137 CLINICAL CONSEQUENCES OF OFF-LABEL REDUCED DOSING OF NOACS IN AF hospitalisation, all-cause mortality and major adverse clinical events (MACE) (defined as cardiovascular mortality, and/or myocardial infarction, and/or a composite of cardiovascular diseases, such as stroke/thromboembolism and bleeding). We selected all original observational studies on stroke prevention in patients with AF without a mechanical heart valve and/or severe mitral valve stenosis, describing the use of any of the registered NOACs (i.e. dabigatran, rivaroxaban, apixaban, and/or edoxaban), and presenting data on clinical outcomes of treatment with an off-label reduced NOAC dose compared with treatment with the on-label (i.e. the recommended) non-reduced NOAC dose. We excluded studies including patients below the age of 18 years or including patients with venous thromboembolism (unless it was possible to analyse AF patients separately), and studies in highly selected patient populations (e.g. patients with a highly specific age, only patients with cancer, severe kidney disease, obesity or coronavirus disease 2019, or those on haemodialysis or after major surgery or arrhythmia surgery). Four reviewers (LJ, RvM, CvdD, and SvD) independently screened the total of selected articles based on title and abstract in duplicate and resolved any uncertainties by discussion. Of all potential studies, three reviewers (LJ, RvM, and SvD) independently evaluated the full text for eligibility in duplicate and resolved any disagreements by discussion. Reasons for exclusion were recorded. For each included study, the reference list was evaluated for any additional relevant studies. Critical appraisal and risk of bias assessment Three reviewers (LJ, RvM, and SvD) critically appraised all included studies and independently performed a risk of bias assessment in duplicate using the NewcastleOttawa quality Scale (NOS) for cohort studies29 supplemented by an item for handling missing data (see Supplementary File S2), and resolved any disagreements by discussion. Data extraction From each included study, three reviewers (LJ, RvM, and SvD) extracted 1) study and patient characteristics (see Supplementary File S3), 2) the absolute number of patients receiving an off-label reduced NOAC dose and the absolute number of patients receiving the on-label non-reduced NOAC dose and 3) the exact definition of each clinical outcome (stroke/thromboembolism, bleeding, all-cause hospitalisation, all-cause mortality, and MACE), its associated relative risk for OLRD compared with OLNRD (if possible stratified by dabigatran, rivaroxaban, apixaban, and edoxaban) and the method used to adjust for confounding. 8
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