Clinical consequences of off-label reduced dosing of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation: a systematic review and meta-analysis

• Published in: Open heart Vol. 10; no. 1; p. e002197
• Main Authors: Joosten, Linda P T, van Maanen, Rosanne, van den Dries, Carline J, Rutten, Frans H, Hoes, Arno W, Granger, Christopher B, Hemels, Martin E W, Geersing, Geert-Jan, van Doorn, Sander
• Format: Journal Article
• Language: English
• Published: England British Cardiovascular Society 01.05.2023; BMJ Publishing Group LTD; BMJ Publishing Group
• Series: Systematic review
• Subjects: Administration, Oral; Age; Anticoagulants; Atrial Fibrillation; Atrial Fibrillation - complications; Atrial Fibrillation - diagnosis; Atrial Fibrillation - drug therapy; Cardiac arrhythmia; Cardiology; Clinical outcomes; Creatinine; Drug dosages; Epidemiology; Gastroesophageal reflux; Hemorrhage - chemically induced; Humans; Ischemia; Meta-Analysis; Mortality; Observational studies; Observational Studies as Topic; Off-Label Use; Patients; Pharmacology, Clinical; Prevention; Stroke; Stroke - diagnosis; Stroke - etiology; Stroke - prevention & control; Systematic review; Systematic Reviews as Topic; Thromboembolism; Thromboembolism - diagnosis; Thromboembolism - etiology; Thromboembolism - prevention & control; Meta-Analysis; Atrial Fibrillation; Epidemiology; Pharmacology, Clinical; Systematic Reviews as Topic
• ISSN: 2053-3624; 2398-595X; 2053-3624
• DOI: 10.1136/openhrt-2022-002197

ObjectivePostmarketing observational studies report that a substantial percentage of patients with atrial fibrillation (AF) receive a reduced non-vitamin K antagonist oral anticoagulant (NOAC) dose without a clear indication. Recently, increasing evidence has become available to explore the clinical consequences of such off-label reduced dosing (OLRD). This study aims to systematically review and meta-analyse observational studies that report clinical outcomes associated with OLRD of NOACs compared with on-label non-reduced dosing (OLNRD) of NOACs in patients with AF.Methods and analysisWe performed a systematic literature review and meta-analysis of observational studies reporting clinical outcomes in AF patients with OLRD of an NOAC compared with AF patients with OLNRD of an NOAC. Using random effects meta-analyses, we estimated the risk of stroke/thromboembolism, bleeding and all-cause mortality.ResultsWe included 19 studies with a total of 170 394 NOAC users. In these studies, the percentage of OLRD among patients with an indication for an on-label non-reduced NOAC dose ranged between 9% and 53%. 7 of these 19 studies met the predefined criteria for meta-analysis (n=80 725 patients). The pooled HR associated with OLRD of NOACs was 1.04 (95% CI 0.83 to 1.29; 95% prediction interval (PI) 0.60 to 1.79) for stroke/thromboembolism, 1.10 (95% CI 0.95 to 1.29; 95% PI 0.81 to 1.50) for bleeding and 1.22 (95% CI 0.81 to 1.84; 95% PI 0.55 to 2.70) for all-cause mortality.ConclusionThis meta-analysis shows 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 of NOACs. Future research may focus on differences between NOACs.