Affiliation:
1. Department of Pharmacy, Affiliated Hospital of Shaoxing University, Shao Xing, China
2. Epidemiological Department, Veneto Region, Venezia, Italy
3. Department of Cardio-Thoraco-Vascular Sciences and Public Health, University of Padua, Padova, Italy
4. Department of Pharmacy, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Abstract
Introduction Off-label, under-, and overdosed direct oral anticoagulants (DOACs) are commonly prescribed to patients with atrial fibrillation (AF), but real-world evidence on their effectiveness and safety is limited. Methods MEDLINE, Embase, and Cochrane Library databases were systematically searched from 01 July 2020 to 28 February 2022 to update a previous systematic review with the same search strategy from the inception to 30 June 2020. Eligible studies were those that reported effectiveness (stroke/systemic embolism and myocardial infarction) or safety (gastrointestinal or major bleeding and death) outcomes of off-label doses of DOACs compared to on-label doses in AF patients. A random-effects meta-analysis was performed to estimate the pooled hazard ratio (HR) and 95% confidence interval (CI). Subgroup analyses were performed by specific DOACs and geographic regions. Results Twenty-two studies were included. Off-label, underdosed DOACs, compared to on-label doses, were not associated with an increased risk of stroke (HR 1.03, 95%CI: 0.88-1.17) but were associated with an increased risk of death (HR 1.26, 95%CI: 1.09-1.43). However, risk varied depending on the active ingredient. No other safety outcomes were associated with underdosed DOACs. No significant differences were observed by geographic regions. Compared to on-label DOACs, overdosing increased the risk of stroke (HR 1.17, 95%CI: 1.04-1.31), major bleeding (HR 1.18, 95%CI: 1.05-1.31), and death (HR 1.19, 95%CI: 1.03-1.35). Risk varied between geographical regions. Conclusions Off-label underdoses, compared to on-label dosing of DOACs, did not increase the risk of stroke but did increase overall mortality. Overdosed DOACs, compared to on-label doses, were associated with an increased risk of stroke, major bleeding, and death. Future studies must examine these associations, focusing on specific active ingredients and geographic settings.
Funder
Clinical Research Innovation and Cultivation Fund of Ren Ji hospital
Clinical Medical Research Special Fund Project of Zhejiang Medical Association
the Research Project of Drug Clinical Comprehensive Evaluation and Drug Treatment Pathway
the Program of General Scientific Project of Zhejiang Education Department
Research Project of Grassroots health science of Zhejiang Province
Ren Ji Boost Project of National Natural Science Foundation of China
Subject
Hematology,General Medicine