144 CHAPTER 8 C. With outcome mortality * Year: starting date of inclusion of patients. NOAC: non-vitamin K antagonist oral anticoagulant; OLRD: off-label reduced dosing; PI: prediction interval; TIA: transient ischaemic attack. DISCUSSION In this systematic review and meta-analysis of observational studies, we found no statistically significant increased risk of stroke/thromboembolism, nor a decreased bleeding risk, nor a difference in risk of all-cause mortality in patients with OLRD compared with OLNRD of NOACs. The effect of OLRD of NOACs Although all point estimates in our meta-analysis lie above 1, indicating a possible harmful effect, it cannot be concluded from our meta-analysis that OLRD of NOACs overall is in fact harmful, not to mention beneficial. However, it should be realised that NOACs differ. First, plasma levels may be more stable for some NOACs than for others due to once daily (rivaroxaban and edoxaban) versus two times daily (dabigatran and apixaban) dosing. Second, NOACs vary in the percentage by which the dose should be reduced (25%–33% for dabigatran and rivaroxaban; 50% for apixaban and edoxaban). Finally, some NOACs have more extensive dose reduction criteria than others, which might suggest that OLNRD of NOACs with more extensive dose reduction criteria is more tailored to the individual patient and that OLRD of these NOACs might cause more harm. This may explain why data in our study suggest a harmful effect of OLRD specifically for apixaban (of the apixaban studies, almost all HRs for stroke/
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