136 CHAPTER 8 patients. However, accrual of postmarketing evidence showed that many patients (in the order of 20%–30%) receive a reduced NOAC dose without any clear indication, likely to mitigate a presumed high risk of bleeding.9–14 This so-called off-label reduced dosing (OLRD) may put patients in need of oral anticoagulants at unnecessary risk of thromboembolism, while the anticipated attenuation of bleeding risk may in fact be negligible, or at least does not justify this OLRD.15 Several systematic reviews have evaluated the clinical consequences of OLRD.14,16–18 However, the included studies in these reviews are highly heterogeneous, suffer from confounding and/or compare patients with OLRD to all patients receiving an on-label dose (i.e. both on-label reduced and on-label non-reduced). A more clinically relevant comparison is the comparison of OLRD to on-label non-reduced dosing (OLNRD) only. After all, clinicians wonder what happens if they reduce the dose in patients who are presumed to be at high risk of bleeding (i.e. the most common incentive for clinicians to opt for OLRD of NOACs), but who do not formally meet the dose reduction criteria and should, therefore, receive an on-label non-reduced NOAC dose. We, therefore, systematically reviewed all observational studies that report clinical outcomes associated with OLRD of NOACs compared with OLNRD of NOACs in patients with AF and estimated the risk of stroke/thromboembolism, bleeding and all-cause mortality performing meta-analyses only in studies meeting predefined criteria (in order to reduce the impact of confounding). METHODS Search strategy We performed a systematic search to identify all observational studies reporting on clinical outcomes associated with OLRD of NOACs for stroke prevention in AF patients from 1 January 2009 to 10 July 2022. We searched PubMed and Embase using search terms for ‘dose reduction’ and ‘NOAC’, including synonyms and MeSH headings where appropriate, and without language restrictions. For the full search syntax, see Supplementary File S1. Definitions and study selection We defined OLRD of NOACs as the use of a NOAC dose lower than the recommended on-label non-reduced NOAC dose in absence of a clear indication for dose reduction as formulated either by the Summary of Product Characteristics (SPC),19–22 the Food and Drug administration (FDA),23–26 the European Society of Cardiology (ESC),27 the European Heart Rhythm Association (EHRA),28 the landmark NOAC trials5–8 (see Table 1), or other guidelines. Clinical outcomes under consideration were stroke/ thromboembolism (defined as (ischaemic) stroke and/or transient ischaemic attack (TIA) and/or thromboembolism), bleeding (defined as (major) bleeding), all-cause
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