145 CLINICAL CONSEQUENCES OF OFF-LABEL REDUCED DOSING OF NOACS IN AF thromboembolism, bleeding, and all-cause mortality are above 1). However, we cannot confirm this, because there were not sufficient studies meeting our inclusion criteria for meta-analysis stratified by the four different NOACs. Comparison with existing literature In a recent meta-analysis, Caso et al. compared OLRD to on-label dosing (i.e. both on-label reduced and on-label non-reduced dosing). This showed that OLRD increased the risk of all-cause mortality (HR 1.28 (95% CI 1.10-1.49)) with a null effect on major bleeding (HR 1.04 (95% CI 0.90-1.19)).18 In another previous meta-analysis, the authors also compared OLRD to, again, on-label dosing and used less stringent inclusion criteria, which allowed them to include more studies and examine each NOAC separately. This showed that OLRD of rivaroxaban may increase the risk of stroke/thromboembolism (HR 1.31 (95% CI 1.051.63)) compared with on-label dosing of rivaroxaban, whereas OLRD of apixaban may increase the incidence of all-cause mortality (HR 1.21 (95% CI 1.05-1.40)) compared with on-label dosing of apixaban. They reported no differences in outcomes when comparing OLRD versus on-label dosing of dabigatran and edoxaban.16 A third meta-analysis combined the four NOACs in their analyses and showed higher risk of stroke/systemic embolism (risk ratio (RR) 1.24 (95% CI 1.14-1.35)) without a reduction in bleeding risk (RR 1.18 (95% CI 0.91-1.53)) and a higher risk of all-cause mortality (RR 1.58 (95% CI 1.25-1.99)) in patients with OLRD compared with on-label dosing. However, this meta-analysis largely lacked measures to prevent confounding. Moreover, it also compared OLRD to on-label dosing (i.e. both on-label reduced and on-label non-reduced) instead of comparing OLRD to OLNRD as we did.17 In contrast to these previous studies, we did not find an increased risk for all-cause mortality in patients with OLDR. The most obvious explanation could be the comparison we choose. Unlike previous meta-analyses, we restricted our included studies to those comparing OLRD to OLNRD. This is the most clinically relevant comparison, as it represents the patient groups in whom clinicians face a dosing dilemma most often (i.e. those without an indication for dose reduction). Strengths and limitations The selection of studies comparing OLDR only with OLNRD is the major strength of our study. Second, we tried to minimise the influence of confounding by indication as best as possible by including only studies meeting predefined criteria, including applying of propensity scoring methods. Finally, we conducted a very comprehensive and thorough systematic search which resulted in a large sample size. 8
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