Clinical effects of off-label reduced doses of Direct Oral Anticoagulants: A systematic review and meta-analysis

Backgound: Atrial Fibrillation (AF) is the most prevalent cardiac arrhythmia among older patients, associated with thromboembolic events. Direct Oral Anticoagulants (DOAC) are the treatment of choice for most patients, but its use may have risks on standard dose. However, it is still unclear the effects related with the use of a lower dose off labelled DOAC.

Objectives: We conducted a systematic review and meta-analysis to assess the effects of off-label underdose use of DOAC in patients with AF.

Methods: MEDLINE, Cochrane Central Register of Controlled Trials, PsycINFO databases and EMBASE were searched for observational longitudinal studies evaluating the outcomes on off label underdosed patients compared with standard dosed patients with AF. We performed a random-effects meta-analysis to estimate the pooled Hazard Ratios (HR) with 95%Cis.

Results: Eighteen cohort studies evaluating 237,533 patients with AF were included. Off-label underdose DOAC use is associated with higher risk of all-cause mortality [HR = 1.27 (95%CI 1.09-1.48)] and cardiovascular composite outcomes [HR = 1.32 (95%CI 1.08-1.62)], when compared with standard dose DOAC use. The effects in thromboembolic events [HR = 1.14 (95%CI 1.00-1.31)], major bleeding [HR = 1.02 (95%CI 0.91-1.15)], and composite of ischemic and bleeding events [HR = 1.22 (95%CI 0.79-1.88)] were not statistically significant. The certainty in the evidence was low or very low.

Conclusions: Off label underdose DOAC use is associated with higher risk of all-cause mortality and cardiovascular composite outcomes, compared with standard dose.