)(11)(12)(13)(14)(15), and severe (≥16). The secondary outcome was a good functional outcome at 3 months, defined as an mRS score of 0-2.…”

“…Indeed, the efficacy and safety of these inappropriate low-dose DOACs remain controversial. For example, prescribed underdoses of DOACs can increase the risk of stroke or systemic embolism, all-cause death [13], ischemic stroke [14], myocardial infarction [15,16], and bleeding complications [15,17]. Conversely, in some studies, patients prescribed underdoses of DOACs had similar risks for vascular events as those prescribed the recommended doses [13,[18][19][20].…”

“…For example, prescribed underdoses of DOACs can increase the risk of stroke or systemic embolism, all-cause death [13], ischemic stroke [14], myocardial infarction [15,16], and bleeding complications [15,17]. Conversely, in some studies, patients prescribed underdoses of DOACs had similar risks for vascular events as those prescribed the recommended doses [13,[18][19][20]. Moreover, there are reports of patients with underdoses of edoxaban who had lower risks of comprehensive severe outcomes than those with standard doses [21], and even low-dose edoxaban (a once-daily 15 mg) was effective at preventing stroke or systemic embolism [22].…”

Off‐label underdosing of four individual NOACs in patients with nonvalvular atrial fibrillation: A systematic review and meta‐analysis of observational studies

“…12 As previously, several meta-analyses have explored the effects of off-label underdosing of NOACs on the effectiveness and safety outcomes in AF patients, suggesting that off-label underdosing of NOACs is associated with higher risks of thromboembolic complications and allcause death. [15][16][17] However, these studies combined different kinds of NOACs in their pooled analyses. Four NOACs are different from each other, including in their important pharmacological properties (e.g.…”